•Functional and radiological requirements for HEBT Beam Dump Shielding are described.•Radiological analysis of Beam Dump Shielding is detailed for its two operational conditions.•Materials and ...dimensions for the Beam Dump Shielding conceptual design are explained.•Two Beam Dump Shielding configuration approaches have been studied and compared.•Benefits and drawbacks for each configuration proposed have been identified.
IFMIF-DONES (International Fusion Materials Irradiation Facility – DEMO Oriented Neutron Source) is currently being developed in the frame of the EUROfusion Early Neutron Source work package (WPENS). It will be an installation for fusion material testing, that will generate a flux of neutrons of 1018 m−2s−1 with a broad peak at 14 MeV by Li(d,xn) nuclear reactions thanks to a deuteron beam colliding on a liquid Li flow.
The accelerator system is in charge of providing such high energy deuterons in order to produce the neutron flux expected. The objective of the Beam Dump, part of the High Energy Beam Transport Line (HEBT), is to stop the pulsed beam at low duty cycle during DONES accelerator commissioning and start-up phases.
The present work explains the radiological design of the beam dump shielding and two different configuration approaches for the materialization of the design. The radiological design considers maintenance and operation, and it was done together with the building walls dimensioning so that the combined radiation attenuation by the local shield and the building leads to dose rates in the different rooms that satisfy the requirements. Activation of the materials in the HEBT line, originated by the leakage of neutrons through the beam dump entrance is evaluated and an ad-hoc solution is proposed for its minimization. Regarding the mechanical design, in the first configuration, the shielding is split into two halves horizontally, the upper-half requiring external lifting capabilities for its commission and maintenance. The second approach consists in a vertical splitting into two halves, which are self-moveable, avoiding the needs of external lifting capabilities for the remote handling of the shielding.
DNA methylation is an important epigenetic modification in many species that is critical for development, and implicated in ageing and many complex diseases, such as cancer. Many cost-effective ...genome-wide analyses of DNA modifications rely on restriction enzymes capable of digesting genomic DNA at defined sequence motifs. There are hundreds of restriction enzyme families but few are used to date, because no tool is available for the systematic evaluation of restriction enzyme combinations that can enrich for certain sites of interest in a genome. Herein, we present customised Reduced Representation Bisulfite Sequencing (cuRRBS), a novel and easy-to-use computational method that solves this problem. By computing the optimal enzymatic digestions and size selection steps required, cuRRBS generalises the traditional MspI-based Reduced Representation Bisulfite Sequencing (RRBS) protocol to all restriction enzyme combinations. In addition, cuRRBS estimates the fold-reduction in sequencing costs and provides a robustness value for the personalised RRBS protocol, allowing users to tailor the protocol to their experimental needs. Moreover, we show in silico that cuRRBS-defined restriction enzymes consistently out-perform MspI digestion in many biological systems, considering both CpG and CHG contexts. Finally, we have validated the accuracy of cuRRBS predictions for single and double enzyme digestions using two independent experimental datasets.
The longevity-promoting NAD⁺–dependent class III histone deacetylase Sirtuin 1 (SIRT1) is involved in stem cell function by controlling cell fate decision and/or by regulating the p53-dependent ...expression of NANOG. We show that SIRT1 is down-regulated precisely during human embryonic stem cell differentiation at both mRNA and protein levels and that the decrease in Sirt1 mRNA is mediated by a molecular pathway that involves the RNA-binding protein HuR and the arginine methyltransferase coactivator-associated arginine methyltransferase 1 (CARM1). SIRT1 down-regulation leads to reactivation of key developmental genes such as the neuroretinal morphogenesis effectors DLL4, TBX3, and PAX6, which are epigenetically repressed by this histone deacetylase in pluripotent human embryonic stem cells. Our results indicate that SIRT1 is regulated during stem cell differentiation in the context of a yet-unknown epigenetic pathway that controls specific developmental genes in embryonic stem cells.
An increase in systemic inflammation (inflammaging) is one of the hallmarks of aging. Epigenetic (DNA methylation) clocks can quantify the degree of biological aging and this can be reversed by ...lifestyle and pharmacological intervention. We aimed to investigate whether a multi-component nutritional supplement could reduce systemic inflammation and epigenetic age in healthy older adults.We recruited 80 healthy older participants (mean age ± SD: 71.85 ± 6.23; males = 31, females = 49). Blood and saliva were obtained pre and post a 12-week course of a multi-component supplement, containing: Vitamin B3, Vitamin C, Vitamin D, Omega 3 fish oils, Resveratrol, Olive fruit phenols and Astaxanthin. Plasma GDF-15 and C-reactive protein (CRP) concentrations were quantified as markers of biological aging and inflammation respectively. DNA methylation was assessed in whole blood and saliva and used to derive epigenetic age using various clock algorithms.No difference between the epigenetic and chronological ages of participants was observed pre- and post-treatment by the blood-based Horvath or Hannum clocks, or the saliva-based InflammAge clock. However, in those with epigenetic age acceleration of ≥ 2 years at baseline, a significant reduction in epigenetic age (p = 0.015) and epigenetic age acceleration (p = 0.0058) was observed post-treatment using the saliva-based InflammAge clock. No differences were observed pre- and post-treatment in plasma GDF-15 and CRP, though participants with CRP indicative of an elevated cardiovascular disease risk (hsCRP ≥ 3µg/ml), had a reduction in CRP post-supplementation (p = 0.0195).Our data suggest a possible benefit of combined nutritional supplementation in individuals with an accelerated epigenetic age and inflammaging.
Cellular senescence is emerging as an important in vivo anticancer response elicited by multiple stresses, including currently used chemotherapeutic drugs. Nutlin-3a is a recently discovered ...small-molecule antagonist of the p53-destabilizing protein murine double minute-2 (MDM2) that induces cell cycle arrest and apoptosis in cancer cells with functional p53. Here, we report that nutlin-3a induces cellular senescence in murine primary fibroblasts, oncogenically transformed fibroblasts, and fibrosarcoma cell lines. No evidence of drug-induced apoptosis was observed in any case. Nutlin-induced senescence was strictly dependent on the presence of functional p53 as revealed by the fact that cells lacking p53 were completely insensitive to the drug, whereas cells lacking the tumor suppressor alternative reading frame product of the CDKN2A locus underwent irreversible cell cycle arrest. Interestingly, irreversibility was achieved in neoplastic cells faster than in their corresponding parental primary cells, suggesting that nutlin-3a and oncogenic signaling cooperate in activating p53. Our current results suggest that senescence could be a major cellular outcome of cancer therapy by antagonists of the p53-MDM2 interaction, such as nutlin-3a.
The exocrine pancreas can undergo acinar-to-ductal metaplasia (ADM), as in the case of pancreatitis where precursor lesions of pancreatic ductal adenocarcinoma (PDAC) can arise. The NAD(+)-dependent ...protein deacetylase Sirtuin-1 (Sirt1) has been implicated in carcinogenesis with dual roles depending on its subcellular localization. In this study, we examined the expression and the role of Sirt1 in different stages of pancreatic carcinogenesis, i.e. ADM models and established PDAC. In addition, we analyzed the expression of KIAA1967, a key mediator of Sirt1 function, along with potential Sirt1 downstream targets. Sirt1 was co-expressed with KIAA1967 in the nuclei of normal pancreatic acinar cells. In ADM, Sirt1 underwent a transient nuclear-to-cytoplasmic shuttling. Experiments where during ADM, we enforced repression of Sirt1 shuttling, inhibition of Sirt1 activity or modulation of its expression, all underscore that the temporary decrease of nuclear and increase of cytoplasmic Sirt1 stimulate ADM. Our results further underscore that important transcriptional regulators of acinar differentiation, that is, Pancreatic transcription factor-1a and β-catenin can be deacetylated by Sirt1. Inhibition of Sirt1 is effective in suppression of ADM and in reducing cell viability in established PDAC tumors. KIAA1967 expression is differentially downregulated in PDAC and impacts on the sensitivity of PDAC cells to the Sirt1/2 inhibitor Tenovin-6. In PDAC, acetylation of β-catenin is not affected, unlike p53, a well-characterized Sirt1-regulated protein in tumor cells. Our results reveal that Sirt1 is an important regulator and potential therapeutic target in pancreatic carcinogenesis.
The marcasite structure FeSe2−δ was synthesized using a simple solvothermal method. Systematic study of the electrical transport properties shows that the transport is dominated by variable-range ...hopping (VRH), with a changeover from Mott VRH at higher temperature to Efros-Shklovskii VRH for temperatures lower than the width of the Coulomb gap. This also confirms the presence of a Coulomb gap in the density of states at the Fermi energy. We observe that Yttrium doping increases the electrical conductivity dramatically without significantly reducing the Seebeck coefficient. This results in remarkably high power factors for thermoelectric performance in the regime where the mean hopping energy shifts from defect dominated to Coulomb repulsion dominated. High resolution transmission electron microscopy, in combination with theoretical calculations, proves the narrowing of the band gap by introducing Se vacancies. This leads to a good conductivity and is responsible for the excellent thermoelectric performance. The formation of nanoclusters, resulting from Se vacancies, is responsible for a dense system of stacking faults and the generally reported weak ferrimagnetism. This also determines the transition between the different electrical transport mechanisms and contributes to the improved thermoelectric performance.
Crosslinked membranes have been synthesized by a casting process using polybenzimidazole (PBI) and poly(vinyl benzyl chloride) (PVBC). The membranes were quaternized with 1,4-diazabicyclo2.2.2octane ...(DABCO) to obtain fixed positive quaternary ammonium groups. XPS analysis has showed insights into the changes from crosslinked to quaternized membranes, demonstrating that the crosslinking reaction and the incorporation of DABCO have occurred, while the 13C-NMR corroborates the reaction of DABCO with PVBC only by one nitrogen atom. Mechanical properties were evaluated, obtaining maximum stress values around 72 MPa and 40 MPa for crosslinked and quaternized membranes, respectively. Resistance to oxidative media was also satisfactory and the membranes were evaluated in single direct ethanol fuel cell. PBI-c-PVBC/OH 1:2 membrane obtained 66 mW cm−2 peak power density, 25% higher than commercial PBI membranes, using 0.5 bar backpressure of pure O2 in the cathode and 1 mL min−1 KOH 2M EtOH 2 M aqueous solution in the anode. When the pressure was increased, the best performance was obtained by the same membrane, reaching 70 mW cm−2 peak power density at 2 bar O2 backpressure. Based on the characterization and single cell performance, PBI-c-PVBC/OH membranes are considered promising candidates as anion exchange electrolytes for direct ethanol fuel cells.
IFMIF-DONES will be an irradiation facility based on a 40 MeV deuteron accelerator. Unavoidable beam losses along the accelerator result in deuterium interactions with the beam facing materials of ...the vacuum beam pipe, some of them leading to material activation. The initial design of the beam pipe was based on stainless steel, but an evaluation of the residual doses from the pipe showed high values after operation of the accelerator. The accelerator beam line must be periodically maintained, and excessive cooling times for reaching acceptable dose levels may result in poorer availability of the facility. A deeper study of the High Energy Beam Transport line (HEBT) showed that a direct reaction between deuterons and iron in steel resulted in the production of Co-56, with a half-life of 77 days. This radioisotope is the main source of the radiation and makes it impractical to wait for a proper attenuation of the radiation field. A redesign of beam line elements has been performed to avoid the presence of stainless steel as a beam facing material and to replace it with aluminum where possible, resulting in faster decay of residual doses. This work contains a summary of the nuclear analysis performed for the computation of residual doses with stainless steel beam pipe, stressing the uncertainties of the calculations, based on the limited availability of nuclear data for the relevant nuclear reaction Fe56 (d,2n). The proposed replacement of element materials is also described, and an updated nuclear analysis shows the reduction of residual radiation, and its impact on possible maintenance operations.
•This document reflects the efforts made within the IFMIF-DONES project towards a safe radiological materials design, following the ALARA principles.•The authors have made nuclear analyses to support the conclusions and change of design.•Some flaws in existing nuclear data have been discovered, relayed to the responsible people in the EU and IAEA framework to correct the deficiencies.
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