Status, Features, and Future Development of the LIFUS5/Mod4 Experimental Facility Design

The Water-Cooled Lithium–Lead (WCLL) is one of the most promising technologies for power conversion and tritium production in future fusion-powered reactors; it will be implemented in one of the Test Breeding Modules (TBM) inside the ITER reactor and the DEMO EU reactor. However, the simultaneous presence in the system of high-temperature PbLi and high-pressure water poses significant safety issues in the event of an in-box LOCA (Loss Of Coolant Accident). For this reason, a complete understanding of the system response is crucial to avoid extensive damage in such a scenario. This paper describes the status and design features of the LIFUS5/Mod4 facility, an experimental plant that is currently being designed and constructed at ENEA CR Brasimone in the framework of the FP9 EUROfusion Horizon Europe to address these issues. This facility aims at being representative of the geometry and operational conditions of the Test Breeding System (TBS) to allow the precise reproduction of its behavior under simulated incidental scenarios. For this reason, peculiar design choices have been made, which will be extensively discussed throughout this work and which will allow the generation of high-quality data useful for the TBS development. Moreover, the facility is expected to become a test stand for the implementation of different safety functions, to identify the best accident-mitigation strategy. Possible upgrade plans for the facility are described as well, with the chance for it to become a fully functional test stand for any component of the TBS in their operative conditions

Experimental and Numerical Results of LIFUS5/Mod3 Series E Test on In-Box LOCA Transient for WCLL-BB

The in-box LOCA (Loss of Coolant Accident) represents a major safety concern to be addressed in the design of the WCLL-BB (water-cooled lead-lithium breeding blanket). Research activities are ongoing to master the phenomena and processes that occur during the postulated accident, to enhance the predictive capability and reliability of numerical tools, and to validate computer models, codes, and procedures for their applications. Following these objectives, ENEA designed and built the new separate effects test facility LIFUS5/Mod3. Two experimental campaigns (Series D and Series E) were executed by injecting water at high pressure into a pool of PbLi in WCLL-BB-relevant parameter ranges. The obtained experimental data were used to check the capabilities of the RELAP5 system code to reproduce the pressure transient of a water system, to validate the chemical model of PbLi/water reactions implemented in the modified version of SIMMER codes for fusion application, to investigate the dynamic effects of energy release on the structures, and to provide relevant feedback for the follow-up experimental campaigns. This work presents the experimental data and the numerical simulations of Test E4.1. The results of the test are presented and critically discussed. The code simulations highlight that SIMMER code is able to reproduce the phenomena connected to PbLi/water interaction, and the relevant test parameters are in agreement with the acquired experimental signals. Moreover, the results obtained by the first approach to SIMMER-RELAP5 code-coupling demonstrate its capability of and strength for predicting the transient scenario in complex geometries, considering multiple physical phenomena and minimizing the computational cost

Combination of BMI1 and MAPK/ERK inhibitors is effective in medulloblastoma.

BACKGROUND: Epigenetic changes play a key role in the pathogenesis of medulloblastoma (MB), the most common malignant paediatric brain tumour. METHODS: We explore the therapeutic potential of BMI1 and MAPK/ERK inhibition in BMI1 High;CHD7 Low MB cells and in a pre-clinical xenograft model. RESULTS: We identify a synergistic vulnerability of BMI1 High;CHD7 Low MB cells to a combination treatment with BMI1 and MAPK/ERK inhibitors. Mechanistically, CHD7-dependent binding of BMI1 to MAPK-regulated genes underpins the CHD7-BMI1-MAPK regulatory axis responsible of the anti-tumour effect of the inhibitors in vitro and in a pre-clinical mouse model. Increased ERK1 and ERK2 phosphorylation activity is found in BMI1 High;CHD7 Low G4 MB patients, raising the possibility that they could be amenable to a similar therapy. CONCLUSIONS: The molecular dissection of the CHD7-BMI1-MAPK regulatory axis in BMI1 High;CHD7 Low MB identifies this signature as a proxy to predict MAPK functional activation, which can be effectively drugged in preclinical models, and paves the way for further exploration of combined BMI1 and MAPK targeting in G4 MB patients

Polycomb-mediated repression of EphrinA5 promotes growth and invasion of glioblastoma

Glioblastoma (GBM) is the most common and most aggressive intrinsic brain tumour in adults. Integrated transcriptomic and epigenomic analyses of glioblastoma initiating cells (GIC) in a mouse model uncovered a novel epigenetic regulation of EfnA5. In this model, Bmi1 enhances H3K27me3 at the EfnA5 locus and reinforces repression of selected target genes in a cellular context-dependent fashion. EfnA5 mediates Bmi1-dependent proliferation and invasion in vitro and tumour formation in an allograft model. Importantly, we show that this novel Polycomb feed-forward loop is also active in human GIC and we provide pre-clinical evidence of druggability of the EFNA5 signalling pathway in GBM xenografts overexpressing Bmi1

STEAM experimental facility. A step forward for the development of the EU DEMO BoP Water Coolant Technology

Within the EUROfusion roadmap for the technological development of the European-DEMOnstration (EU-DEMO) reactor, a key point has been identified in the discontinuous operation (pulse-dwell-pulse) of the machine. Water Cooled Lithium Lead (WCLL) Breeding Blanket (BB) Primary Heat Transfer Systems (PHTSs) adopt technology and components commonly used in nuclear fission power plants, whose performances could be negatively affected by the above mentioned pulsation,as well as by low-load operation in the dwell phase. This makes mandatory a full assessment of the functional feasibility of such components through accurate design and validation. For this purpose, ENEA Experimental Engineering Division at Brasimone R.C. aims at realizing STEAM, a water operated facility forming part of the multipurpose experimental infrastructure Water cooled lithium lead -thermal-HYDRAulic (W-HYDRA), conceived to investigate the water technologies applied to the DEMO BB and Balance of Plant systems and components. The experimental validation has the two main objectives of reproducing the DEMO operational phases by means of steady-state and transient tests, as well as performing dedicated tests on the steam generator aiming at demonstrating its ability to perform as intended during the power phases of the machine. STEAM is mainly composed of primary and secondary water systems reproducing the thermodynamic conditions of the DEMO WCLL BB PHTS and power conversion system, respectively. The significance of the STEAM facility resides in its capacity to amass experimental data relevant for the advancement of fusion-related technologies. This capability is attributable to the comprehensive array of instruments with which the facility will be equipped and whose strategic location is described in this work. The operational phases of the STEAM facility at different power levels are presented, according to the requirements of the experiments. Furthermore, a preliminary analysis for the definition of the control strategy for the OTSG mock-up was performed. In particular, two different control strategies were identified and tested, both keeping the primary mass flow constant and regulating the feedwater mass flow to follow a temperature set-point in the primary loop. The obtained numerical results yielded preliminary feedback on the regulation capability of the DEMO steam generator mock-up during pulsed operation, showing that no relevant overtemperature jeopardized the facility integrity, thanks to the high system responsivity to rapid load variations

Inositol treatment inhibits medulloblastoma through suppression of epigenetic-driven metabolic adaptation.

Deregulation of chromatin modifiers plays an essential role in the pathogenesis of medulloblastoma, the most common paediatric malignant brain tumour. Here, we identify a BMI1-dependent sensitivity to deregulation of inositol metabolism in a proportion of medulloblastoma. We demonstrate mTOR pathway activation and metabolic adaptation specifically in medulloblastoma of the molecular subgroup G4 characterised by a BMI1High;CHD7Low signature and show this can be counteracted by IP6 treatment. Finally, we demonstrate that IP6 synergises with cisplatin to enhance its cytotoxicity in vitro and extends survival in a pre-clinical BMI1High;CHD7Low xenograft model

Insights into APC/C: from cellular function to diseases and therapeutics

Anaphase-promoting complex/cyclosome (APC/C) is a multifunctional ubiquitin-protein ligase that targets different substrates for ubiquitylation and therefore regulates a variety of cellular processes such as cell division, differentiation, genome stability, energy metabolism, cell death, autophagy as well as carcinogenesis. Activity of APC/C is principally governed by two WD-40 domain proteins, Cdc20 and Cdh1, in and beyond cell cycle. In the past decade, the results based on numerous biochemical, 3D structural, mouse genetic and small molecule inhibitor studies have largely attracted our attention into the emerging role of APC/C and its regulation in biological function, human diseases and potential therapeutics. This review will aim to summarize some recently reported insights into APC/C in regulating cellular function, connection of its dysfunction with human diseases and its implication of therapeutics

DEVELOPMENT AND VALIDATION OF A SIMMER-III/ANSYS CODE CHAIN METHODOLOGY FOR THE INTEGRAL SAFETY ANALYSIS OF WCLL FUSION REACTOR COMPONENTS

In the framework of the development of fusion energy, one of the most prominent technologies arising to address the issues of tritium breeding and power conversion is the Water-Cooled Lithium-Lead (WCLL). This technology utilizes a molten eutectic alloy of Lithium and Lead which circulates inside the Breeding Blankets (BB) and is irradiated with neutrons to produce tritium. Water is then circulated inside the system to cool the components. The simultaneous presence inside critical areas of the reactor of molten metal alloys and water, at high temperature and pressure, poses significant safety concerns. For this reason, adequate design and analysis techniques are required to ensure the ability of the system to survive and mitigate any possible damage in case of the in-box Loss Of Coolant Accident (LOCA), the most critical postulated accidental scenario. This work introduces a new methodology for the integral safety analysis of WCLL components, with a particular focus on the WCLL Breeding Blankets, which is based on a fully automated code-chain technique. Its goal is to couple the calculations performed in the fluid domain by the SIMMER-III code, which models the chemical and thermodynamical interactions between the water and the alloy, and the structural simulations performed by the ANSYS code on the mechanical components. The entire process is validated against experimental data provided by the LIFUS5 facility operating at ENEA Brasimone Research Centre. The resulting comparison between these data and codes' predictions allows a careful evaluation of the errors introduced in each step of the chain. Moreover, it provides confidence in the capacity of the methodology to correctly predict the ability of the structures to withstand incidental loads without suffering extensive damage. This work aims at providing engineers with a usable and powerful tool that allows for the safety analysis of WCLL-based components during the early stages of the design phase. This would help save time, and effort and reduce the economic cost that might arise from any undetected issue propagating downstream the design process