Nuclear Regulatory Research Articles

Analysis of Stakeholders' Trust Level in the Nuclear Energy Domain in Japan

Abstract In discussions on the nuclear restart policy in Japan, trust among stakeholders in nuclear power is often raised as an issue. However, the discussion has progressed without analyzing the trust demanded by the Japanese public. A questionnaire survey was conducted to analyze the level of trust that 4,700 Japanese citizens (100 from each of the 47 prefectures) have in nuclear stakeholders by breaking trust down into three elements: “Perceived Competence,” “Perceived Motivation,” and “Salient Value Similarity” (SVS), which have been reported in the literature. In the survey, nine stakeholders were targeted: the Nuclear Regulation Authority; the Ministry of Economy, Trade and Industry; the courts; the Diet; host municipalities; nuclear power operators and manufacturers; experts; research and international organizations; and the mass media. The analysis showed that the Japanese public is particularly interested in SVS with “nuclear power operators and manufacturers” among the various nuclear stakeholders. The SVS of “nuclear power operators and manufacturers” was highly correlated with that of organizations promoting nuclear power, suggesting that the public tends to perceive these organizations as sharing similar values. These results offer suggestions for actions that should be taken by each nuclear stakeholder to restore and improve trust.

N,N-Diarylsulfonamide Reduces Proinflammatory Cytokine Interleukin-6 Levels in Cells through Nuclear Factor-κB Regulation.

The arylsulfonamides were synthesized from aryl sulfonyl chloride and aromatic amines in dichloromethane in the presence of pyridine. The aryne chemistry was used to prepare diarylsulfonamide from arylsulfonamides and O-silylaryl triflate with CsF in acetonitrile at room temperature for 30 min. The synthesized compounds were evaluated for cytotoxicity followed by the cytokine/inflammatory marker's inhibition capability and its mechanism of action in RAW-264.7 cells. Elevated interleukin-6 (IL-6) levels have been reported in inflammatory conditions and inflammation-associated disorders. Hence, reducing the IL-6 levels in inflammatory conditions can serve as an attractive therapeutic target in dealing the inflammation. Among 42 compounds, seven compounds showed significant inhibition of IL-6 levels in lipopolysaccharide (LPS) challenged RAW-264.7 cells at 12.5 μM concentration. Further, investigation revealed that the IC50 value of these compounds for reducing IL-6 levels was found to be in the range of 2.6 to 9.7 μM. The promising compounds 5y (IC50 of 2.6 μM) and 5n (IC50 of 4.1 μM) along with other derivatives fulfil drug-likeness parameters laid down by Lipinski's rule of five. Further, RT-qPCR and Western-blot analysis revealed that treatment with 5n significantly reduced the expression of pro-inflammatory, inflammatory and macrophage marker's expression (IL-1β, CCL2, COX2 and CD68) compared to LPS control. The mechanistic evaluation showed that 5n exhibited anti-inflammatory properties by modulating the nuclear factor-κB (NF-κB) activation. The identified compound can be a promising candidate for further discovery efforts to generate a preclinical candidate effective in inflammation.

Preliminary MELCOR Input Deck for Steady State and Turbine Trip Analysis of the NuScale US600 SMR

This paper models NuScale’s SMR using MELCOR by relying on specifications in the latest Final Safety Assessment Report (FSAR) submitted to the U.S. Nuclear Regulatory Commission (USNRC). The input deck was crafted from scratch using only publicly available data and reasonable assumptions. Benchmark results for steady state and a turbine trip transient are presented, with the former showing excellent agreement with the reference values, while the latter produces shows slight deviations in the mass flow rates. As a preliminary study, the results are within acceptable limits and encourage further refinement to the model for use in other accident progression cases.

Selection of Key Socio-Economic Factors for Establishing Relese Criteria Patients after Radioioidine Therapy

Purpose: To assess the association between socioeconomic factors and release criteria after iodine-131 radionuclide therapy in different countries. Material and methods: 15 countries and 104 socioeconomic characteristics were selected for the study. The association between characteristics and the residual activity level at which a patient may be released for different countries was established according to the value of Pearson product moment correlation coefficient (r>0.3). A linear regression model was constructed for the selected characteristics using Microsoft Excel analysis package. The model was used to calculate the acceptable activity level at which a patient may be released for Russia. Results: A fundamental difference between the model used for calculation of release criteria after radionuclide therapy with iodine-131 in Russia and the model recommended by the Nuclear Regulatory Commission was shown: the use of the effective half-life in the second one. Replacing the physical halflife by the effective half life allows increasing the discharge criteria of patients after therapy with Na131I by 30 %. A moderate correlation was found between the value of acceptable activity at patient discharge after radioactive iodine therapy and the following socioeconomic characteristics: scientific activity (r=0.32), quality of higher education (r=0.36), Global Health Security Index (r=0.34), length of roads (r=0.36), population growth rate (r=0.36), average housing area (r=0.38), and average salary per year (r=–0.33). A linear regression was constructed using the factors listed above. The following recommended value of activity and effective dose rate at patient discharge from hospital was obtained: 0.6 GBq and 30 µSv/hour. Conclusion: The study demonstrates that the release criteria for radioactive iodine therapy used in the Russian Federation (0.4 GBq and 20 µSv/h) do not correspond to the standard of living achieved in Russia, which is reflected by the socio-economic factors considered in the paper. The proposed arguments raise the task of revising the currently used model with a consequent increase in the discharge criteria. It was observed that the release criteria in the world are independent of some factors that are directly related to population exposure. The need to develop a unified objective algorithm for establishing release criteria, which takes into account different socio-economic status of states and can be applied for different radionuclides and radiopharmaceuticals, including innovative ones, has been identified.

Simulated safety analysis of a total loss of feedwater accident in the steam generator of CPR1000 nuclear power plant

As M310 series units, CPR1000 Nuclear Power Plant in China is also the first batch of demonstration nuclear power plants in China to try out SOP(the state-oriented procedure) accident procedures. The establishment of SOP accident regulations is an important work to mitigate the consequences of radioactive accidents in the design of nuclear power plants, and it is also the embodiment of the defense-in-depth requirements in the implementation of nuclear safety regulations. It can handle superimposed accidents, human errors in program implementation and events not considered in the primary cause sequence. In order to study the efficiency of its upgraded SOP procedure and its ability to deal with severe accidents, the typical primary cause event of severe accidents in nuclear power plants–such as the total loss of feedwater accident of steam generators has been adopted for research. The initial state of the simulation is the full power operation of the nuclear power plant, the simulation process is from the loss of all the water supply accidents to the whole accident processing. A total of 30 simulation experiments were carried out. The temperature and pressure of the key parameters obtained are the average values of 30 simulation experiments. The stability and efficiency of the updated SOP are evaluated by the treatment time of the water supply loss accident and the changes of reactor temperature and pressure after the accident. The results show that the upgraded SOP procedure is more stable and efficient. The upgraded SOP procedure, when dealing with other types of accidents, has improved the treatment of residual heat conduction in the core, increased the efficiency of accident treatment, and enhanced the safety of the reactor. At the same time, based on the weaknesses of the upgraded SOP procedure, constructive suggestions on changing the setting value of the steam generator bypass valve have also been put forward accordingly. Furthermore, it can be concluded from many simulated accidents that this change will win about 5% more of the disposal time for nuclear power plants under accidents, which provides references for the subsequent upgrading of M310 series power plant procedures.

A literature review of pyroprocessing safeguards

Pyroprocessing is a promising technology for reprocessing used nuclear fuel (UNF) from light water reactors (LWR) and sodium fast reactors (SFR). With the advancement of fast reactors with projects from companies such as TerraPower, the prospects of pyroprocessing are more promising than ever before, as fast reactors can consume all actinides, not just uranium and plutonium. Before pyroprocessing can be implemented commercially, pre-existing safeguards used for aqueous reprocessing must be adapted for pyroprocessing. Safeguards, as determined by both the Nuclear Regulatory Commission (NRC) and the International Atomic Energy Agency (IAEA), are discussed in this review as guidelines for approaches used in both domestic and international reprocessing plants. The implementation of safeguards in aqueous reprocessing was then reviewed based on the experience from existing aqueous facilities. The experimental pyroprocessing facilities were identified as pyroprocessing plants in the design stage with one operating exception of the Fuel Conditioning Facility (FCF). The safeguard methods implemented or designed for each and the accompanying challenges of utilizing existing safeguards in pyroprocessing are considered and a summary of applicable approaches is included.

NEAT1 regulates VSMC differentiation and calcification in as long noncoding RNA NEAT1 enhances phenotypic and osteogenic switching of vascular smooth muscle cells in atherosclerosis via scaffolding EZH2.

Atherosclerosis (AS) is a significant contributor to cardio-cerebrovascular ischemia diseases, resulting in high mortality rates worldwide. During AS, vascular smooth muscle cells (VSMCs) play a crucial role in plaque formation by undergoing phenotypic and osteogenic switching. Long noncoding RNA nuclear paraspeckle assembly transcript 1 (NEAT1) has previously been identified as a nuclear regulator that promotes tumorigenesis and metastasis, but its role in regulating VSMCs in AS remains unclear. Our study aimed to investigate the biological functions and specific mechanisms of NEAT1 in regulating VSMCs in AS. We found that NEAT1 was upregulated in the aortas of AS mouse models and dedifferentiated primary VSMCs. Silencing NEAT1 in vitro attenuated the proliferation, migration, and osteogenic differentiation of VSMCs, while NEAT1 overexpression had the opposite effect. Furthermore, NEAT1 promoted VSMC osteogenic differentiation and vascular calcification in both in vivo and in vitro vascular calcification models. We also discovered that NEAT1 directly activates enhancer of zeste homolog 2 (EZH2), an epigenetic enzyme that suppresses the expression of senescence- and antimigration-related genes, by translocating it into the nucleus. CUT&Tag assay revealed that NEAT1 guides EZH2 to the promoters of senescence-related genes (P16, P21, and TIMP3), methylating local histones to reduce their transcription. Our findings suggest that NEAT1 functions in AS by modulating the epigenetic function of EZH2, which enhances the proliferation, migration, and osteogenic differentiation of VSMCs. This study provides new insights into the molecular mechanisms underlying the pathogenesis of AS and highlights the potential of NEAT1 as a therapeutic target of AS.NEW & NOTEWORTHY Our study demonstrates that the upregulation of long noncoding RNA nuclear paraspeckle assembly transcript 1 (NEAT1) promotes proliferation and migration during phenotypic switching of vascular smooth muscle cells in atherosclerosis. We also provide in vivo and in vitro evidence that NEAT1 accelerates vascular calcification. Our findings identified the direct interaction between enhancer of zeste homolog 2 (EZH2) and NEAT1 during atherosclerosis. NEAT1 is necessary for EZH2 to translocate from the cytoplasm to the nucleus, where EZH2 epigenetically inhibits the expression of genes related to senescence and antimigration.

Towards an international regulatory framework for AI safety: lessons from the IAEA’s nuclear safety regulations

This study explores the necessity and direction of safety regulations for Artificial Intelligence (AI), drawing parallels from the regulatory practices of the International Atomic Energy Agency (IAEA) for nuclear safety. The rapid advancement and global proliferation of AI technologies necessitate the establishment of standardized safety norms to minimize discrepancies between national regulations and enhance the consistency and effectiveness of these rules. The study emphasizes the importance of international collaboration and the engagement of various stakeholders to strengthen the appropriateness of regulations and ensure their continuous updating in response to the evolving risks associated with technological advancements. The paper highlights the critical role of subgoal setting mechanisms in AI’s decision-making processes, underscoring their significance in ensuring the technology’s stability and social acceptability. Improperly tuned subgoal setting mechanisms may lead to outcomes that conflict with human intentions, posing risks to users and society at large. The study draws attention to the hidden risks often embedded within AI’s core decision-making mechanisms and advocates for regulatory approaches to guarantee safe and predictable AI operations. Furthermore, the study acknowledges the limitations of directly applying IAEA’s nuclear safety cases to AI due to the distinct characteristics and risks of the two fields. The paper calls for future research to delve deeper into the need for an independent regulatory framework tailored to AI’s unique features. Additionally, the study emphasizes the importance of accelerating international consensus, developing flexible regulatory models that reflect the situation in each country, exploring harmonization with existing regulations, and researching timely regulatory responses to the fast-paced development of AI technology.

원자력규제기관활동이 방사선작업종사자의 원자력규제정책 만족도에 미치는 매개효과(mediation effect) 분석

In order to prevent radiation-related disasters for radiation workers, the higher the average radiation exposure dose for each industry, the stronger the regulatory level of nuclear and radiation safety regulatory agencies is for its purpose and relevance. Therefore, nuclear regulatory agencies must apply radiation safety-related licensing and technical standards for nuclear power facilities differently for each type of nuclear business operator depending on the degree of risk of exposure to radiation. From the perspective of a nuclear regulatory agency with limited administrative and financial resources, this study was conducted to efficiently prioritize the regulated sectors of nuclear power operators and promote scientification of regulatory administration by incorporating evidence-based administration. Using the results of the 「2021 Nuclear Safety Survey」 conducted on 2,000 radiation workers, we investigated how radiation workers' satisfaction with nuclear regulation policy changes depending on the activities of nuclear regulatory agencies between independent, mediating, and dependent variables. Direct effects and indirect effects were measured and tested. Four exogenous factors, including the accident response human management system (ERHMS), accident response material management system (ERMMS), in-house safety culture (CISC), and recurrence prevention safety education system (RPSES) for radiation workers subject to nuclear regulation by the nuclear regulatory administrative agency. The regulatory agency activity satisfaction (RAAS), which is a mediating factor, and the endogenous factor 'nuclear energy and radiation safety' regulatory policy satisfaction (NRPS) were set as independent variables, mediators, and dependent variables, respectively. We examined whether the reliability, validity, and correlation between survey items and measurement variables were significant through reliability analysis, correlation analysis, and factor analysis. As a result of multiple regression analysis and structural equation modeling (SEM) mediation effect analysis, the 'activities of regulatory agencies' regarding the accident response human and material management system, in-house safety culture, and accident recurrence prevention education system are related to the nuclear and radiation safety regulatory policy of radiation workers. It was confirmed that it was an influential factor that made a significant difference in satisfaction. When comparing the sizes of standardization coefficients, the sizes of factors affecting satisfaction with nuclear regulation policy are: in-house safety culture (β=0.395), accident response human management system (β=0.080), accident response material management system (β=0.077), Relapse prevention safety education system (β=0.042) appeared in that order. The implications of this study are that the direction of the nuclear safety regulation policy of regulatory agencies that carry out nuclear regulation administration with limited administrative and financial resources is related to the in-house safety culture (CISC) and accident response human management system of nuclear power operators to prevent nuclear and radiation safety accidents. It can be said that it has been verified through quantitative research that strengthening nuclear safety through reinforcement is more effective and efficient

Порівняння майстер кривої з нормативним методом оцінки в'язкості руйнування металу корпусу реактора ВВЕР-1000

The paper considers the generalized temperature dependence of the stress intensity factor KJC in the WWER-1000 reactor pressure vessel metal, which was derived based on the surveillance test data for fracture toughness. The consistency of the shape of the Master curve and 95 % upper and lower confidence bounds with the experimental dependence of crack resistance parameters on temperature was studied. From the point of view of the level of conservatism and acceptability, a comparison of the normative curves of fracture toughness according to NPRR (Nuclear Power Rules and Regulations) G-7-002-86 and SOU NNEGC (Standard of organization of Ukraine, National Nuclear Energy Generating Company) 177:2019 with a 5 % confidence bound of the Master curve was carried out. The possibility of using RT0 temperature as a temperature index instead of TK for the normative fracture toughness curve of SOU NNEGC 177:2019 was considered.

Abstract 3006: Morphogen-driven regulation of nuclear shape and its implication for colorectal cancer

Abstract Colorectal cancer (CRC) is the second leading cause of cancer-related deaths worldwide despite improved rates of early detection and development of targeted treatments. Dysregulation of nuclear shape and the emergence of aberrant chromatin architecture correlate with cancer onset and progression, including CRC. Both extrinsic and intrinsic factors, most critically cytoskeletal and nucleoskeletal organization, chromatin architecture, and metabolic signaling, impact nuclear shape. Yet, what precisely determines nuclear shape in health and disease and how it is linked to cell fate and function remains a fundamental open question. In the case of over 75% of CRC cases, the first transformative genetic event is the loss of function in the tumor suppressor gene, adenomatous polyposis coli (APC). Mechanistically, perturbed APC signaling leads to aberrant activation of Wnt/beta-catenin signaling. This pathway is essential for intestinal homeostasis, as is the regulation of proper nuclear shape and function. Here, we aim to decipher the crosstalk between Wnt gradients and nuclear shape regulation in non-transformed and APC-mutated epithelial cells in vitro, as well as in WT and APC-mutant mouse colon tissues. The long-term goal of this work is to test whether a mechanistic link exists between Wnt-driven cellular transformation and the emergence of aberrant nuclear shape and function. Citation Format: Mona A. El Gendi, Solène Hervé, Sudeep Gautam, Yekaterina A. Miroshnikova. Morphogen-driven regulation of nuclear shape and its implication for colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3006.

Causal Model Framework for Nuclear Power Plant Licensing Process

Interests in clean energy revived the nuclear power industry. For the first time in decades, innovative technologies and plant designs are being considered by regulatory agencies. This paper explores a Bayesian Network and AHP approach to causal modeling of the Combined License review process for new nuclear power plants (NPP). Historically lengthy and expensive, NPP licensing is critical to ensuring safe operation of the plants. With this comes a high standard for applicants to reach that can result in multiple revision cycles and long review times.The U.S. Nuclear Regulatory Commission's combined license process is examined in this study as an opportunity to predict delays based on project criteria and aid informed decision making. A Bayesian Network combined with Analytic Hierarchy Process inputs is presented to show causality relationships between licensing process steps, plant parameters, and time delays.

Culture substrate stiffness impacts human myoblast contractility-dependent proliferation and nuclear envelope wrinkling.

Understanding how biophysical and biochemical microenvironmental cues together influence the regenerative activities of muscle stem cells and their progeny is crucial in strategizing remedies for pathological dysregulation of these cues in aging and disease. In this study, we investigated the cell-level influences of extracellular matrix (ECM) ligands and culture substrate stiffness on primary human myoblast contractility and proliferation within 16 h of plating and found that tethered fibronectin led to stronger stiffness-dependent responses compared to laminin and collagen. A proteome-wide analysis further uncovered cell metabolism, cytoskeletal and nuclear component regulation distinctions between cells cultured on soft and stiff substrates. Interestingly, we found that softer substrates increased the incidence of myoblasts with a wrinkled nucleus, and that the extent of wrinkling could predict Ki67 (also known as MKI67) expression. Nuclear wrinkling and Ki67 expression could be controlled by pharmacological manipulation of cellular contractility, offering a potential cellular mechanism. These results provide new insights into the regulation of human myoblast stiffness-dependent contractility response by ECM ligands and highlight a link between myoblast contractility and proliferation.

A Consequence-Informed Licensing Path Selection for the Design of Physical Protection Systems at Commercial Nuclear Power Facilities

The survivability of the domestic nuclear power industry depends on the cost-competitiveness of safe and secure nuclear power generation. Advanced reactor design concepts aim to have increased safety margins over traditional large light water reactors (LWRs). With increased safety margins comes the potential for a corresponding decrease in off-site risk to the general public from a hypothetical release of radioactivity due to sabotage or theft. Without sacrificing safety or security, advanced reactor designers may be able to achieve operational cost improvements over current LWRs in part by designing less burdensome physical protection systems (PPSs) and by replacing on-site response forces with off-site response forces. To accommodate these developments, the U.S. Nuclear Regulatory Commission is drafting new rulemakings for physical security when licensing through the current frameworks in 10 CFR 50 or 10 CFR 52 along with drafting an entirely new licensing framework: 10 CFR 53. A novel technology-inclusive consequence-informed methodology for the selection of the optimal licensing path for the design of PPSs at advanced fixed-site commercial nuclear power facilities is presented herein. This methodology proposes integrating security considerations at the beginning of a reactor facility design effort to streamline the licensing process. Off-site total effective dose equivalents at the exclusion area and low population zone boundaries were identified as the key metrics when determining a design’s most appropriate licensing path that in turn affects the design requirements placed upon the PPS. Given these metrics, source-term generation of potential adversary-induced physics-based sabotage actions utilizing severe accident modeling software and off-site plume dispersal modeling were identified as appropriate for determining siting constraints, potential target sets for hypothetical sabotage events, and their subsequent off-site dose consequences. The methodology proposes using the consequence results from the sabotage modeling, in combination with desired cost-saving PPS characteristics, to help inform the licensing path selection. Once a licensing path is chosen, the methodology utilizes the Design and Evaluation Process Outline to evaluate an effective PPS following the licensing requirements placed on the facility. This paper also presents examples of hypothetical commercial nuclear power facilities with varying consequence levels and demonstrations of how to select the optimal licensing pathways for each.

Non-canonical retinoid signaling in neural development, regeneration and synaptic function.

Canonical retinoid signaling via nuclear receptors and gene regulation is critical for the initiation of developmental processes such as cellular differentiation, patterning and neurite outgrowth, but also mediates nerve regeneration and synaptic functions in adult nervous systems. In addition to canonical transcriptional regulation, retinoids also exert rapid effects, and there are now multiple lines of evidence supporting non-canonical retinoid actions outside of the nucleus, including in dendrites and axons. Together, canonical and non-canonical retinoid signaling provide the precise temporal and spatial control necessary to achieve the fine cellular coordination required for proper nervous system function. Here, we examine and discuss the evidence supporting non-canonical actions of retinoids in neural development and regeneration as well as synaptic function, including a review of the proposed molecular mechanisms involved.

Similarity Coefficient Generation Using Adjoint-Based Sensitivity and Uncertainty Method and Stochastic Sampling Method

In this study, a similarity coefficient generation code system was established using the Monte Carlo Code for Advanced Reactor Design (McCARD) transport code and the MIG multi-correlated input sampling code. We considered the adjoint-based sensitivity and uncertainty (S/U) and stochastic sampling (S.S.) approaches to the generation of the ck similarity coefficient. To examine the code system, the ck similarity coefficients of 23 relevant critical experiments and the System-Integrated Modular Advanced Reactor (SMART) small modular reactor (SMR) target system were generated using ENDF/B-VII.1 covariance data with the Los Alamos National Laboratory (LANL) 30-group energy group structure. Our results show that the similarity coefficients between the 16 LEU thermal-spectrum-based critical experiments and SMART are more than 0.90, which is the recommended criterion of the U.S. Nuclear Regulatory Commission (NRC). These results are very helpful for licensees and can be used to justify the determination of critical experiment benchmarks for computational bias estimations of the SMART target system. To examine the discrepancy in the similarity coefficient, ck, due to the covariance data, similarity analyses for a 24 × 24 benchmark matrix were performed using ENDF-VIII.0, JENDL-5.0, and JEFF-3.3 covariance data. The results show that the selection of the covariance data used for ck generation significantly impacts the similarity coefficient. Moreover, it was observed that the current results for the SCALE 6.1 covariance data show a consistent trend with the results reported in earlier studies.

Recommendations for the future regulation of fusion power plants

The discussion in the international community on how fusion power plants (FPPs) will be licenced and regulated is ongoing. As such, there is a concerted drive from the European stakeholders to understand the requirements from such a framework and how to best establish it with the aim of easing the licensing process of FPPs. Initiated by the EUROfusion consortium, a group of European experts were convened to produce a set of recommendations on the regulatory framework for the safety and licensing of FPPs. To do so effectively, the group assessed lessons learned from existing fusion facilities, reports by International Atomic Energy Agency and European Commission on FPP safety and the on-going work by the UK government, US Nuclear Regulatory Commission and Canadian Nuclear Safety Commission, as well as the licensing process of ITER. As a result, commonalities between fusion and fission were identified in terms of fundamental safety objectives which could facilitate parity in certain framework aspects. However, significant differences to any such implementation were also identified, particularly with respect to the lower hazard potential inherent to FPPs and how to remain proportionate to the associated safety challenges and the physical principles behind these two types of reactors together with their associated technologies. The recognition of the differences in the safety challenges in FPPs and fission-based nuclear power plants (NPPs) is paramount to future regulatory framework development. Ultimately, regulatory frameworks depend upon a country’s legal framework, therefore it is apparent that a common global regulatory framework for FPPs is not possible. However, as with present-day NPP regulation, efforts could be made to develop harmonised approaches to FPP regulation to provide common levels of protection. In view of this objective, 12 recommendations are presented across 4 topics: regulations, international databases, codes and standards, safety demonstration rules and regulatory approaches. These recommendations are provided to inform and advise potential future actions on FPP regulatory framework and licencing process principles.

PIGB maintains nuclear lamina organization in skeletal muscle of Drosophila.

The nuclear lamina (NL) plays various roles and participates in nuclear integrity, chromatin organization, and transcriptional regulation. Lamin proteins, the main components of the NL, form a homogeneous meshwork structure under the nuclear envelope. Lamins are essential, but it is unknown whether their homogeneous distribution is important for nuclear function. Here, we found that PIGB, an enzyme involved in glycosylphosphatidylinositol (GPI) synthesis, is responsible for the homogeneous lamin meshwork in Drosophila. Loss of PIGB resulted in heterogeneous distributions of B-type lamin and lamin-binding proteins in larval muscles. These phenotypes were rescued by expression of PIGB lacking GPI synthesis activity. The PIGB mutant exhibited changes in lamina-associated domains that are large heterochromatic genomic regions in the NL, reduction of nuclear stiffness, and deformation of muscle fibers. These results suggest that PIGB maintains the homogeneous meshwork of the NL, which may be essential for chromatin distribution and nuclear mechanical properties.

Hydroxynorketamine, but not ketamine, acts via α7 nicotinic acetylcholine receptor to control presynaptic function and gene expression

Ketamine is clinically used fast-acting antidepressant. Its metabolite hydroxynorketamine (HNK) shows a robust antidepressant effect in animal studies. It is unclear, how these chemically distinct compounds converge on similar neuronal effects. While KET acts mostly as N-methyl-d-aspartate receptor (NMDAR) antagonist, the molecular target of HNK remains enigmatic. Here, we show that KET and HNK converge on rapid inhibition of glutamate release by reducing the release competence of synaptic vesicles and induce nuclear translocation of pCREB that controls expression of neuroplasticity genes connected to KET- and HNK-mediated antidepressant action. Ro25-6981, a selective antagonist of GluN2B, mimics effect of KET indicating that GluN2B-containing NMDAR might mediate the presynaptic effect of KET. Selective antagonist of α7 nicotinic acetylcholine receptors (α7nAChRs) or genetic deletion of Chrna7, its pore-forming subunit, fully abolishes HNK-induced synaptic and nuclear regulations, but leaves KET-dependent cellular effects unaffected. Thus, KET or HNK-induced modulation of synaptic transmission and nuclear translocation of pCREB can be mediated by selective signaling via NMDAR or α7nAChRs, respectively. Due to the rapid metabolism of KET to HNK, it is conceivable that subsequent modulation of glutamatergic and cholinergic neurotransmission affects circuits in a cell-type-specific manner and contributes to the therapeutic potency of KET. This finding promotes further exploration of new combined medications for mood disorders.

Post-quench ductility limits of coated ATF with various zirconium-based alloys and coating designs

Post Quench Ductility (PQD) of various Cr-coated cladding designs with respect to base cladding materials, Cr coating methods, and its thickness were investigated to explore Emergency Core Cooling System (ECCS) limits. Both inner wall and outer wall of coated (Cr and Cr/CrN) claddings were steam oxidized at ∼1204 °C and then water quenched. The post-oxidized specimens were ring compressed to attain offset strains based on which ductility was assessed in compliance with the U.S. Nuclear Regulatory Commission (U.S. NRC)’s protocols. Weight gain-based Equivalent Cladding Reacted (ECR) limits of coated specimens (Cr and Cr/CrN) are consistently lower than those of the base cladding materials due to the early load drop under Ring Compression Test (RCT). Yet, time needed to reach the ECR limit is still increased for coated specimens because it effectively undergoes single side oxidation with protective coating. Cracks imitated from ZrCr2 are primarily responsible for the early major load drop observed for tested coating thicknesses (8.9 µm and 18.9 µm), and hence reduced ECR limits compared to bare Zircaloy. The cracks from ZrCr2 was promoted by an increased oxygen concentration of the interfacing Zr matrix owing to the diffusion of oxygen through the coating. The thicker coating reduces this oxygen level, thereby delaying the load drop from ZrCr2 during RCT and increases the ECR limit. The maximum attainable ECR limit of coated ECR limits is affected by the base Zircaloy as it gives as the ECR ceiling from which ECR reduction for coated cladding occurs. For the tested base cladding materials (Opt. ZIRLO™ and HANA-6), ECR 19 %, which is the limit for Cr-coated (8.9 µm) HANA-6, may serve as the lower envelope limit. Hence, ECR 19 % (single-side ECR) can conservatively serve as the conservative, yet non-design specific, Cr-coated ECR limit for the most of the modern base Zircaloy materials (Opt. ZIRLO™ and HANA-6).