Nuclear Regulatory Research Articles

Proposal of Application Method for Concentration Averaging of Radioactive Waste in Korea by Using CA BTP of US NRC

Proposal of Application Method for Concentration Averaging of Radioactive Waste in Korea by Using CA BTP of US NRC

Oestrogen receptor-independent actions of oestrogen in cancer.

Oestrogen, the primary female sex hormone, plays a significant role in tumourigenesis. The major pathway for oestrogen is via binding to its receptor [oestrogen receptor (ERα or β)], followed by nuclear translocation and transcriptional regulation of target genes. Almost 70% of breast tumours are ER + , and endocrine therapies with selective ER modulators (tamoxifen) have been successfully applied. As many as 25% of tamoxifen-treated patients experience disease relapse within 5years upon completion of chemotherapy. In such cases, the ER-independent oestrogen actions provide a plausible explanation for the resistance, as well as expands the existing horizon of available drug targets. ER-independent oestrogen signalling occurs via one of the following pathways: signalling through membrane receptors, oxidative catabolism giving rise to genotoxic metabolites, effects on mitochondria and redox balance, and induction of inflammatory cytokines. The current review focuses on the non-classical oestrogen signalling, its role in cancer, and its clinical significance.

Impact Analysis of a Commercial Airplane Over a Nuclear Spent Fuel Dry Storage Cask

The evaluation of the structural integrity of a vertical cask that is used for spent nuclear fuel dry storage is reported. The cask diameter and height are 3.566 m (140 in.) and 5.28 m (207.75 in.), respectively. The analysis focuses on such a cask being impacted by a commercial airplane. The dry storage container standards, which are under evaluation and approval by the U.S. Nuclear Regulatory Commission, are considered. The storage container inner basket is made of a stainless steel plate cylinder. It is located within an outer shell. The last one is manufactured with concrete and has internal and external steel liners. The commercial airplane considered in this analysis has a length of 40.39 m (132 ft, 6 in.). Its wingspan and height are 35.23 m (115 ft, 7 in.) and 11.98 m (39 ft, 4 in.), respectively. Its take-off weight is 81 090 kg (178 773 lb). An explicit analysis with the finite element method is carried out. The impact angles were 0, 30, 45, and 60 deg with respect to the horizontal. The mesh of the domain has 1 104 229 hexahedral elements and 1 516 156 nodes. Initially, all the structures are considered without restrictions and free of stresses. The vertical container for dry storage is at rest on a rigid concrete base. The aircraft velocity is 234 m/s or 842 km/h (523 mph). The impact event is simulated in an interval of 0.03 s. The maximum principal stress fields show that there are points at the lid of the container that are above the elastic limit and the ultimate strength. Under these conditions, brittle failure is expected.

Research Activities Associated with the Treatment of Potential Common-Cause Failures in Event and Condition Assessments

The U.S. Nuclear Regulatory Commission (NRC) and the nuclear power industry have evaluated and discussed various assumptions and methods for the treatment of potential common-cause failures (CCFs) in event and condition assessments (ECAs), specifically risk assessments performed as part of the NRC’s Significance Determination Process (SDP) in recent years. The basis for how a potential CCF is treated in SDP risk assessments is provided in NUREG-2225, “Basis for the Treatment of Potential Common-Cause Failure in the Significance Determination Process.” In light of new information and advancements in probabilistic risk assessment technology, the NRC and Idaho National Laboratory (INL) have continued the development of the causal alpha factor method (CAFM) for potential use in ECAs. The NRC and INL evaluated the suitability of using CAFM in SDP evaluations and reviewed the methodology to identify any potential data gaps. Furthermore, an investigation was performed on the practice of common-cause component groups to determine if changes are needed to ensure that CCF is appropriately accounted for in the Standardized Plant Analysis Risk models. In addition, a focused review of the existing method that estimates CCF parameters was performed to determine if the assumptions used in the existing process result in CCF parameters that are representative of current industry performance. It was also desired to gather a better understanding of the aspects of the alpha factor method and data calculation process that either have significant effects on the CCF parameters and/or increase the uncertainties associated with these parameters. This paper provides a summary of recently completed work, including insights, conclusions, and recommendations from this effort.

An ex-ante method to verify commercial U.S. nuclear power plant decommissioning cost estimates

There are billions of dollars at stake in the US nuclear power plant decommissioning market. Approximately 92 nuclear power plants are still operating but will come offline and need to be decommissioned over the next few decades. The Nuclear Regulatory Commission (NRC) mandates that the operators of these plants set money aside in segregated funds to finance decommissioning work. However, it is hard for external stakeholders to verify the cost estimations, which ultimately determine how much operators are required to save. In this paper, we develop a method to validate the existing cost models and calculate a contingency empirically for these models. We extend Reference Class Forecasting methods using adaptive kernel fitting and the Wilks’ formula. Based on this method, and assuming a social tolerance for potential cost overruns of 20%, we calculate a new contingency of 48% of the estimated radiological decommissioning cost. After a “stress test” of the current decommissioning trust funds of operating reactor sites, we find that 48% of reactors have sufficient funding—in many cases substantially more than required—and could therefore finance the potential scale of overrun. However, we find that 28 plants would fall short on average $211 million. Still, overruns at every plant are not a foregone conclusion because—while overruns are probable, based on past experience, the actual scale and frequency is not known. Nevertheless, our results add further evidence to the mounting call for the NRC to revise its cost models in light of new information.

The role of the IAEA in establishing international standards for the use of atomic energy (retrospective analysis)

Paradoxically, the peaceful use of nuclear energy and all the prospects it opens up for humanity often coexist with the prospect of nuclear proliferation and nuclear war. This difficult perception is understandable: the materials, knowledge, and expertise needed to produce nuclear weapons are generally no different from those needed to produce nuclear energy and conduct nuclear research.Therefore, ensuring the peaceful and safe use of nuclear energy has always been in the center of attention of the international community. The approach is determined by a complex of national and international measures. It is generally accepted that the primary responsibility for regulating the use of nuclear energy rests with national authorities, but it is also clear that other countries may also be affected. Thus, like many other human activities with potentially transboundary consequences, nuclear energy regulation requires a residual, and in some cases joint, responsibility on the part of the international community to ensure the harmonization of standards, coordination and pooling of resources and services, and regulatory cooperation this activity.In this regard, the IAEA and other international and regional organizations play the role of coordination centers. Article II of the IAEA Statute states that the organization shall seek to accelerate and increase the contribution of atomic energy to world peace, health and prosperity and shall provide, as far as possible, assistance upon request. IAEA supervision or control shall not be used to achieve any military objective.International peration in the field of nuclear energy over the past six decades has resulted in legally binding norms and advisory standards and regulations. This article outlines this global legal framework for the safe and peaceful development of nuclear energy. In particular, it concerns nuclear safety, radiation protection, radioactive waste management, transportation of radioactive materials, emergency assistance and planning, civil liability for nuclear damage, physical protection of nuclear material, armed attack on nuclear facilities, safeguards and controls carried out and provided by the IAEA.

Nuclear pore complex and nucleocytoplasmic transport disruption in neurodegeneration.

Nuclear pore complexes (NPCs) play a critical role in maintaining the equilibrium between the nucleus and cytoplasm, enabling bidirectional transport across the nuclear envelope, and are essential for proper nuclear organization and gene regulation. Perturbations in the regulatory mechanisms governing NPCs and nuclear envelope homeostasis have been implicated in the pathogenesis of several neurodegenerative diseases. The ESCRT-III pathway emerges as a critical player in the surveillance and preservation of well-assembled, functional NPCs, as well as nuclear envelope sealing. Recent studies have provided insights into the involvement of nuclear ESCRT-III in the selective reduction of specific nucleoporins associated with neurodegenerative pathologies. Thus, maintaining quality control of the nuclear envelope and NPCs represents a pivotal element in the pathological cascade leading to neurodegenerative diseases. This review describes the constituents of the nuclear-cytoplasmic transport machinery, encompassing the nuclear envelope, NPC, and ESCRT proteins, and how their structural and functional alterations contribute to the development of neurodegenerative diseases.

Identification of a natural PLA2 inhibitor from the marine fungus Aspergillus sp. c1 for MAFLD treatment that suppressed lipotoxicity by inhibiting the IRE-1α/XBP-1s axis and JNK signaling

Lipotoxicity is a pivotal factor that initiates and exacerbates liver injury and is involved in the development of metabolic-associated fatty liver disease (MAFLD). However, there are few reported lipotoxicity inhibitors. Here, we identified a natural anti-lipotoxicity candidate, HN-001, from the marine fungus Aspergillus sp. C1. HN-001 dose- and time- dependently reversed palmitic acid (PA)-induced hepatocyte death. This protection was associated with IRE-1α-mediated XBP-1 splicing inhibition, which resulted in suppression of XBP-1s nuclear translocation and transcriptional regulation. Knockdown of XBP-1s attenuated lipotoxicity, but no additional ameliorative effect of HN-001 on lipotoxicity was observed in XBP-1s knockdown hepatocytes. Notably, the ER stress and lipotoxicity amelioration was associated with PLA2. Both HN-001 and the PLA2 inhibitor MAFP inhibited PLA2 activity, reduced lysophosphatidylcholine (LPC) level, subsequently ameliorated lipotoxicity. In contrast, overexpression of PLA2 caused exacerbation of lipotoxicity and weakened the anti-lipotoxic effects of HN-001. Additionally, HN-001 treatment suppressed the downstream pro-apoptotic JNK pathway. In vivo, chronic administration of HN-001 (i.p.) in mice alleviated all manifestations of MAFLD, including hepatic steatosis, liver injury, inflammation, and fibrogenesis. These effects were correlated with PLA2/IRE-1α/XBP-1s axis and JNK signaling suppression. These data indicate that HN-001 has therapeutic potential for MAFLD because it suppresses lipotoxicity, and provide a natural structural basis for developing anti-MAFLD candidates.

Understanding the regulator-regulatee relationship for developing safety culture.

Regulatory authorities in safety-critical industries typically seek to influence the safety culture of the organizations they oversee. However, we know little about how regulatory authorities achieve this influence (e.g., what roles are adopted, relationship characteristics) and, more generally, about how external actors shape an organization's safety culture. Using a qualitative design in the nuclear industry, we developed our conceptual and empirical understanding of the roles through which a regulator influences the safety culture of their regulated organizations and what characteristics within the regulator-regulatee relationship facilitate positive safety culture developments. Data were collected through interviews with inspectors from a nuclear regulator and employees of regulated nuclear organizations, and from an inspection of regulatory documents. The findings identified that the regulator was perceived to hold three complementary roles for safety culture development: being an enforcer, working as a partner (providing opportunities for licenseholders to improve beyond compliance), and acting as an advisor to regulated organizations. Analysis also showed that effective relationships in these roles, and which were central to influencing safety culture, were perceived to be characterized by professionalism, transparency, and balance between formal enforcement and informal exchange. Theoretical implications to advance conceptualizations of safety culture as well as practical implications for risk regulators are discussed.

CONTAINER STORAGE AS AN ELEMENT OF ENHANCEMENT OF ENVIRONMENTAL SAFETY AND A STATE POLICY TOOL FOR DEALING WITH TECHNOLOGICALLY ENHANCED SOURCES OF IONIZING RADIATION

In order to implement the state environmental policy and ensure environmental safety, a number of normative legal acts, laws and state standards have been implemented on the territory of Ukraine. Special attention was paid to the State Targeted Environmental Program for the Management of Radioactive Waste, the main principle of which is the implementation of the protection of the population and the natural environment in order to create safe conditions for the existence of current and future generations and ensure sustainable development. The article highlights the results of research and development works on the development and certification of a set of packaging type IR-2 for the transportation and temporary storage of low- and medium-level solid radioactive waste KTTZ-NS-1-02.00.00, as a key element of environmental protection technologies during handling with radioactive waste. The urgent task of handling radioactive waste, which is caused by the accumulation of a significant amount of sludge in the territories of the oil and gas production complex enterprises and requires temporary storage and transportation, has been solved, as a prerequisite for increasing the efficiency of ensuring the environmental safety of the mentioned objects of formation. The technical characteristics of the packaging kit are described in detail, schematic drawings are provided, and the main parameters and dimensions of the developed packaging kit type IR-2 are provided. The scheme of the main stages of the testing of this packaging set and the certificates obtained as a result of such work, which were carried out jointly with representatives of the State Inspection of Nuclear Regulation, are presented. The developed packaging set significantly exceeds the performance of the packaging set currently used in temporary storage facilities. Keywords: environmental safety, technogenically enhanced radioactive waste, protection technologies, containers, low- and medium-level waste.

MODELLING OF DEBRIS MOTION DRIVEN BY TSUNAMI WAVE BREAKING

When a giant tsunami approaches onshore, offshore vessels and other floating objects move following the current of the tsunami. Some of the waterborne debris are transported to tsunami inundation areas and those debris impact buildings. For evaluations of debris impact loads, types of debris having the potential to impact and damage the structures are identified by considering debris impact hazard region. According to ASCE7-22, the debris impact hazard region shall be determined by the empirical model proposed by Naito et al. (2014) in a simple manner. Furthermore, numerical debris transport modelling using massless tracers also shall be permitted to use for the determination. On the other hand, numerical debris tracking (nDT) modellings which solve the equation of motion of debris have been developed (e.g., Kihara and Kaida, 2019). In this study, a surface roller modelling is incorporated into the nDT model of Kihara and Kaida (2019) to simulate debris motions driven by tsunami wave breaking. To validate the model, simulations of hydraulic experiments focusing on the motion of offshore debris reported by the Nuclear Regulation Authority (NRA) of Japan are carried out (Oda et al., 2021).

Safety considerations related to boron redistribution during Loss-of-Coolant-Accident initiated beyond design basis events for the NuScale power module

The authors, as staff at the U.S. Nuclear Regulatory Commission (NRC), evaluated the potential consequences of boron dilution under beyond design basis conditions in the NuScale Power Module to inform NRC staff’s safety evaluation report for the NuScale design certification review. The authors identified the small break loss of coolant accident with coincident failure of control rods to insert as the scenario with the most adverse boron dilution and reactivity insertion consequences. The authors evaluated the sequence of events for the scenario to determine which conditions or phenomena could produce the potential for a core flow surge to yield core damage because of a super-prompt reactivity excursion. The authors screened the conditions and phenomena that could potentially cause a core flow surge based on the dynamic speed of the incursion compared to key reactivity feedback mechanisms: thermal–hydraulic coupling via rod heat transfer and convective mixing. Based on the screening process, the authors were able to identify two processes that could potentially lead to a power excursion. However, the authors’ analysis relies heavily on assumptions regarding convective mixing, making this an important phenomenon worth careful consideration in any evaluation of boron redistribution.

Pharmacological perturbation of the phase-separating protein SMNDC1

SMNDC1 is a Tudor domain protein that recognizes di-methylated arginines and controls gene expression as an essential splicing factor. Here, we study the specific contributions of the SMNDC1 Tudor domain to protein-protein interactions, subcellular localization, and molecular function. To perturb the protein function in cells, we develop small molecule inhibitors targeting the dimethylarginine binding pocket of the SMNDC1 Tudor domain. We find that SMNDC1 localizes to phase-separated membraneless organelles that partially overlap with nuclear speckles. This condensation behavior is driven by the unstructured C-terminal region of SMNDC1, depends on RNA interaction and can be recapitulated in vitro. Inhibitors of the protein’s Tudor domain drastically alter protein-protein interactions and subcellular localization, causing splicing changes for SMNDC1-dependent genes. These compounds will enable further pharmacological studies on the role of SMNDC1 in the regulation of nuclear condensates, gene regulation and cell identity.

Verification strategy for artificial intelligence components in nuclear plant instrumentation and control systems

The application of artificial intelligence (AI) systems in nuclear power plants has the potential to facilitate significant advancements in the industry. However, nuclear system engineers and regulators have expressed concerns regarding the reliability of AI components owing to a lack of documentation and appropriate verification methods that differ from those used for traditional software. Accordingly, this study proposes a systematic approach for the verification and validation of AI components based on nuclear software regulatory guidelines. The proposed strategy includes process verification and functional testing activities specifically tailored to AI components for instrumentation and control systems. This approach serves as a foundation for fostering understanding and agreement among system engineers, operating licensees, and regulatory bodies on the use of AI components in nuclear power plants.

Negating Non-proliferation? The Potential Sino-South Challenge to Nuclear Market Regulation

ABSTRACT Developing industrial-scale nuclear energy projects requires substantial technical expertise, access to complex fuel supply chains and long-term financial capital. For developing countries investing in civil nuclear energy programmes, securing external support is crucial. However, the nuclear technology trade market is heavily regulated and rather thin. Exporter states must balance commercial opportunity with security interests, given nuclear technology’s dual use. Because of this, incumbent exporters bear responsibility in crafting and enforcing market regulations. As highlighted by the budding Chinese-Argentinian relationship, newly capable market entrants, particularly the People’s Republic of China (PRC), have the potential to challenge international non-proliferation norms by fulfilling market demand where other, predominately Western, states have demurred. The strength of nuclear markets’ non-proliferation-oriented regulatory structures hinges on nascent relationships between entrepreneurial exporters and participating Global South states.

Characterization of Fast Neutron Transmission Through an Iron Shield

In this paper we give an analysis of the neutron transmission through an iron sphere using Monte Carlo and transport theory methods based on ENDF/B-VII.1 general purpose library. The motivation for this investigation comes from a well-known deficiency in the iron inelastic data from the older library evaluation (ENDF/B-V), giving a concern for a fast neutron flux underestimation within the reactor pressure vessels. In order to benchmark the next-generation ENDF/B-VI iron data, the U.S. Nuclear Regulatory Commission and the former Czechoslovakian National Research Institute have jointly preformed several experiments in 1990s, addressing neutron leakage spectra obtained for a 252Cf fission source in a centre of an iron sphere. It was shown that the ENDF/B-VI iron cross section, containing several improvements over previous evaluations, will not entirely resolve the neutron spectrum discrepancies observed at high neutron energies. Since safety analyses of reactor pressure vessel embrittlement are often based on neutron transport calculations using specific multigroup cross section libraries, simulation of this benchmark was performed using a hybrid shielding methodology of ADVANTG3.0.3 and MCNP6.1.1b codes. Comparison of calculated and referenced dosimeter activation rates are presented for several "standard" nuclear reactions, often used in reactor pressure vessel dosimetry. For that purpose, the new IRDFF-II special library from the IAEA Nuclear Data Services was used as a reference source of dosimetry cross sections. The MCNP6.1.1b code was used for calculation of reaction rates, which were also compared with previous IRDFF-1.05 special library and general purpose ENDF/B-VII.1 library.

SIRT1 regulates osteoblast senescence through SOD2 acetylation and mitochondrial dysfunction in the progression of Osteoporosis caused by Cadmium exposure

Environmental Cadmium (Cd) is a toxicant with widespread exposure, documented adverse effects on bone homeostasis, and makes the onset of osteoporosis (OP), one of the age-related chronic diseases an enormous burden to modern societies worldwide. Aging is the largest risk factor for a multitude of age-related diseases and osteoblasts senescence reduces bone formation and is a key factor for osteoporosis. Despite anti-aging molecules the nuclear silent information regulator of transcription 1 (SIRT1) actions in chondrocytes and bone cells are critical for normal skeletal development and homeostasis, much less is known about the role of SIRT1 in osteoporosis. Here, we aim to demonstrate that SIRT1 mediates osteoblasts' senescence response to OP caused by Cd. The senescent osteoblasts accumulation and their viability were analyzed after Cd exposure. To explore the effects and mechanism of SIRT1 in Cd-induced osteoblastic senescence, we generated SIRT1-overexpressed osteoblast and SIRT1 conditional overexpression in the rat femur. Meanwhile, the OP rat model was established by removing bilateral ovaries. We found decreased SIRT1 expression and senescent osteoblasts accumulation after Cd exposure. Meanwhile, Cd exposure increased P53, P16INK4a, and P21CIPI proteins level, triggered DNA damage response (DDR) through the phosphorylation of ATM and H2AX, and caused mitochondrial dysfunction by the increased acetylation of SOD2 and excessive mitophagy. SIRT1 overexpression attenuated DDR and mitochondrial dysfunction and downregulated the increase of hall makers senescence caused by Cd in osteoblasts. We found overexpression of osteoblastic SIRT1 protects against Cd-induced senescence, which is likely driven by ATM-mediated DDR and SOD2ace-mediated mitochondrial dysfunction. Our study demonstrates the mechanism of SIRT1 in mediating bone homeostasis via senescence. Further mechanistic studies using specific SIRT1 mutations elucidating how SIRT1 modulates bone cell senescence, will provide new therapeutic strategies for human osteoporosis.

Mcl-1 deficiency in murine livers leads to nuclear polyploidisation and mitotic errors: Implications for hepatocellular carcinoma

Background & AimsMcl-1, an antiapoptotic protein overexpressed in many tumours, including hepatocellular carcinoma (HCC), represents a promising target for cancer treatment. Although Mcl-1 non-apoptotic roles might critically influence the therapeutic potential of Mcl-1 inhibitors, these functions remain poorly understood. We aimed to investigate the effects of hepatic Mcl-1 deficiency (Mcl-1Δhep) on hepatocyte ploidy and cell cycle in murine liver in vivo and the possible implications on HCC. MethodsLivers of young Mcl-1Δhep and wild-type (WT) mice were analysed for ploidy profile, mitotic figures, in situ chromosome segregation, gene set enrichment analysis and were subjected to two-thirds partial hepatectomy to assess Mcl-1 deficiency effect on cell cycle progression in vivo. Mcl-1Δhep tumours in older mice were analysed for ploidy profile, chromosomal instability, and mutational signatures via whole exome sequencing. ResultsIn young mice, Mcl-1 deficiency leads to nuclear polyploidy and to high rates of mitotic errors with abnormal spindle figures and chromosome mis-segregation along with a prolonged spindle assembly checkpoint activation signature. Chromosomal instability and altered ploidy profile are observed in Mcl-1Δhep tumours of old mice as well as a characteristic mutational signature of currently unknown aetiology. ConclusionsOur study suggests novel non-apoptotic effects of Mcl-1 deficiency on nuclear ploidy, mitotic regulation, and chromosomal segregation in hepatocytes in vivo. In addition, the Mcl-1 deficiency characteristic mutational signature might reflect mitotic issues. These results are of importance to consider when developing anti-Mcl-1 therapies to treat cancer. Impact and implicationsAlthough Mcl-1 inhibitors represent promising hepatocellular carcinoma treatment, the still poorly understood non-apoptotic roles of Mcl-1 might compromise their successful clinical application. Our study shows that Mcl-1 deficiency leads to nuclear polyploidy, mitotic errors, and aberrant chromosomal segregation in hepatocytes in vivo, whereas hepatocellular tumours spontaneously induced by Mcl-1 deficiency exhibit chromosomal instability and a mutational signature potentially reflecting mitotic issues. These results have potential implications for the development of anti-Mcl-1 therapies to treat hepatocellular carcinoma, especially as hyperproliferative liver is a clinically relevant situation.

Preliminary analysis focusing on in-vessel thermal hydraulics in loss-of-heat removal systems in a sodium-cooled fast reactor

Accident scenarios for the safety evaluation of sodium-cooled fast reactors (SFRs) are categorized into two groups: Anticipated Transient Without Scram (ATWS) and Loss-of-Heat Removal System (LOHRS). The latter is subdivided into two scenarios—Loss-of-Heat Sink (LOHS) and Loss-of-Reactor Level (LORL)—depending on the initiating event. With the development of SFRs, research on ATWS has been paid much attention to due to its rapid accident progression, which could lead to significant radioactive release. Conversely, the significance of LOHRS has increased in recent decades due to lessons learned from accidents at the Fukushima Daiichi Nuclear Power Plant of Tokyo Electric Power Company. However, compared with ATWS, finding and evaluation tools for LOHRS have been limited. Hence, code development is initiated to enhance the severe accident analysis code AZORES, which the Nuclear Regulation Authority developed for the safety evaluation of SFR accidents. This enhancement is achieved by coupling AZORES with plant dynamics code ADYTUM in order to deal with more detailed thermal hydraulics behavior in reactor cooling system. The paper describes the coupling methodology, focusing on the thermal–hydraulic model as the first step of code development and its application. The coupling has been confirmed to be well achieved through a preliminary analysis of LOHS, comparing the results of coupled and single AZORES. The comparison of the analysis results between LOHS and LORL by the AZORES coupled with ADYTUM has been conducted to identify the key phenomena in accident progression. The comparison shows that the coolant leak area and the pressure drop at the piping of the reactor cooling system affect accident progression in LOHS. Consequently, the coupled AZORES is capable of predicting in-vessel thermal–hydraulic behavior in LOHRS successfully, reflecting accident conditions and plant design appropriately.

RANBP1, a member of the nuclear-cytoplasmic trafficking-regulator complex, is the terminal-striking point of the SGK1-dependent Th17+ pathological differentiation.

The Th17+ arrangement is critical for orchestrating both innate and acquired immune responses. In this context, the serum and glucocorticoid regulated kinase 1 (SGK1) exerts a key role in the governance of IL-23R-dependent Th17+ maturation, through the phosphorylation-dependent control of FOXO1 localization. Our previous work has shown that some of the SGK1-key functions are dependent on RAN-binding protein 1 (RANBP1), a terminal gene in the nuclear transport regulation. Here, we show that RANBP1, similarly to SGK1, is modulated during Th17+ differentiation and that RANBP1 fluctuations mediate the SGK1-dependent effects on Th17+ maturation. RANBP1, as the final effector of the SGK1 pathway, affects FOXO1 transport from the nucleus to the cytoplasm, thus enabling RORγt activation. In this light, RANBP1 represents the missing piece, in an essential and rate-limiting manner, underlying the Th17+ immune asset.