Search

Abstract HOIL-1L deficiency was recently reported to be one of the causes of myopathy and dilated cardiomyopathy (DCM). However, the mechanisms by which myopathy and DCM develop have not been clearly elucidated. Here, we sought to elucidate these mechanisms using the murine myoblast cell line C2C12 and disease-specific human induced pluripotent stem cells (hiPSCs). Myotubes differentiated from HOIL-1L-KO C2C12 cells exhibited deteriorated differentiation and mitotic cell accumulation. CMs differentiated from patient-derived hiPSCs had an abnormal morphology with a larger size and were excessively multinucleated compared with CMs differentiated from control hiPSCs. Further analysis of hiPSC-derived CMs showed that HOIL-1L deficiency caused cell cycle alteration and mitotic cell accumulation. These results demonstrate that abnormal cell maturation possibly contribute to the development of myopathy and DCM. In conclusion, HOIL-1L is an important intrinsic regulator of cell cycle-related myotube and CM maturation and cell proliferation.

Continuous observations of atmospheric δ(O2/N2) and CO2 amount fractions have been carried out at Ryori (RYO), Japan, since August 2017. In these observations, the O2 : CO2 exchange ratio (ER, -Δy(O2)Δy(CO2)-1) has frequently been lower than expected from short-term variations in emissions from terrestrial biospheric activities and combustion of liquid, gas, and solid fuels. This finding suggests a substantial effect of CO2 emissions from a cement plant located about 6 km northwest of RYO. To evaluate this effect quantitatively, we simulated CO2 amount fractions in the area around RYO by using a fine-scale atmospheric transport model that incorporated CO2 fluxes from terrestrial biospheric activities, fossil fuel combustion, and cement production. The simulated CO2 amount fractions were converted to O2 amount fractions by using the respective ER values of 1.1, 1.4, and 0 for the terrestrial biospheric activities, fossil fuel combustion, and cement production. Thus obtained O2 and CO2 amount fraction changes were used to derive a simulated ER for comparison with the observed ER. To extract the contribution of CO2 emissions from the cement plant, we used y(CO2∗) as an indicator variable, where y(CO2∗) is a conservative variable for terrestrial biospheric activities and fossil fuel combustion obtained by simultaneous analysis of observed δ(O2/N2) and CO2 amount fractions and simulated ERs. We confirmed that the observed and simulated ER values and also the y(CO2∗) values and simulated CO2 amount fractions due only to cement production were generally consistent. These results suggest that combined measurements of δ(O2/N2) and CO2 amount fractions will be useful for evaluating CO2 capture from flue gas at carbon capture and storage (CCS) plants, which, similar to a cement plant, change CO2 amount fractions without changing O2 values, although CCS plants differ from cement plants in the direction of CO2 exchange with the atmosphere.

Abstract Background Disease-specific induced pluripotent stem cells (iPSCs) are useful tools for pathological analysis and diagnosis of rare diseases. Given the limited available resources, banking such disease-derived iPSCs and promoting their widespread use would be a promising approach for untangling the mysteries of rare diseases. Herein, we comprehensively established iPSCs from patients with designated intractable diseases in Japan and evaluated their properties to enrich rare disease iPSC resources. Methods Patients with designated intractable diseases were recruited for the study and blood samples were collected after written informed consent was obtained from the patients or their guardians. From the obtained samples, iPSCs were established using the episomal method. The established iPSCs were deposited in a cell bank. Results We established 1,532 iPSC clones from 259 patients with 139 designated intractable diseases. The efficiency of iPSC establishment did not vary based on age and sex. Most iPSC clones originated from non-T and non-B hematopoietic cells. All iPSC clones expressed key transcription factors, OCT3/4 (range 0.27–1.51; mean 0.79) and NANOG (range 0.15–3.03; mean 1.00), relative to the reference 201B7 iPSC clone. Conclusions These newly established iPSCs are readily available to the researchers and can prove to be a useful resource for research on rare intractable diseases.

ABSTRACTRice production in sub-Saharan Africa (SSA) has increaed ten-fold since 1961, whereas its consumption has exceeded the production and the regional self-sufficiency rate is only 48% in 2020. Increase in rice production has come mainly from increased harvested area. Yield increase has been limited and the current average yield in SSA is around 2 t ha−1. This paper aims to provide the status quo of (i) current rice production and its challenges, (ii) selected achievements in rice agronomy research mainly by the Africa Rice Center and its partners, and (iii) perspectives for future research on rice agronomy in SSA. The major problems confronting rice production include low yield in rainfed environments, accounting for 70% of the total rice harvested area. Rainfed rice yields are strongly affected by climate extremes such as water stresses, soil-related constraints, and sub-optimum natural resource management and crop management practices by smallholder farmers including poor water management, and suboptimal use of fertilizers, herbicides, and machineries. For alleviating these constraints, a wide range of technologies have been developed and introduced over the last three decades. These include water conservation technologies in rainfed and irrigated lowland rice, site-specific nutrient management practices, decision support tools such as crop growth simulation models, and labor-saving technologies. We conclude that further research efforts are needed to develop locally adapted agronomic solutions for sustainable intensification, especially in rainfed rice to enhance the resilience to climate change and increase land and labor productivity and sustainability of rice cultivation in SSA.

Summary: Recent regenerative studies using human pluripotent stem cells (hPSCs) have developed multiple kidney-lineage cells and organoids. However, to further form functional segments of the kidney, interactions of epithelial and interstitial cells are required. Here we describe a selective differentiation of renal interstitial progenitor-like cells (IPLCs) from human induced pluripotent stem cells (hiPSCs) by modifying our previous induction method for nephron progenitor cells (NPCs) and analyzing mouse embryonic interstitial progenitor cell (IPC) development. Our IPLCs combined with hiPSC-derived NPCs and nephric duct cells form nephrogenic niche- and mesangium-like structures in vitro. Furthermore, we successfully induce hiPSC-derived IPLCs to differentiate into mesangial and erythropoietin-producing cell lineages in vitro by screening differentiation-inducing factors and confirm that p38 MAPK, hypoxia, and VEGF signaling pathways are involved in the differentiation of mesangial-lineage cells. These findings indicate that our IPC-lineage induction method contributes to kidney regeneration and developmental research.

Summary: Cell differentiation is achieved by acquiring a cell type-specific transcriptional program and epigenetic landscape. While the cell type-specific patterning of enhancers has been shown to precede cell fate decisions, it remains unclear how regulators of these enhancers are induced to initiate cell specification and how they appropriately restrict cells that differentiate. Here, using embryonic stem cell–derived hematopoietic cell differentiation cultures, we show the activation of some hematopoietic enhancers during arterialization of hemogenic endothelium, a prerequisite for hematopoiesis. We further reveal that ZEB2, a factor involved in the transcriptional regulation of arterial endothelial cells, and a hematopoietic regulator MEIS1 are independently required for activating these enhancers. Concomitantly, ZEB2 or MEIS1 deficiency impaired hematopoietic cell development. These results suggest that multiple regulators expressed from an earlier developmental stage non-redundantly contribute to the establishment of hematopoietic enhancer landscape, thereby restricting cell differentiation despite the unrestricted expression of these regulators to hematopoietic cells.

Summary: Interstitial lung disease (ILD) represents a large group of diseases characterized by chronic inflammation and fibrosis of the lungs, for which therapeutic options are limited. Among several causative genes of familial ILD with autosomal dominant inheritance, the mutations in the BRICHOS domain of SFTPC cause protein accumulation and endoplasmic reticulum stress by misfolding its proprotein. Through a screening system using these two phenotypes in HEK293 cells and evaluation using alveolar epithelial type 2 (AT2) cells differentiated from patient-derived induced pluripotent stem cells (iPSCs), we identified Cryptotanshinone (CPT) as a potential therapeutic agent for ILD. CPT decreased cell death induced by mutant SFTPC overexpression in A549 and HEK293 cells and ameliorated the bleomycin-induced contraction of the matrix in fibroblast-dependent alveolar organoids derived from iPSCs with SFTPC mutation. CPT and this screening strategy can apply to abnormal protein-folding-associated ILD and other protein-misfolding diseases.

Abstract Background Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disease characterized by progressive heterotopic ossification (HO) in soft tissues due to a heterozygous mutation of the ACVR1A gene (FOP-ACVR1A), which erroneously transduces the BMP signal by Activin-A. Although inflammation is known to trigger HO in FOP, the role of FOP-ACVR1A on inflammatory cells remains to be elucidated. Results We generated immortalized monocytic cell lines from FOP-iPSCs (FOP-ML) and mutation rescued iPSCs (resFOP-ML). Cell morphology was evaluated during the monocyte induction and after immortalization. Fluorescence-activated cell sorting (FACS) was performed to evaluate the cell surface markers CD14 and CD16 on MLs. MLs were stimulated with lipopolysaccharide or Activin-A and the gene expression was evaluated by quantitative PCR and microarray analysis. Histological analysis was performed for HO tissue obtained from wild type mice and FOP-ACVR1A mice which conditionally express human mutant ACVR1A gene by doxycycline administration. Without any stimulation, FOP-ML showed the pro-inflammatory signature of CD16+ monocytes with an upregulation of INHBA gene, and treatment of resFOP-ML with Activin-A induced an expression profile mimicking that of FOP-ML at baseline. Treatment of FOP-ML with Activin-A further induced the inflammatory profile with an up-regulation of inflammation-associated genes, of which some, but not all, of which were suppressed by corticosteroid. Experiments using an inhibitor for TGFβ or BMP signal demonstrated that Activin-A-induced genes such as CD16 and CCL7, were regulated by both signals, indicating Activin-A transduced dual signals in FOP-ML. A comparison with resFOP-ML identified several down-regulated genes in FOP-ML including LYVE-1, which is known to suppress matrix-formation in vivo. The down-regulation of LYVE-1 in HO tissues was confirmed in FOP model mice, verifying the significance of the in vitro experiments. Conclusion These results indicate that FOP-ML faithfully recapitulated the phenotype of primary monocytes of FOP and the combination with resFOP-ML is a useful tool to investigate molecular events at the initial inflammation stage of HO in FOP.

IntroductionBlau syndrome is a rare autosomal dominant autoinflammatory granulomatous disease caused by a mutation in the NOD2 gene. It is characterized by a clinical trial of granulomatous dermatitis, arthritis, and uveitis. Tofacitinib is a pan Janus kinase (JAK) inhibitor used for treatment of Blau syndrome and idiopathic sarcoidosis. Here, we evaluated its effect on inflammatory pathways associated with Blau syndrome. The effect of tofacitinib on downstream pathways regulated by mutant NOD2 was analyzed using luciferase assays with overexpression of NOD2 mutants.MethodsThe effect of tofacitinib on the upstream pathway for the induction of NOD2 expression and proinflammatory cytokine production was assessed using monocytic cell lines differentiated from Blau syndrome patient-derived induced pluripotent stem cells.ResultsTofacitinib did not suppress the increased spontaneous transcriptional activity of NF-κB by mutant NOD2. In addition, mutant NOD2 was not involved in the transcription of ISRE and GAS, which are activated by type 1 and type 2 interferons (IFN), respectively. On the other hand, IFNγ induced the expression of NOD2, which led to the production of inflammatory cytokines by an autoinflammatory mechanism only in cells with mutant NOD2. DiscussionTofacitinib suppressed the induction of NOD2 by IFNγ, thereby inhibiting the production of pro-inflammatory cytokines. Thus, tofacitinib showed anti-inflammatory effects through suppression of NOD2 expression. The JAK inhibitor tofacitinib is a potential therapeutic agent for Blau syndrome because it suppresses the autoinflammation seen in Blau syndrome by inhibiting the expression of NOD2.

Preceding a core-collapse supernova (CCSN), various processes produce an increasing amount of neutrinos of all flavors characterized by mounting energies from the interior of massive stars. Among them, the electron antineutrinos are potentially detectable by terrestrial neutrino experiments such as KamLAND and Super-Kamiokande (SK) via inverse beta decay interactions. Once these pre-supernova (pre-SN) neutrinos are observed, an early warning of the upcoming CCSN can be provided. In light of this, KamLAND and SK, both located in the Kamioka mine in Japan, have been monitoring pre-SN neutrinos since 2015 and 2021, respectively. Recently, we performed a joint study between KamLAND and SK on pre-SN neutrino detection. A pre-SN alert system combining the KamLAND detector and the SK detector was developed and put into operation, which can provide a supernova alert to the astrophysics community. Fully leveraging the complementary properties of these two detectors, the combined alert is expected to resolve a pre-SN neutrino signal from a 15 M _⊙ star within 510 pc of the Earth at a significance level corresponding to a false alarm rate of no more than 1 per century. For a Betelgeuse-like model with optimistic parameters, it can provide early warnings up to 12 hr in advance.

In 2023, the manufacturing of all the ITER TF coils has been completed 15 years after the sign of procurement arrangements in 2008. This paper has been jointly submitted by F4E and QST to recollect the lessons learnt in the production of the two parties along the last 15 years.

Recently, experiments on basic plasma physics issues for solving future problems in fusion energy have been performed on a Large Helical Device. There are several problems to be solved in future devices for fusion energy. Emerging issues in burning plasma are: alpha-channeling (ion heating by alpha particles), turbulence and transport in electron dominant heating helium ash exhaust, reduction of the divertor heat load. To solve these problems, understanding the basic plasma physics of (1) wave–particle interaction through (inverse) Landau damping, (2) characteristics of electron-scale (high- k ) turbulence, (3) ion mixing and the isotope effect, and (4) turbulence spreading and detachment, is necessary. This overview discusses the experimental studies on these issues and turbulent transport in multi-ion plasma and other issues in the appendix.

The results of the first experimental series to produce a plasma using the radio frequency discharge (RF) above the ion cyclotron frequency at relatively low magnetic fields (0.5–0.6 T) in the Large Helical Device (LHD) are presented 1.43 MW of RF power produced target plasma with density up to 6 × 10 ^18 m ^−3 to deuterium. Tangential NBI application into such a plasma increases plasma parameters. Electron temperatures up to ≈0.9 keV and densities up to ≈2.4 × 10 ^19 m ^−3 had been achieved, and the maximum value of < β _dia > was 2.6%. These experiments open possibilities for new regimes of LHD operation which are also interested to W7-X.

Skeletal muscle has a highly regenerative capacity, but the detailed process is not fully understood. Several in vitro skeletal muscle regeneration models have been developed to elucidate this, all of which rely on specialized culture conditions that limit the accessibility and their application to many general experiments. Here, we established a concise in vitro skeletal muscle regeneration model using mouse primary cells. This model allows evaluation of skeletal muscle regeneration in two-dimensional culture system similar to a typical cell culture, showing a macrophage-dependent regenerative capacity, which is an important process in skeletal muscle regeneration. Based on the concept that this model could assess the contribution of macrophages of various phenotypes to skeletal muscle regeneration, we evaluated the effect of endotoxin pre-stimulation for inducing various changes in gene expression on macrophages and found that the contribution to skeletal muscle regeneration was significantly reduced. The gene expression patterns differed from those of naive macrophages, especially immediately after skeletal muscle injury, suggesting that the difference in responsiveness contributed to the difference in regenerative efficiency. Our findings provide a concise in vitro model that enables the evaluation of the contribution of individual cell types, such as macrophages and muscle stem cells, on skeletal muscle regeneration.

We analyzed air samples collected on board a C-130 cargo aircraft over the western North Pacific from May 2012 to March 2020 for atmospheric δ(O2 / N2) and CO2 amount fraction. Observations were corrected for significant artificial fractionation of O2 and N2 caused by thermal diffusion during the air sample collection using the simultaneously measured δ(Ar / N2). The observed seasonal cycles of the δ(O2 / N2) and atmospheric potential oxygen (δ(APO)) varied nearly in opposite phase to the cycle of the CO2 amount fraction at all latitudes and altitudes. Seasonal amplitudes of δ(APO) decreased with latitude from 34 to 25∘ N, as well as with increasing altitude from the surface to 6 km by 50 %–70 %, while those of the CO2 amount fraction decreased by less than 20 %. By comparing the observed values with the simulated δ(APO) and CO2 amount fraction values generated by an atmospheric transport model, we found that the seasonal δ(APO) cycle in the middle troposphere was modified significantly by a combination of the northern and southern hemispheric seasonal cycles due to the interhemispheric mixing of air. The simulated δ(APO) underestimated the observed interannual variation in δ(APO) significantly, probably due to the interannual variation in the annual mean air–sea O2 flux. Interannual variation in δ(APO) driven by the net marine biological activities, obtained by subtracting the assumed solubility-driven component of δ(APO) from the total variation, indicated a clear influence on annual net sea–air marine biological O2 flux during El Niño and net air–sea flux during La Niña. By analyzing the observed secular trends of δ(O2 / N2) and the CO2 amount fraction, global average terrestrial biospheric and oceanic CO2 uptakes for the period 2012–2019 were estimated to be (1.8±0.9) and (2.8±0.6) Pg a−1 (C equivalents), respectively.

Emissions from biomass burning (BB) are a key source of atmospheric tracer gases that affect the atmospheric carbon cycle. We developed four sets of global BB emissions estimates (named GlcGlob, GlcGeoc, McdGlob, and McdGeoc) using a bottom-up approach and by combining the remote sensing products related to fire distribution with two aboveground biomass (AGB) and two land cover classification (LCC) distributions. The sensitivity of the estimates of BB emissions to the AGB and LCC data was evaluated using the carbon monoxide (CO) emissions associated with each BB estimate. Using the AGB and/or LCC data led to substantially different spatial estimates of CO emissions, with a large (factor of approximately 3) spread of estimates for the mean annual CO emissions: 526±53, 219±35, 624±57, and 293±44 Tg CO yr−1 for GlcGlob, GlcGeoc, McdGlob, and McdGeoc, respectively, and 415±47 Tg CO yr−1 for their ensemble average (EsmAve). We simulated atmospheric CO variability at an approximately 2.5∘ grid using an atmospheric tracer transport model and the BB emissions estimates and compared it with ground-based and satellite observations. At ground-based observation sites during fire seasons, the impact of intermittent fire events was poorly defined in our simulations due to the coarse resolution, which obscured temporal and spatial variability in the simulated atmospheric CO concentration. However, when compared at the regional and global scales, the distribution of atmospheric CO concentrations in the simulations shows substantial differences among the estimates of BB emissions. These results indicate that the estimates of BB emissions are highly sensitive to the AGB and LCC data.

We report the serendipitous discovery of VVV-WIT-12, an unusual variable source that seems to induce variability in its surrounding nebula. The source belongs to the rare objects that we call WITs (short for What Is This?) discovered within the VISTA Variables in the Vía Láctea (VVV) survey. VVV-WIT-12 was discovered during a pilot search for light echoes from distant supernovae in the Milky Way using the near-IR images of the VVV survey. This source has an extremely red spectral energy distribution, consistent with a very reddened ( A _V ∼ 100 mag) long-period variable star ( P ∼ 1525 days). Furthermore, it is enshrouded in a nebula that changes brightness and color with time, apparently in sync with the central source variations. The near-IR light curve and complementary follow-up spectroscopy observations are consistent with a variable young stellar object illuminating its surrounding nebula. In this case the source periodic variation along the cycles produces an unprecedented light echo in the different regions of the nebula.

PurposeUpregulation of type I interferon (IFN) signaling has been increasingly detected in inflammatory diseases. Recently, upregulation of the IFN signature has been suggested as a potential biomarker of IFN-driven inflammatory diseases. Yet, it remains unclear to what extent type I IFN is involved in the pathogenesis of undifferentiated inflammatory diseases. This study aimed to quantify the type I IFN signature in clinically undiagnosed patients and assess clinical characteristics in those with a high IFN signature.MethodsThe type I IFN signature was measured in patients’ whole blood cells. Clinical and biological data were collected retrospectively, and an intensive genetic analysis was performed in undiagnosed patients with a high IFN signature.ResultsA total of 117 samples from 94 patients with inflammatory diseases, including 37 undiagnosed cases, were analyzed. Increased IFN signaling was observed in 19 undiagnosed patients, with 10 exhibiting clinical features commonly found in type I interferonopathies. Skin manifestations, observed in eight patients, were macroscopically and histologically similar to those found in proteasome-associated autoinflammatory syndrome. Genetic analysis identified novel mutations in the PSMB8 gene of one patient, and rare variants of unknown significance in genes linked to type I IFN signaling in four patients. A JAK inhibitor effectively treated the patient with the PSMB8 mutations. Patients with clinically quiescent idiopathic pulmonary hemosiderosis and A20 haploinsufficiency showed enhanced IFN signaling.ConclusionsHalf of the patients examined in this study, with undifferentiated inflammatory diseases, clinically quiescent A20 haploinsufficiency, or idiopathic pulmonary hemosiderosis, had an elevated type I IFN signature.

Abstract Down syndrome (DS) is caused by the trisomy of chromosome 21. Among the many disabilities found in individuals with DS is an increased risk of early-onset Alzheimer's disease (AD). Although higher oxidative stress and an upregulation of amyloid β (Aβ) peptides from an extra copy of the APP gene are attributed to the AD susceptibility, the relationship between the two factors is unclear. To address this issue, we established an in vitro cellular model using neurons differentiated from DS patient-derived induced pluripotent stem cells (iPSCs) and isogenic euploid iPSCs. Neurons differentiated from DS patient-derived iPSCs secreted more Aβ compared to those differentiated from the euploid iPSCs. Treatment of the neurons with an antioxidant, N-acetylcysteine, significantly suppressed the Aβ secretion. These findings suggest that oxidative stress has an important role in controlling the Aβ level in neurons differentiated from DS patient-derived iPSCs and that N-acetylcysteine can be a potential therapeutic option to ameliorate the Aβ secretion.

Abstract Nakajo‐Nishimura syndrome (NNS) is an autoinflammatory disorder caused by a homozygous mutations in the PSMB8 gene. The administration of systemic corticosteroids is partially effective, but continuous treatment causes severe side effects. We previously established a pluripotent stem cell (PSC)‐derived NNS disease model that reproduces several inflammatory phenotypes, including the overproduction of monocyte chemoattractant protein‐1 (MCP‐1) and interferon gamma‐induced protein‐10 (IP‐10). Here we performed high‐throughput compound screening (HTS) using this PSC‐derived NNS model to find potential therapeutic candidates and identified CUDC‐907 as an effective inhibitor of the release of MCP‐1 and IP‐10. Short‐term treatment of CUDC‐907 did not induce cell death within therapeutic concentrations and was also effective on primary patient cells. Further analysis indicated that the inhibitory effect was post‐transcriptional. These findings suggest that HTS with PSC‐derived disease models is useful for finding drug candidates for autoinflammatory diseases.

The degradation of permafrost is a large source of uncertainty in understanding the behaviour and projecting the future impacts of Earth's climate system. The spatial distributions of soil organic carbon (SOC) and ground ice (ICE) provide essential information for the assessment and projection of risks and impacts of permafrost degradation. However, uncertainties regarding the geographical distribution and estimated range of the total amount of stored carbon and ice are still substantial. A numerical soil organic carbon–ground ice budget model, SOC-ICE-v1.0, that considers essential aspects of carbon and hydrological processes in above-ground and subsurface environments and permanently frozen ground (permafrost) and land cover changes (ice sheets and coastlines) was developed to calculate the long-term evolution of local SOC and ICE. The model was integrated to cover the last 125 kyr – from the last interglacial to date for areas north of 50∘ N at 1∘ resolution – to simulate the balance between accumulation and dissipation of SOC and ICE. Model performance was compared with observation-based data and evaluated to assess allogenic (external) impacts on soil carbon dynamics in the circum-Arctic region on a glacial–interglacial timescale. Despite the limitation of forcing climate data being constructed on the basis of a single Greenland ice core dataset, the simulated results successfully reproduced temporal changes in northern SOC and ICE, consist with current knowledge. The simulation also captured regional differences in different geographical and climatic characteristics within the circum-Arctic region. The model quantitatively demonstrated allogenic controls on soil carbon evolution represented by a key parameter that reflects climatological and topo-geographical factors. The resulting circum-Arctic set of simulated time series can be compiled to produce snapshot maps of SOC and ICE distributions for past and present assessments or future projection simulations. Examples of 1∘ resolution maps for the Last Glacial Maximum and mid-Holocene periods were provided. Despite a simple modelling framework, SOC-ICE-v1.0 provided substantial information on the temporal evolution and spatial distribution of circum-Arctic SOC and ICE. Model improvements in terms of forcing climate data, improvement of SOC and ICE dynamics, and choice of initial values are, however, required for future research.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Blau syndrome is a systemic autoinflammatory granulomatous disease caused by mutations in the nucleotide-binding oligomerization domain 2 (NOD2) gene. NOD2 is an intracellular pathogen recognition receptor. Upon binding to muramyl dipeptide (MDP), NOD2 activates the NF-κB pathway, leading to the upregulation of proinflammatory cytokines. Clinical manifestations of Blau syndrome appear in patients before the age of four. Skin manifestations resolve spontaneously in some cases; however, joint and eye manifestations are progressive, and lead to serious complications, such as joint contracture and blindness. Currently, there is no specific curative treatment for the disease. Administration of high-dose oral steroids can improve clinical manifestations; however, treatments is difficult to maintain due to the severity of the side effects, especially in children. While several new therapies have been reported, including JAK inhibitors, anti-IL-6 and anti-IL-1 therapies, anti-TNF therapy plays a central role in the treatment of Blau syndrome. We recently performed an ex vivo study, using peripheral blood and induced pluripotent stem cells from patients. This study demonstrated that abnormal cytokine expression in macrophages from untreated patients requires IFNγ stimulation, and that anti-TNF treatment corrects the abnormalities associated with Blau syndrome, even in the presence of IFNγ. Therefore, although the molecular mechanisms by which the genetic mutations in NOD2 lead to granuloma formation remain unclear, it is possible that prior exposure to TNFα combined with IFNγ stimulation may provide the impetus for the clinical manifestations of Blau syndrome.

DiGeorge syndrome (22q11.2 deletion syndrome, or CATCH22 syndrome), caused by hemizygous deletion of chromosome 22q11.2, results in the poor development of multiple organs. Here we have generated DiGeorge syndrome-specific human induced pluripotsnt stem cells (hiPSCs) derived from four patients. These established hiPSC lines showed self-renewal and pluripotency and carried a hemizygous deletion in 22q11.2. Since the molecular pathogenesis of DiGeorge syndrome caused by the 22q11.2 deletion is largely unknown, these cell resources will be useful for recapitulating disease phenotypes and for developing new therapies for DiGeorge syndrome.

The concept of autoinflammation, first proposed in 1999, refers to a seemingly unprovoked episode of sterile inflammation manifesting as unexplained fever, skin rashes, and arthralgia. Autoinflammatory diseases are caused mainly by hereditary abnormalities of innate immunity, without the production of autoantibodies or autoreactive T cells. The revolutionary discovery of induced pluripotent stem cells (iPSCs), whereby a patient’s somatic cells can be reprogrammed into an embryonic pluripotent state by forced expression of a defined set of transcription factors, has the transformative potential to enable in vitro disease modeling and drug candidate screening, as well as to provide a resource for cell replacement therapy. Recent reports demonstrate that recapitulating a disease phenotype in vitro is feasible for numerous monogenic diseases, including autoinflammatory diseases. In this review, we provide a comprehensive overview of current advances in research into autoinflammatory diseases involving iPSC-derived monocytes/macrophages. This review may aid in the planning of new studies of autoinflammatory diseases.

This paper is a continuation of the authors' previous paper (Part 1) on the feasibility of ensemble flood forecasting for a small dam catchment (Kasahori dam; approx. 70 km2) in Niigata, Japan, using a distributed rainfall–runoff model and rainfall ensemble forecasts. The ensemble forecasts were given by an advanced four-dimensional, variational-ensemble assimilation system using the Japan Meteorological Agency nonhydrostatic model (4D-EnVar-NHM). A noteworthy feature of this system was the use of a very large number of ensemble members (1600), which yielded a significant improvement in the rainfall forecast compared to Part 1. The ensemble flood forecasting using the 1600 rainfalls succeeded in indicating the necessity of emergency flood operation with the occurrence probability and enough lead time (e.g., 12 h) with regard to an extreme event. A new method for dynamical selection of the best ensemble member based on the Bayesian reasoning with different evaluation periods is proposed. As the result, it is recognized that the selection based on Nash–Sutcliffe efficiency (NSE) does not provide an exact discharge forecast with several hours lead time, but it can provide some trend in the near future.

This study aim is to develop further an ion cyclotron range of frequencies (ICRF) method of plasma production in stellarators based on the minority heating. The previous studies demonstrate production of low density plasma (9.5 × 10 ^17 m ^−3 ) at low power of up to 0.2 MW. The higher ICRF heating power experiments become possible after introducing a programmable ICRF power ramp up at the front of the ICRF pulse. With this trick, all the shots went with the antenna voltage within the safe range. Increase of the ICRF power predictably results in increase of the density of produced plasma. Without pre-ionization the plasma density achieved was 6 × 10 ^18 m ^−3 which is 6 times higher than in previous experiments. However, the electron temperature was not high, the light impurities were hot fully stripped, and there were no recombination peaks after termination of the ICRF pulse. Plasma density is too low to provide good conditions for efficient plasma heating. For the reference, the ICRF heating of high density cold plasma prepared by electron cyclotron resonance heating is performed. Both electrons and ions were heated to high temperatures, and this plasma state is sustained. The antenna–plasma coupling was much better which result in larger heating power with the lower antenna voltage.

It is crucial to correctly predict the S -matrix with plasma and set the optimal impedance matching device in the ion cyclotron resonance heating (ICRH) antenna system design. In this paper, a hybrid circuit/3DLHDAP code to verify the S -matrix measurements in the presence of plasma and optimize the load-resilient conjugate-T circuit for Large Helical Device (LHD) ICRH antennas has been developed and benchmarked. The variation of S -matrices for handshake form (HAS) and field-aligned-impedance-transforming (FAIT) antenna systems with density, magnetic field and coupling distance during heating obtained by the code’s simulations agrees with that of with the LHD ICRH experiments. The mutual coupling of toroidally aligned HAS antennas is larger than that of poloidally aligned FAIT antennas over a wide range of densities. When the density and coupling distance increase, under a magnetic field on the magnetic axis of 2.75 T and 1.0 T, within a certain density change range, at the minimum voltage position with vacuum injection, the change rule of the antennas’ S _a_minV_ _11 and S _a_minV_ _22 with density is opposite to that with coupling distance, which means that under certain conditions, adjusting the coupling distance may make up for the S -parameters changes caused by plasma density variation, keeping the minimum voltage position fixed, and may make impedance matching easier to achieve during long-pulse operation. Based on obtaining the S parameters, conjugate-T circuits for the HAS and FAIT antennas are designed with the hybrid circuit/3DLHDAP code, which can keep the reflection coefficients low without controlling impedance matching device over a wide range of plasma parameters region. The related results in this paper may provide some guidance for the high-power long-pulse operation of the ICRH antenna system on the fusion device.

DNA repair by microhomology-mediated end joining creates precise deletions based on flanking microhomologies. Here the authors use CRISPR-Cas9 to recreate pathogenic deletion mutations using existing microhomologies in the human genome identified by their program MHcut.

Outer radial glial cells (oRGs) are undifferentiated cells that divide in the subventricular zone during neurodevelopment, but the underlying mechanisms are not fully understood. Here the authors show that Lzts1 positively controls both neuronal delamination and generation of oRG-like cell types.

Abstract Nakajo-Nishimura syndrome is a proteasome-associated autoinflammatory syndrome with a distinct homozygous mutation in the PSMB8 gene encoding an inducible β5i subunit of the immunoproteasome. Although it is considered that immunoproteasome dysfunction causes cellular stress and contributes to the production of inflammatory cytokines and chemokines, its detailed mechanism is still unknown. On the other hand, hereditary autoinflammatory diseases are considered as a good target for the analyses using induced pluripotent stem cells, whose differentiation systems to the innate immune cells such as neutrophils and monocytes have been established. Therefore, to elucidate the pathogenesis of Nakajo-Nishimura syndrome, we attempted in vitro disease modeling using patient-derived induced pluripotent stem cells. For analyses, isogenic control cells in which the responsible mutation was repaired and another pair of healthy embryonic stem cells and isogenic mutant cells in which the same mutation was introduced had also been prepared with genetic engineering. By comparing a pair of isogenic cells with the wild-type and the mutant PSMB8 gene after differentiation into monocytes and immortalization to synchronize their differentiation stages, the reduction of immunoproteasome enzyme activity and increased cytokine and chemokine production in the mutant cells without stimulation or with interferon-γ plus tumor necrosis factor-α stimulation were observed, and therefore, the autoinflammatory phenotype was successfully reproduced. Decreased cytokine production was observed by the addition of antioxidants as well as inhibitors for Janus kinase and p38-mitogen-activated protein kinase. At the same time, the increased production of reactive oxygen species and phosphorylation of both signal transducers and activator of transcription 1 and p38-mitogen-activated protein kinase were detected without stimulation. Notably, an antioxidant specifically decreased the constitutive phosphorylation of signal transducers and activator of transcription 1. These results indicate the usefulness of a disease modeling using pluripotent stem cell-derived cells in clarification of the pathomechanism and discovery of new therapeutic drugs for Nakajo-Nishimura syndrome and related proteasome-associated autoinflammatory syndromes.

Classification, segmentation, and recognition techniques based on deep-learning algorithms are used for smart farming. It is an important and challenging task to reduce the time, burden, and cost of annotation procedures for collected datasets from fields and crops that are changing in a wide variety of ways according to growing, weather patterns, and seasons. This study was conducted to generate crop image datasets for semantic segmentation based on an image style transfer using generative adversarial networks (GANs). To assess data-augmented performance and calculation burdens, our proposed framework comprises contrastive unpaired translation (CUT) for a conditional GAN, pix2pixHD for an unconditional GAN, and DeepLabV3+ for semantic segmentation. Using these networks, the proposed framework provides not only image generation for data augmentation, but also automatic labeling based on distinctive feature learning among domains. The Fréchet inception distance (FID) and mean intersection over union (mIoU) were used, respectively, as evaluation metrics for GANs and semantic segmentation. We used a public benchmark dataset and two original benchmark datasets to evaluate our framework of four image-augmentation types compared with the baseline without using GANs. The experimentally obtained results showed the efficacy of using augmented images, which we evaluated using FID and mIoU. The mIoU scores for the public benchmark dataset improved by 0.03 for the training subset, while remaining similar on the test subset. For the first original benchmark dataset, the mIoU scores improved by 0.01 for the test subset, while they dropped by 0.03 for the training subset. Finally, the mIoU scores for the second original benchmark dataset improved by 0.18 for the training subset and 0.03 for the test subset.

Adrenoleukodystrophy (ALD) is an X-linked genetic disorder, characterized by demyelination in the central nervous system and adrenal insufficiency. Human induced pluripotent stem cell (hiPSC) lines derived from two Japanese male patients with ALD were generated from skin fibroblasts using retroviral vectors. The generated hiPSC lines showed self-renewal and pluripotency, and carried either a missense or a nonsense mutation in ABCD1 gene. Since the molecular pathogenesis caused by ABCD1 dysfunction remains unclear, these cell resources provide useful tools to establish disease models and to develop new therapies for X-ALD.

[This corrects the article DOI: 10.1371/journal.pone.0237030.].

Children with Down syndrome (DS) are susceptible to two blood disorders, transient abnormal myelopoiesis (TAM) and Down syndrome-associated acute megakaryocytic leukemia (DS-AMKL). Mutations in GATA binding protein 1 (GATA1) have been identified as the cause of these diseases, and the expression levels of the resulting protein, short-form GATA1 (GATA1s), are known to correlate with the severity of TAM. On the other hand, despite the presence of GATA1 mutations in almost all cases of DS-AMKL, the incidence of DS-AMKL in TAM patients is inversely correlated with the expression of GATA1s. This discovery has required the need to clarify the role of GATA1s in generating the cells of origin linked to the risk of both diseases. Focusing on this point, we examined the characteristics of GATA1 mutant trisomy-21 pluripotent stem cells transfected with a doxycycline (Dox)-inducible GATA1s expression cassette in a stepwise hematopoietic differentiation protocol. We found that higher GATA1s expression significantly reduced commitment into the megakaryocytic lineage at the early hematopoietic progenitor cell (HPC) stage, but once committed, the effect was reversed in progenitor cells and acted to maintain the progenitors. These differentiation stage-dependent reversal effects were in contrast to the results of myeloid lineage, where GATA1s simply sustained and increased the number of immature myeloid cells. These results suggest that although GATA1 mutant cells cause the increase in myeloid and megakaryocytic progenitors regardless of the intensity of GATA1s expression, the pathways vary with the expression level. This study provides experimental support for the paradoxical clinical features of GATA1 mutations in the two diseases.