Nrf2 (NF-E2-related factor-2) transcription factor regulates oxidative/xenobiotic stress response and also represses inflammation. However, the mechanisms how Nrf2 alleviates inflammation are still ...unclear. Here, we demonstrate that Nrf2 interferes with lipopolysaccharide-induced transcriptional upregulation of proinflammatory cytokines, including IL-6 and IL-1β. Chromatin immunoprecipitation (ChIP)-seq and ChIP-qPCR analyses revealed that Nrf2 binds to the proximity of these genes in macrophages and inhibits RNA Pol II recruitment. Further, we found that Nrf2-mediated inhibition is independent of the Nrf2-binding motif and reactive oxygen species level. Murine inflammatory models further demonstrated that Nrf2 interferes with IL6 induction and inflammatory phenotypes in vivo. Thus, contrary to the widely accepted view that Nrf2 suppresses inflammation through redox control, we demonstrate here that Nrf2 opposes transcriptional upregulation of proinflammatory cytokine genes. This study identifies Nrf2 as the upstream regulator of cytokine production and establishes a molecular basis for an Nrf2-mediated anti-inflammation approach.
Atopic dermatitis is increasing worldwide in correlation with air pollution. Various organic components of pollutants activate the transcription factor AhR (aryl hydrocarbon receptor). Through the ...use of AhR-CA mice, whose keratinocytes express constitutively active AhR and that develop atopic-dermatitis-like phenotypes, we identified Artn as a keratinocyte-specific AhR target gene whose product (the neurotrophic factor artemin) was responsible for epidermal hyper-innervation that led to hypersensitivity to pruritus. The activation of AhR via air pollutants induced expression of artemin, alloknesis, epidermal hyper-innervation and inflammation. AhR activation and ARTN expression were positively correlated in the epidermis of patients with atopic dermatitis. Thus, AhR in keratinocytes senses environmental stimuli and elicits an atopic-dermatitis pathology. We propose a mechanism of air-pollution-induced atopic dermatitis via activation of AhR.
The first cell fate commitment during mammalian development is the specification of the inner cell mass and trophectoderm. This irreversible cell fate commitment should be epigenetically regulated, ...but the precise mechanism is largely unknown in humans. Here, we show that naïve human embryonic stem (hES) cells can transdifferentiate into trophoblast stem (hTS) cells, but primed hES cells cannot. Our transcriptome and methylome analyses reveal that a primate-specific miRNA cluster on chromosome 19 (C19MC) is active in naïve hES cells but epigenetically silenced in primed ones. Moreover, genome and epigenome editing using CRISPR/Cas systems demonstrate that C19MC is essential for hTS cell maintenance and C19MC-reactivated primed hES cells can give rise to hTS cells. Thus, we reveal that C19MC activation confers differentiation potential into trophoblast lineages on hES cells. Our findings are fundamental to understanding the epigenetic regulation of human early development and pluripotency.
Human placental villi have essential roles in producing hormones, mediating nutrient and waste exchange, and protecting the fetus from exposure to xenobiotics. Human trophoblast organoids that ...recapitulate the structure of villi could provide an important in vitro tool to understand placental development and the transplacental passage of xenobiotics. However, such organoids do not currently exist. Here we describe the generation of trophoblast organoids using human trophoblast stem (TS) cells. Following treatment with three kinds of culture medium, TS cells form spherical organoids with a single outer layer of syncytiotrophoblast (ST) cells that display a barrier function. Furthermore, we develop a column-type ST barrier model based on the culture condition of the trophoblast organoids. The bottom membrane of the column is almost entirely covered with syndecan 1-positive ST cells. The barrier integrity and maturation levels of the model are confirmed by measuring transepithelial/transendothelial electrical resistance (TEER) and the amount of human chorionic gonadotropin. Further analysis reveals that the model can be used to derive the apparent permeability coefficients of model compounds. In addition to providing a suite of tools for the study of placental development, our trophoblast models allow the evaluation of compound transfer and toxicity, which will facilitate drug development.
ABSTRACT
Planetesimal accretion is a key source for heavy-element enrichment in giant planets. It has been suggested that Jupiter’s enriched envelope is a result of planetesimal accretion during its ...growth, assuming it formed in a massive planetesimal disc. In this study, we simulate Jupiter’s formation in this scenario. We assume in situ formation and perform N-body simulations to infer the solid accretion rate. We find that tens-Earth masses of planetesimals can be captured by proto-Jupiter during the rapid gas accretion phase. However, if several embryos are formed near Jupiter’s core, which is an expected outcome in the case of a massive planetesimal disc, scattering from the embryos increases the eccentricity and inclination of planetesimals and therefore significantly reduces the accretion efficiency. We also compare our results with published semi-analytical models and show that these models cannot reproduce the N-body simulations especially when the planetesimal disc has a large eccentricity and inclination. We show that when the dynamical evolution of planetesimals is carefully modelled, the total mass of captured planetesimals Mcap,tot is 2M⊕ ≲ Mcap,tot ≲ 18M⊕. The metallicity of Jupiter’s envelope can be explained by the planetesimal accretion in our massive disc model despite the low accretion efficiency coming from the high eccentricity and inclination of planetesimals. Our study demonstrates the importance of detailed modelling of planetesimal accretion during the planetary growth and its implications to the heavy-element mass in gaseous planets.
Transgenic mice expressing a constitutively active form of the aryl hydrocarbon receptor in keratinocytes (AhR-CA mice) develop severe dermatitis that substantially recapitulates the pathology of ...human atopic dermatitis. The neurotrophic factor artemin (Artn) is highly expressed in the epidermis of AhR-CA mice and causes hypersensitivity to itch (alloknesis) by elongating nerves into the epidermis. However, whether the Artn gene is regulated directly by AhR or indirectly through complex regulation associated with AhR remains unclear. To this end, we previously conducted chromatin immunoprecipitation-sequencing analyses of the Artn locus and found a xenobiotic response element (XRE) motif located far upstream (52 kb) of the gene. Therefore, in this study, we addressed whether the XRE actually regulates the Artn gene expression by deleting the region containing the motif. We generated two lines of Artn
ΔXRE
mice. In the mouse epidermis, inducible expression of the Artn gene by the AhR agonist 3-methylcholanthrene was substantially suppressed compared to that in wild-type mice. Importantly, in AhR-CA::Artn
ΔXRE
mice, Artn expression was significantly suppressed, and alloknesis was improved. These results demonstrate that the Artn gene is indeed regulated by the distal XRE-containing enhancer, and alloknesis in AhR-CA mice is provoked by the AhR-mediated direct induction of the Artn gene.
Recently, neural network (NN) nonlinear equalizers which are expected to reduce computational complexity have attracted attention as fiber nonlinear compensation methods for coherent optical ...transmission systems. However, these fiber nonlinear compensation methods have problems that training of NN is not easy for long-distance transmission systems because of accumulated phase noise. In this letter, we propose a training method of NN nonlinear equalizer using the target outputs including phase noise which is produced by received signals. The phase noise is estimated by the inverse modulation of received signals and filtering. The estimated phase noise is added to transmitter signals, and the target outputs are obtained. The target outputs allow training of NN in long-distance coherent optical transmission systems. Since the NN trained by this proposed method compensates only for fiber nonlinearities, the phase locked loop (PLL) is placed after the NN to compensate for phase noise. The performances are evaluated by the simulation of 32 Gbaud 16QAM 4000 km long-distance coherent optical transmission. These results indicate that the proposed training method is effective in training NN nonlinear equalizer in long-distance coherent optical transmission in the presence of phase noise.
Between 2003 and 2007, 99 knees in 77 patients underwent opening wedge high tibial osteotomy. We evaluated the effect of initial stable fixation combined with an artificial bone substitute on the ...mid- to long-term outcome after medial opening-wedge high tibial osteotomy (HTO) for medial compartmental osteoarthritis or spontaneous osteonecrosis of the knee in 78 knees in 64 patients available for review at a minimum of five years (mean age 68 years; 49 to 82). The mean follow-up was 6.5 years (5 to 10). The mean Knee Society knee score and function score improved from 49.6 (SD 11.4, 26 to 72) and 56.6 (SD 15.6, 5 to 100) before surgery to 88.1 (SD 12.5, 14 to 100) and 89.4 (SD 15.6, 5 to 100) at final follow-up (p < 0.001) respectively. There were no significant differences between patients aged ≥ 70 and < 70 years. The mean standing femorotibial angle was corrected significantly from 181.7° (SD 2.7°, 175° to 185°) pre-operatively to 169.7° (SD 2.4°, 164° to 175°) at one year's follow-up (p < 0.001) and 169.6° (SD 3.0°, 157° to 179°) at the final follow-up (p = 0.69 vs one year). Opening-wedge HTO using a stable plate fixation system combined with a bone substitute is a reliable procedure that provides excellent results. Although this treatment might seem challenging for older patients, our results strongly suggest that the results are equally good.
Context.
Heavily obscured active galactic nuclei (AGNs) are known to show deep silicate absorption features in the mid-infrared (mid-IR) wavelength range of 10–20 μm. The detailed profiles of the ...features reflect the properties of silicate dust, which are likely to include information on AGN activities obscured by large amounts of dust.
Aims.
We reveal AGN activities obscured by large amounts of dust through the silicate dust properties obtained from the mid-IR spectral bands.
Methods.
We selected 115 mid-IR spectra of heavily obscured AGNs observed by
Spitzer
/IRS and systematically analyzed the composition of silicate dust by spectral fitting using the 10 μm amorphous and 23 μm crystalline bands.
Results.
We find that the main component of the silicate dust obscuring AGNs is amorphous olivine, the median mass column density of which is one order of magnitude higher than those of the minor components of amorphous pyroxene and crystalline forsterite. The median mass fraction of the amorphous pyroxene, ∼2%, is significantly lower than that of the diffuse interstellar medium (ISM) dust in our Galaxy, while the median mass fraction of the crystalline forsterite, ∼6%, is higher than that of the diffuse ISM dust. We also find that the mass fractions of the amorphous pyroxene and the crystalline forsterite positively correlate with each other.
Conclusions.
The low mass fraction of the amorphous pyroxene suggests that the obscuring silicate dust is newly formed, originating from starburst activities. The relatively high mass fraction of crystalline forsterite implies that the silicate dust is processed in the high temperature environment close to the nucleus and transported to outer cooler regions by molecular outflows. The positive correlation between the mass fractions can be naturally explained considering that amorphous pyroxene is transformed from crystalline forsterite by ion bombardments. We also find that spectra with high ratios of the H
2
O ice absorption to silicate mass column density tend to indicate low mass fractions of amorphous pyroxene and crystalline forsterite, which is consistent with the scenario of the thermal dust processing close to the nucleus.
Abstract Liquid hydrogen (LH2) is a potential coolant of high-temperature superconducting (HTS) devices. However, owing to the high flammability of hydrogen and the risk of hydrogen embrittlement in ...materials, studies on LH2-cooled superconducting devices are rare. We developed an LH2 test apparatus to analyze the basic characteristics of LH2 as a coolant and evaluate the energizing characteristics of LH2-cooled superconducting wires. A REBCO external field coil was designed and manufactured for conducting cooling stability tests on various HTS coils cooled by LH2. The field coil, comprising eight single pancake coils of 4 mm wide REBCO wires, with inner diameter 106 mm and outer diameter 250 mm was divided into upper and lower sections. The test coil was placed in the central space. A magnetic field perpendicular to the test coil’s wire surface was generated by running currents in opposite directions through the upper and lower sections. Each double pancake coil was securely placed in a stainless-steel housing to withstand repulsive electromagnetic forces. The manufactured field coil was cooled using LH2, energized to 150 A, and successfully generated the intended magnetic field of 1.75 T. No increase in voltage was observed in any of the double pancake coils, and there was no mechanical degradation due to electromagnetic forces. Subsequently, we initiated thermal runaway tests on various HTS coils using the manufactured field coil to assess the cooling stability of LH2-cooled HTS coils. The study will facilitate the development of explosion-proof designs and safety technologies for LH2-cooled superconducting devices and cooling systems.
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