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Plant homeodomain finger protein 8 (PHF8) is a histone demethylase that regulates the expression of various genes. PHF8 targets repressor histone markers and activates gene expression. Although PHF8 has been involved in X-linked mental retardation and certain types of cancers, the role of PHF8 remains largely unknown, and its relevance to the pathogenesis of these diseases is also uncertain. In the present study, we aimed to clarify the cellular function of PHF8 in P19 cells using Phf8 knockout (KO) cells generated via the CRISPR-Cas9 system and by performing PHF8 specific inhibitor experiments, instead of using PHF8 small interfering RNA transfection. After establishing Phf8 KO cells, we analyzed the effects of PHF8 on neuronal differentiation and cell proliferation. Both PHF8 deficiency and inhibition of its activity did not considerably affect neuronal differentiation, however, they showed an increased trend of promoted neurite outgrowth. Moreover, we found that PHF8 regulated cell proliferation via the MEK/ERK pathway. PHF8 deficiency and activity inhibition reduced the phosphorylation of ERK and MEK. The MEK expression level was associated with PHF8 expression, as revealed by chromatin immunoprecipitation analysis. These results suggested that PHF8 regulates cell proliferation via the MEK/ERK pathway in P19 embryonic carcinoma cells.

Summary: Background: Observational studies show inverse associations between serum 25-hydroxyvitamin D concentrations and sarcopenia incidence; however, it remains unclear whether treatment with vitamin D prevents its development. We aimed to assess whether treatment with active vitamin D (eldecalcitol [0·75 μg per day]) can reduce the development of sarcopenia among adults with prediabetes. Methods: This randomised, double-blind, placebo-controlled, multicenter trial as an ancillary study was conducted at 32 clinics and hospital sites in Japan. Participants were assigned (1:1) by using a central randomisation method in which a randomisation list was made for each hospital separately using a stratified permuted block procedure. The primary endpoint was sarcopenia incidence during 3 years in the intention-to-treat population defined as weak handgrip strength (

Abstract Ocean bottom pressure-gauge (OBP) records play an essential role in seafloor geodesy. Oceanographic fluctuations in OBP data, however, pose as a significant noise source in seafloor transient crustal deformation observations, including slow slip events (SSEs), making it crucial to evaluate them quantitatively. To extract the significant fluctuation phenomena common to multiple observation networks, including oceanographic fluctuations and tectonic signals, we applied principal component analysis (PCA) to the 3-year Dense Oceanfloor Network System for Earthquakes and Tsunamis (DONET) OBP time series for 40 stations during 2016–2019. PCA could separate several oceanographic signals based on the characteristics of their spatial distributions, although evident transient tectonic signals could not be confirmed from the observed pressure records during this observed period. The spatial distribution of the first four principal components (PCs) reflected the common component, inclined component along sea depth, longitude component, and parabola-like pattern, respectively. By subtracting each PC (in particular, PC-2 and PC-4) from the time series, we could significantly reduce the sea depth dependence of OBP records, which has been highlighted in several previous studies and is also evident in this region. We interpreted PCs 2–4 as the reflection of the strength and meandering of ocean geostrophic currents based on a comparison with the PC spatial distribution of the numerical oceanographic models. In addition, to evaluate the ability of PCA to separate transient tectonic signal from OBP time series, including oceanographic fluctuations, we conducted a synthetic ramp assuming an SSE by rectangular fault and then applied PCA. The assumed synthetic tectonic signal could be separated from the oceanographic signals and included in the principal component independently depending on its amplitude, suggesting that the spatial distribution of each PC would change if the amplitude of the synthetic signal were sufficiently large. We propose a transient event-detection method based on the spatial distribution difference of a specific PC with or without a tectonic signal. We used the normalized inner product (NIP) between these PCs as the indicator of their similarities. This method can detect transient tectonic signals more significantly than the moment-magnitude scale of 5.9 from OBP records. Graphical Abstract

Abstract We investigated temperature records associated with seafloor pressure observations at eight stations that experienced the 2011 M w 9 Tohoku earthquake near its epicenter. The temperature data were based on the temperature measured inside the pressure transducer. We proposed a method to estimate ambient water temperature from the internal temperature using an equation of heat conduction. The estimated seafloor water temperature showed remarkable anomalies, especially increases several hours after the M w 9 earthquake. A station of P03 (sea depth of 1.1 km) showed an abrupt temperature increase of + 0.19 °C that occurred ~ 3 h after the earthquake, which lasted for several hours. At stations of GJT3 (sea depth of 3.3 km) and TJT1 (sea depth of 5.8 km), there were abrupt temperature anomalies of + 0.20 °C and + 0.10 °C that began to occur 3–4 h after the earthquake. These anomalies both decayed to their original levels over a few tens of days. During the decay processes, only TJT1 showed several intermittent temperature rises. A water temperature anomaly within + 0.03 °C was found up to ~ 500 m above TJT1 2 weeks after the earthquake. There was no significant anomaly at the other five stations. Processes to cause these seafloor temperature anomalies were discussed. The temperature anomaly of P03 was reasonably caused by a tsunami-generated turbidity current, as also suggested by a previous study. Meanwhile, we proposed a scenario that the abrupt temperature anomalies of GJT3/TJT1 and the intermittent anomalies of TJT1 were caused by warm water discharges from the subseafloor. The pathways of the warm water were probably composed of the branch normal fault between GJT3 and TJT1, the reverse fault near TJT1, the backstop interface, and perhaps reverse faults at the frontal prism. The proposed scenario was almost compatible with other studies based on epicentral observations. We estimated the heat properties of the initial temperature anomalies of GJT3/TJT1. The estimated heat source might be explained by that most of the geothermal fluids trapped in those fault pathways were discharged to the seafloor immediately after the earthquake. The onsets of the subsequent intermittent anomalies of TJT1 were possibly activated by low or falling ocean tidal loading.

The dynamic assembly and disassembly of atoms and molecules is challenging to characterize in real time, with atomic resolution and elemental identification. Here, the authors report direct observation of more than twenty homo and hetero-metallic compounds, including labile Ag-Cu dimers and Au-Ag-Cu trimers.

Abstract The concentrations of polycyclic aromatic hydrocarbons (PAHs) in aerosol were measured in Shinjuku, which is central Tokyo, Japan, for 10 years from 2007 to 2016. The effects of changes in emission sources and their degradation by reaction with ozone were assessed in this study. There was no significant increasing or decreasing trend of the PAH concentrations during 10 years (P > 0.05). The average selected seven the PAH concentrations (0.88 ng m−3) during 10 years was lower than those in New York and Paris. However, the trend of ozone concentrations is increasing in central Tokyo. This inconsistency raises a question. Did the fact that the ozone concentration was higher than the PAH concentrations promote PAH degradation? To apportion the PAH sources, we used PAH concentration profiles and positive matrix factorization analysis. The contribution of vehicle emissions to the PAHs ranged from 40 to 80%. Ozone concentrations increased by 3.70%/year during 10 years. The theoretical degradation rates of PAHs by ozone, which were calculated using a pseudo-first-order rate equation, suggested that the lifetimes of benzo[a]pyrene (BaP) decreased by 1 min from 2007 to 2016. We investigated the aging of BaP using the profile of the isomer ratios. We found that the aging of BaP at the urban and roadside sites were nearly identical indicating aging regardless of the season. Although the decomposition of BaP is promoted by the photochemical oxidation reaction, this result suggests that a certain threshold value exists as the degree of the decomposition. This degradation of PAH can improve chemical loss processes in air quality model.

RationaleTherapies that inhibit CETP (cholesteryl ester transfer protein) have failed to demonstrate a reduction in risk for coronary heart disease (CHD). Human DNA sequence variants that truncate the CETP gene may provide insight into the efficacy of CETP inhibition.ObjectiveTo test whether protein-truncating variants (PTVs) at the CETP gene were associated with plasma lipid levels and CHD.Methods and resultsWe sequenced the exons of the CETP gene in 58 469 participants from 12 case-control studies (18 817 CHD cases, 39 652 CHD-free controls). We defined PTV as those that lead to a premature stop, disrupt canonical splice sites, or lead to insertions/deletions that shift frame. We also genotyped 1 Japanese-specific PTV in 27561 participants from 3 case-control studies (14 286 CHD cases, 13 275 CHD-free controls). We tested association of CETP PTV carrier status with both plasma lipids and CHD. Among 58 469 participants with CETP gene-sequencing data available, average age was 51.5 years and 43% were women; 1 in 975 participants carried a PTV at the CETP gene. Compared with noncarriers, carriers of PTV at CETP had higher high-density lipoprotein cholesterol (effect size, 22.6 mg/dL; 95% confidence interval, 18-27; P

Miniaturization of electrochemical components has become less common in the last decade, with the focus predominantly being the design and development of state-of-the-art microelectrodes for achieving small volume analysis of samples. However, such microelectrodes involve cumbersome processing procedures to convert the base material for the required application. A potential paradigm shift in such miniaturization could be achieved by using cheaper alternatives such as plastics to build electrochemical components, such as micropipette tips made of polypropylene, which are commercially available at ease. Hence, this work presents the design of an electrochemical working electrode based upon a micropipette tip, involving minimal processing procedures. Furthermore, such a working electrode was realized by sputtering silver onto a bare micropipette tip using a radio-frequency sputtering technique, to obtain electrical contacts on the tip, followed by hydrothermal growth of ZnO, which acted as the active electrode material. The ZnO nanostructures grown on the micropipette tip were characterized for their morphology and surface properties using a scanning electron microscope (SEM), laser microscope, Raman spectrometer, and X-ray photoelectron spectrometer (XPS). The developed micropipette tip-based electrode was then used as the working electrode in a three-electrode system, wherein its electrochemical stability and properties were analyzed using cyclic voltammetry (CV). Furthermore, the above system was used to detect glucose concentrations of 10–200 µM, to evaluate its sensing properties using amperometry. The developed working electrode exhibited a sensitivity of 69.02 µA/µM cm−2 and limit of detection of 67.5 µM, indicating the potential for using such modified micropipette tips as low-cost miniaturized sensors to detect various bio-analytes in sample solutions.

Alzheimer’s disease (AD) is thought to be a series of neuroinflammatory diseases caused by abnormal deposits of amyloid-β (Aβ) and tau protein in the brain as part of its etiology. We focused on Aβ aggregation and M1 and M2 microglial polarity in microglia to search for novel therapeutic agents. It has been reported that the inhibition of choline uptake via choline transporter-like protein 1 (CTL1) in microglia preferentially induces M2 microglial polarity. However, the role of the choline transport system on the regulation of microglial M1/M2 polarity in AD is not fully understood. Licochalcones (Licos) A–E, flavonoids extracted from licorice, have been reported to have immunological anti-inflammatory effects, and Lico A inhibits Aβ aggregation. In this study, we compared the efficacy of five Licos, from Lico A to E, at inhibiting Aβ1-42 aggregation. Among the five Licos, Lico E was selected to investigate the relationship between the inhibition of choline uptake and microglial M1/M2 polarization using the immortalized mouse microglial cell line SIM-A9. We newly found that Lico E inhibited choline uptake and Aβ1-42 aggregation in SIM-A9 cells in a concentration-dependent manner, suggesting that the inhibitory effect of Lico E on choline uptake is mediated by CTL1. The mRNA expression of tumor necrosis factor (TNF-α), a marker of M1 microglia, was increased by Aβ1-42, and its effect was inhibited by choline deprivation and Lico E in a concentration-dependent manner. In contrast, the mRNA expression of arginase-1 (Arg-1), a marker of M2 microglia, was increased by IL-4, and its effect was enhanced by choline deprivation and Lico E. We found that Lico E has an inhibitory effect on Aβ aggregation and promotes polarity from M1 to M2 microglia via inhibition of the CTL1 function in microglia. Thus, Lico E may become a leading compound for a novel treatment of AD.

Background. Diabetic retinopathy (DR) is a diabetic microvascular complication and a leading cause of vision loss. However, there is a lack of effective strategies to reduce the risk of DR currently. The present study is aimed at assessing the causal effect of lipid‐regulating targets on DR risk using a two‐sample Mendelian randomization (MR) study. Method. Genetic variants within or near drug target genes, including eight lipid‐regulating targets for LDL‐C (HMGCR, PCSK9, and NPC1L1), HDL‐C (CETP, SCARB1, and PPARG), and TG (PPARA and LPL), were selected as exposures. The exposure data were obtained from the IEU OpenGWAS project. The outcome dataset related to DR was obtained from the FinnGen research project. Inverse‐variance‐weighted MR (IVW‐MR) was used to calculate the effect estimates by each target. Sensitivity analyses were performed to verify the robustness of the results. Results. There was suggestive evidence that PCSK9‐mediated LDL‐C levels were positively associated with DR, with OR (95% CI) of 1.34 (1.02‐1.77). No significant association was found between the expression of HMGCR‐ and NPC1L1‐mediated LDL‐C levels; CETP‐, SCARB1‐, and PPARG‐mediated HDL‐C levels; PPARA‐ and LPL‐mediated TG levels; and DR risk. Conclusions. This is the first study to reveal a genetically causal relationship between lipid‐regulating drug targets and DR risk. PCSK9‐mediated LDL‐C levels maybe positively associated with DR risk at the genetic level. This study provides suggestive evidence that PCSK9 inhibition may reduce the risk of DR. [ABSTRACT FROM AUTHOR]

The highly phosphorylated nucleotide, guanosine tetraphosphate (ppGpp), functions as a secondary messenger in bacteria and chloroplasts. The accumulation of ppGpp alters plastidial gene expression and metabolism, which are required for proper photosynthetic regulation and robust plant growth. However, because four plastid-localized ppGpp synthases/hydrolases function redundantly, the impact of the loss of ppGpp-dependent stringent response on plant physiology remains unclear. We used CRISPR/Cas9 technology to generate an Arabidopsis thaliana mutant lacking all four ppGpp synthases/hydrolases and characterized its phenotype. The mutant showed over 20-fold less ppGpp levels than the wild type under normal growth conditions and exhibited leaf chlorosis and increased expression of defense-related genes as well as salicylic acid and jasmonate levels upon transition to nitrogen-starvation conditions. These results demonstrate that proper levels of ppGpp in plastids are required for controlling not only plastid metabolism but also phytohormone signaling, which is essential for plant defense. [ABSTRACT FROM AUTHOR]

To support teachers in enhancing ocean literacy, the Center for Microbial Oceanography: Research and Education (C-MORE) has developed a series of portable, hands-on science kits on selected topics in oceanography. This paper provides an overview of kit content, describes how the kits were developed, and evaluates their efficacy as a curriculum supplement in formal classroom environments by using two studies, a qualitative assessment of teacher experience and a quantitative assessment of student learning. The teacher surveys (n = 45) indicate the kits were used in a wide range of class types and grade levels, describe the kits as useful classroom tools that actively engaged students and resulted in meaningful learning, and strongly indicate that the teachers plan to continue to use the kits in the future. The student learning assessment (n = 1,236) employed a pretest, posttest 1, and posttest 2 methodology. The pretest and posttest 1 were given immediately before and after instruction, respectively; posttest 2 was given at least 2 weeks after instruction. Engaging with the science kits resulted in significant knowledge acquisition (pretest-posttest 1 mean differences of 0.21-0.41) and retention (pretest-posttest 2 mean differences of 0.18 to 0.39), with significance defined at the a = 0.05 level. In the 2 weeks after kit instruction, all kits showed a slight, nonsignificant loss in knowledge (mean differences of -0.01 to -0.04). Together, the teacher and student evaluations indicate that the C-MORE kits are effective classroom tools that can serve as a model for hands-on curriculum supplements.

Abstract We have explored tsunami current signals in maritime Automatic Identification System (AIS) data during the 2011 Tohoku, Japan, tsunami. The AIS data were investigated in detail taking into account ship motion and response to tsunami current. Ship velocity derived from AIS data was divided into two components in terms of the ship heading: heading-normal and heading-parallel directions. The heading-normal velocity showed good agreement with the simulated tsunami current, as mentioned in our former research. Here, we found the heading-normal velocity was contaminated by non-tsunami noises that were mostly related to the ship yaw motion around the pivot point. The noises due to the yaw motion were reasonably corrected in the heading-normal velocity. The corrected heading-normal velocity clearly showed better agreement with the simulated tsunami current. Although the heading-parallel velocity is basically the navigation speed, and is mostly controlled by ships’ captain, we could find the heading-parallel velocity was also drifted by tsunami currents. The corrected heading-normal velocity was still a ship response to the tsunami current. Based on an equation of a ship response to tsunami currents, we numerically estimated tsunami current from the corrected heading-normal velocity. We could find very slight improvements in estimating the tsunami currents, which indicated that this operation possibly worked as a secondary correction. Tsunami currents of tens of centimeters per second are expected to be suitably detected using AIS based on discussion on detection limit.

Abstract On December 7, 2012, an earthquake occurred within the Pacific Plate near the Japan Trench, which was composed of deep reverse- and shallow normal-faulting subevents (Mw 7.2 and 7.1, respectively) with a time interval of ~10 s. It had been known that the stress state within the plate was characterized by shallow tensile and deep horizontal compressional stresses due to the bending of the plate (bending stress). This study estimates the fault model of the doublet earthquake utilizing tsunami, teleseismic, and aftershock data and discusses the stress state within the incoming plate and spatiotemporal changes seen in it after the 2011 Tohoku-Oki earthquake. We obtained the vertical extents of the fault planes of deep and shallow subevents as ~45–70 km and ~5 (the seafloor)–35 km, respectively. The down-dip edge of the shallow normal-faulting seismic zone (~30–35 km) deepened significantly compared to what it was in 2007 (~25 km). However, a quantitative comparison of the brittle strength and bending stress suggested that the change in stress after the Tohoku-Oki earthquake was too small to deepen the down-dip end of the seismicity by ~10 km. To explain the seismicity that occurred at a depth of ~30–35 km, the frictional coefficient in the normal-faulting depth range required would have had to be ~0.07 ≤ μ ≤ ~0.2, which is significantly smaller than the typical friction coefficient. This suggests the infiltration of pore fluid along the bending faults, down to ~30–35 km. It is considered that the plate had already yielded to a depth of ~35 km before 2011 and that the seismicity of the area was reactivated by the increase in stress from the Tohoku-Oki earthquake.

Abstract There has been a long-standing need for guidelines on the diagnosis and treatment of keloids and hypertrophic scars that are based on an understanding of the pathomechanisms that underlie these skin fibrotic diseases. This is particularly true for clinicians who deal with Asian and African patients because these ethnicities are highly prone to these diseases. By contrast, Caucasians are less likely to develop keloids and hypertrophic scars, and if they do, the scars tend not to be severe. This ethnic disparity also means that countries vary in terms of their differential diagnostic algorithms. The lack of clear treatment guidelines also means that primary care physicians are currently applying a hotchpotch of treatments, with uneven outcomes. To overcome these issues, the Japan Scar Workshop (JSW) has created a tool that allows clinicians to objectively diagnose and distinguish between keloids, hypertrophic scars, and mature scars. This tool is called the JSW Scar Scale (JSS) and it involves scoring the risk factors of the individual patients and the affected areas. The tool is simple and easy to use. As a result, even physicians who are not accustomed to keloids and hypertrophic scars can easily diagnose them and judge their severity. The JSW has also established a committee that, in cooperation with outside experts in various fields, has prepared a Consensus Document on keloid and hypertrophic scar treatment guidelines. These guidelines are simple and will allow even inexperienced clinicians to choose the most appropriate treatment strategy. The Consensus Document is provided in this article. It describes (1) the diagnostic algorithm for pathological scars and how to differentiate them from clinically similar benign and malignant tumors, (2) the general treatment algorithms for keloids and hypertrophic scars at different medical facilities, (3) the rationale behind each treatment for keloids and hypertrophic scars, and (4) the body site-specific treatment protocols for these scars. We believe that this Consensus Document will be helpful for physicians from all over the world who treat keloids and hypertrophic scars.

Cyclin-dependent kinase-like 5 (CDKL5) is a serine/threonine protein kinase whose pathological mutations cause CDKL5 deficiency disorder. Most missense mutations are concentrated in the catalytic domain. Therefore, anticipating whether mutations in this region affect CDKL5 function is informative for clinical diagnosis. This study comprehensively predicted the pathogenicity of all 5700 missense substitutions in the catalytic domain of CDKL5 using in silico analysis and evaluating their accuracy. Each missense substitution was evaluated as “pathogenic” or “benign”. In silico tools PolyPhen-2 HumDiv mode/HumVar mode, PROVEAN, and SIFT were selected individually or in combination with one another to determine their performance using 36 previously reported mutations as a reference. Substitutions predicted as pathogenic were over 88.0% accurate using each of the three tools. The best performance score (accuracy, 97.2%; sensitivity, 100%; specificity, 66.7%; and Matthew’s correlation coefficient (MCC), 0.804) was achieved by combining PolyPhen-2 HumDiv, PolyPhen-2 HumVar, and PROVEAN. This provided comprehensive information that could accurately predict the pathogenicity of the disease, which might be used as an aid for clinical diagnosis.

In this engaging interview, John D. Inazu identifies confident pluralism as the way for us to thrive in connection even when divided by deep differences. Since our differences are not just going to go away, we need to learn to live with others with whom we do not agree. Inazu explains that tolerance, humility, and patience are the foundational principles to do this. They provide the tools to respect others as people without accepting their viewpoints, to accept that we may not be able to convince people of the correctness of our viewpoint, and to allow room for ourselves and others to make mistakes and still keep the conversation going.

Background: Microglia are key cells of the immune system in the central nervous system and are suggested to be deeply involved in the development of neurodegenerative diseases. It is well known that microglia have functional plasticity, with an inflammatory M1 phenotype and an anti-inflammatory M2 phenotype. Inhibition of choline transport in macrophages has been reported to suppress the secretion of inflammatory cytokines. However, the role of the choline transport system in regulating microglial M1/M2 polarization has not been fully elucidated to date. In this study, we investigated the mechanism of choline uptake in microglia, and its association with microglial M1/M2 polarization. Methods: The immortalized mouse microglial cell line SIM-A9 was used for [3H]choline uptake and expression analysis of choline transporters. The association between the choline uptake system and the M1/M2 polarization of microglia was also analyzed. Results: Choline transporter-like protein (CTL) 1 and CTL2 were highly expressed in SIM-A9 cells, and CTL1 and CTL2 were localized in the plasma membrane and mitochondria, respectively. Functional analysis of choline uptake demonstrated the existence of Na+-independent, pH-dependent, and intermediate-affinity choline transport systems. Choline uptake was concentration-dependently inhibited by hemicholinium-3 (HC-3), an inhibitor of choline uptake, and increased by lipopolysaccharide (LPS) and interleukin-4 (IL-4). Expression of the mRNA of M1 microglia markers IL-1β and IL-6 was increased by LPS, and their effects were suppressed by choline deprivation and HC-3. In contrast, mRNA expression of the M2 microglial marker arginase-1 (Arg-1) was increased by IL-4, and the effect was enhanced by choline deprivation and HC-3. Conclusions: Our results suggest that inhibition of CTL1-mediated choline uptake in microglia preferentially induces M2 microglia polarization, which is a potential therapeutic approach for inflammatory brain diseases.

Three tsukudani seasoning liquid models of soy sauce and amino acid seasoning liquid mixed with rare sugar syrup (RSS, main rare sugars: D-allulose, D-sorbose, D-tagatose, D-allose), glucose-fructose liquid sugar (GF), and white sugar (WS) were heated in a headspace sampler to create a delicious aroma. The aroma components generated were then analyzed using HS-GC/MS. As a result of the Maillard reaction, brown color intensity measured at absorbance 420 nm in the RSS liquid was significantly higher than in the GF and WS liquids. Principal component analysis of the quantitative data of the aroma compounds revealed 1.1-4.5 times more furans such as furfural, furfuryl alcohol, 2,5-diethyl tetrahydrofuran, and 3-phenylfuran were released from RSS than from GF and WS, which contributed to the characteristic aroma components of the tsukudani seasoning liquid. These results suggest that the four main rare sugars in the RSS are involved in the aroma formation. [ABSTRACT FROM AUTHOR]