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Volatile and organic-rich C-type asteroids may have been one of the main sources of Earth’s water. Our best insight into their chemistry is currently provided by carbonaceous chondritic meteorites, but the meteorite record is biased: only the strongest types survive atmospheric entry and are then modified by interaction with the terrestrial environment. Here we present the results of a detailed bulk and microanalytical study of pristine Ryugu particles, brought to Earth by the Hayabusa2 spacecraft. Ryugu particles display a close compositional match with the chemically unfractionated, but aqueously altered, CI (Ivuna-type) chondrites, which are widely used as a proxy for the bulk Solar System composition. The sample shows an intricate spatial relationship between aliphatic-rich organics and phyllosilicates and indicates maximum temperatures of ~30 °C during aqueous alteration. We find that heavy hydrogen and nitrogen abundances are consistent with an outer Solar System origin. Ryugu particles are the most uncontaminated and unfractionated extraterrestrial materials studied so far, and provide the best available match to the bulk Solar System composition.

Presented here are the observations and interpretations from a comprehensive analysis of 16 representative particles returned from the C-type asteroid Ryugu by the Hayabusa2 mission. On average Ryugu particles consist of 50% phyllosilicate matrix, 41% porosity and 9% minor phases, including organic matter. The abundances of 70 elements from the particles are in close agreement with those of CI chondrites. Bulk Ryugu particles show higher δ18O, Δ17O, and ε54Cr values than CI chondrites. As such, Ryugu sampled the most primitive and least-thermally processed protosolar nebula reservoirs. Such a finding is consistent with multi-scale H-C-N isotopic compositions that are compatible with an origin for Ryugu organic matter within both the protosolar nebula and the interstellar medium. The analytical data obtained here, suggests that complex soluble organic matter formed during aqueous alteration on the Ryugu progenitor planetesimal (several 10’s of km)

Background: Cardiac-specific myosin light chain kinase (cMLCK), encoded by MYLK3 , regulates cardiac contractility through phosphorylation of ventricular myosin regulatory light chain. However, the pathophysiological and therapeutic implications of cMLCK in human heart failure remain unclear. We aimed to investigate whether cMLCK dysregulation causes cardiac dysfunction and whether the restoration of cMLCK could be a novel myotropic therapy for systolic heart failure. Methods: We generated the knock-in mice ( Mylk3 +/fs and Mylk 3 fs/fs ) with a familial dilated cardiomyopathy–associated MYLK3 frameshift mutation ( MYLK3 +/fs ) that had been identified previously by us (c.1951-1G>T; p.P639Vfs*15) and the human induced pluripotent stem cell–derived cardiomyocytes from the carrier of the mutation. We also developed a new small-molecule activator of cMLCK (LEUO-1154). Results: Both mice ( Mylk3 +/fs and Mylk 3 fs/fs ) showed reduced cMLCK expression due to nonsense-mediated messenger RNA decay, reduced MLC2v (ventricular myosin regulatory light chain) phosphorylation in the myocardium, and systolic dysfunction in a cMLCK dose–dependent manner. Consistent with this result, myocardium from the mutant mice showed an increased ratio of cardiac superrelaxation/disordered relaxation states that may contribute to impaired cardiac contractility. The phenotypes observed in the knock-in mice were rescued by cMLCK replenishment through the AAV9_ MYLK3 vector. MYLK3 +/fs induced pluripotent stem cell–derived cardiomyocytes reduced cMLCK expression by 50% and contractile dysfunction, accompanied by an increased superrelaxation/disordered relaxation ratio. CRISPR-mediated gene correction, or cMLCK replenishment by AAV9_ MYLK3 vector, successfully recovered cMLCK expression, the superrelaxation/disordered relaxation ratio, and contractile dysfunction. LEUO-1154 increased human cMLCK activity ≈2-fold in the V max for ventricular myosin regulatory light chain phosphorylation without affecting the K m . LEUO-1154 treatment of human MYLK3 +/fs induced pluripotent stem cell–derived cardiomyocytes restored the ventricular myosin regulatory light chain phosphorylation level and superrelaxation/disordered relaxation ratio and improved cardiac contractility without affecting calcium transients, indicating that the cMLCK activator acts as a myotrope. Finally, human myocardium from advanced heart failure with a wide variety of causes had a significantly lower MYLK3 / PPP1R12B messenger RNA expression ratio than control hearts, suggesting an altered balance between myosin regulatory light chain kinase and phosphatase in the failing myocardium, irrespective of the causes. Conclusions: cMLCK dysregulation contributes to the development of cardiac systolic dysfunction in humans. Our strategy to restore cMLCK activity could form the basis of a novel myotropic therapy for advanced systolic heart failure.

Without a protective atmosphere, space-exposed surfaces of airless Solar System bodies gradually experience an alteration in composition, structure and optical properties through a collective process called space weathering. The return of samples from near-Earth asteroid (162173) Ryugu by Hayabusa2 provides the first opportunity for laboratory study of space-weathering signatures on the most abundant type of inner solar system body: a C-type asteroid, composed of materials largely unchanged since the formation of the Solar System. Weathered Ryugu grains show areas of surface amorphization and partial melting of phyllosilicates, in which reduction from Fe3+ to Fe2+ and dehydration developed. Space weathering probably contributed to dehydration by dehydroxylation of Ryugu surface phyllosilicates that had already lost interlayer water molecules and to weakening of the 2.7 µm hydroxyl (–OH) band in reflectance spectra. For C-type asteroids in general, this indicates that a weak 2.7 µm band can signify space-weathering-induced surface dehydration, rather than bulk volatile loss.

Aims Natriuretic peptides have reportedly been associated with cardiac hypertrophy and insulin resistance; however, it has not been established if B‐type natriuretic peptide (BNP) is associated with either insulin resistance or cardiac remodelling in a population with normal plasma BNP levels. We investigated the relationship among plasma BNP levels, insulin resistance, and left ventricular (LV) remodelling in a population with normal physiological plasma BNP levels. Methods and results Among 1632 individuals who participated in annual health checks between 2005 and 2008 in Arita‐cho, Saga, Japan, 675 individuals [median (interquartile range) for age 62 (51–69) years; 227 men (34%)] with LV ejection fraction 50% and BNP level 0.42; LV mass index ≤115 g/m2 in men and ≤95 g/m2 in women) was observed in 107 (16%) participants, while normal LV geometry (RWT ≤0.42; LV mass index ≤115 g/m2 in men and ≤95 g/m2 in women) was seen in 423 (63%), and LV hypertrophy (LV mass index >115 g/m2 in men and >95 g/m2 in women) in 145 (21%). Both low BNP level and higher insulin resistance were independently linked to LV concentric remodelling after multivariate adjustment (1 SD increment in BNP = aOR 0.714, 95% CI 0.544–0.938, P = 0.015; HOMA‐IR ≥ 1.37 vs.

C-type asteroids likely formed in the outer Solar System and were then scattered inwards during giant planet migration (Walsh et al., 2011). They may have transported volatiles to the inner Solar System and created the conditions suitable for life on Earth(Alexander, 2017). Carbonaceous chondrites are fragments from C-type asteroids and provide evidence that these generally organic-rich (Garvie and Buseck, 2007) bodies experienced extensive aqueous alteration early in Solar System history (Alexander et al., 2014). On 6th December 2020, ~5.4g of material was delivered to Earth from the C-type asteroid 162173 Ryugu by the Hayabusa2 spacecraft (Yada et al., 2021). Here we present the results of an integrated bulk and micro-analytical study of Ryugu particles, which provides a unique insight into the interrelationship between aliphatic-rich organics and surrounding hydrous minerals at a sub-micrometer scale. This dataset has clear implications for better understanding the origin and early evolution of Solar System organic matter and demonstrates that Ryugu particles are among the most uncontaminated extraterrestrial materials so far studied.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that shows progressive muscle weakness. A few treatments exist including symptomatic therapies, which can prolong survival or reduce a symptom; however, no fundamental therapies have been found. As a therapeutic strategy, enhancing muscle force is important for patients’ quality of life. In this study, we focused on skeletal muscle-specific myosin regulatory light chain kinase (skMLCK), which potentially enhances muscle contraction, as overexpression of skMLCK was thought to improve muscle function. The adeno-associated virus serotype 6 encoding skMLCK (AAV6/skMLCK) and eGFP (control) was produced and injected intramuscularly into the lower limbs of SOD1G37R mice, which are a familial ALS model. AAV6/skMLCK showed the successful expression of skMLCK in the muscle tissues. Although the control did not affect the muscle force in both of the WT and SOD1G37R mice, AAV6/skMLCK enhanced the twitch force of SOD1G37R mice and the tetanic force of WT and SOD1G37R mice. These results indicate that overexpression of skMLCK can enhance the tetanic force of healthy muscle as well as rescue weakened muscle function. In conclusion, the gene transfer of skMLCK has the potential to be a new therapy for ALS as well as for other neuromuscular diseases.

Many small boulders with reflectance values higher than 1.5 times the average reflectance have been found on the near-Earth asteroid 162173 Ryugu. Based on their visible wavelength spectral differences, Tatsumi et al. (2021) defined two bright boulder classes: C-type and S-type. These two classifications of bright boulders have different size distributions and spectral trends. In this study, we measured the spectra of 79 bright boulders and investigated their detailed spectral properties. Analyses obtained a number of important results. First, S-type bright boulders on Ryugu have spectra that are similar to those found for two different ordinary chondrites with different initial spectra that have been experimentally space weathered the same way. This suggests that there may be two populations of S-type bright boulders on Ryugu, perhaps originating from two different impactors that hit its parent body. Second, the model space-weathering ages of meter-size S-type bright boulders, based on spectral change rates derived in previous experimentally irradiated ordinary chondrites, are 0.1-1 Myr, which is consistent with the crater retention age (, Comment: 21 pages, 20 Figures, 1 Table, Published in Icarus, November 15 2021, 369 114591

ObjectiveAtrial functional mitral regurgitation (A-FMR) has been suggested as a new aetiology of functional MR (MR); however, its prognosis and prognostic predictors are not fully elucidated. Aim of this study was to investigate the prognosis and prognostic predictors of A-FMR in comparison with ventricular functional MR (V-FMR).MethodsThree hundred and seventy-eight consecutive patients with moderate-to-severe or severe functional MR were studied. Functional MR was classified into V-FMR (N=288) and A-FMR (N=90) depending on the alterations of left ventricle (LV) or left atrium (LA) along with clinical context and diagnosis of ischaemic heart disease or cardiomyopathy.ResultsDuring a median follow-up of 4.1 (2.0–6.7) years, all-cause mortality, cardiovascular mortality and heart failure (HF) hospitalisation occurred in 98 (26%), 81 (21%) and 177 (47%) patients, respectively, and rates of these events and the composite end point of all-cause mortality and HF hospitalisation were consistently higher in V-FMR than A-FMR (unadjusted HR 1.762 (95% CI 1.250 to 2.438), pConclusionsThe prognosis of V-FMR was significantly worse than that of A-FMR, and prognostic predictors were different between V-FMR and A-FMR. Our study suggests the importance of discriminating A-FMR and V-FMR, and that different treatment strategies may be considered for each aetiology.

Tissue amino acid profiles depend on the cell types and extracellular components that constitute the tissue, and their functions and activities. We aimed to characterize the tissue amino acid profiles in several types of pancreatic tumors and lesions. We examined tissue amino acid profiles in 311 patients with pancreatic tumors or lesions. We used newly developed LC-MS/MS methods to obtain the profiles, which were compared with clinicopathological data. Each tumor or lesion presented a characteristic tissue amino acid profile. Certain amino acids were markedly altered during the multistep pancreatic carcinogenesis and pancreatic ductal adenocarcinoma (PDAC) progression. A tissue amino acid index (TAAI) was developed based on the amino acids that were notably changed during both carcinogenesis and cancer progression. Univariate and multivariate survival analyses revealed that PDAC patients with a high TAAI exhibited a significantly shorter survival rate, and these findings were validated using a second cohort. We suggest that tissue amino acid profiles are characteristic for normal tissue type, tumor histological type, and pathological lesion, and are representative of the cancer grade or progression stage in multistep carcinogenesis and of malignant characteristics. The TAAI could serve as an independent prognosticator for patients with PDAC.

Enhancers regulate gene expressions in a tissue- and pathology-specific manner by altering its activities. Plasma levels of atrial and brain natriuretic peptides, encoded by the Nppa and Nppb, respectively, and synthesized predominantly in cardiomyocytes, vary depending on the severity of heart failure. We previously identified the noncoding conserved region 9 (CR9) element as a putative Nppb enhancer at 22-kb upstream from the Nppb gene. However, its regulatory mechanism remains unknown. Here, we therefore investigated the mechanism of CR9 activation in cardiomyocytes using different kinds of drugs that induce either cardiac hypertrophy or cardiac failure accompanied by natriuretic peptides upregulation. Chronic treatment of mice with either catecholamines or doxorubicin increased CR9 activity during the progression of cardiac hypertrophy to failure, which is accompanied by proportional increases in Nppb expression. Conversely, for cultured cardiomyocytes, doxorubicin decreased CR9 activity and Nppb expression, while catecholamines increased both. However, exposing cultured cardiomyocytes to mechanical loads, such as mechanical stretch or hydrostatic pressure, upregulate CR9 activity and Nppb expression even in the presence of doxorubicin. Furthermore, the enhancement of CR9 activity and Nppa and Nppb expressions by either catecholamines or mechanical loads can be blunted by suppressing mechanosensing and mechanotransduction pathways, such as muscle LIM protein (MLP) or myosin tension. Finally, the CR9 element showed a more robust and cell-specific response to mechanical loads than the -520-bp BNP promoter. We concluded that the CR9 element is a novel enhancer that responds to mechanical loads by upregulating natriuretic peptides expression in cardiomyocytes.

The near-Earth asteroid (162173) Ryugu displays a Cb-type average spectrum and a very low average normal albedo of 0.04. Although the majority of boulders on Ryugu have reflectance spectra and albedo similar to the Ryugu average, a small fraction of boulders exhibit anomalously high albedo and distinctively different spectra. A previous study (Tatsumi et al., 2021) based on the 2.7-km observations and a series of low-altitude (down to 68 m) descent observations conducted prior to the first touchdown have shown that the spectra of these anomalous boulders can be classified into two distinct groups corresponding to S and C type asteroids. The former originate most likely from an impactor that collided with Ryugu's parent body, whereas the latter may be from portions of Ryugu's parent body that experienced a different temperature history than experienced by the majority of boulder materials. In this study, we analyzed images captured after the first touchdown to determine the quantitative properties of these bright boulders on Ryugu. We measured the sizes of more than a thousand bright boulders and characterized the morphologic properties of the largest ones. Analyses revealed many properties of bright boulders important for the evolution of Ryugu and its parent body. The size-frequency distributions of S- and C-type bright boulders follow power laws. We obtained the ratios of the total volume and surface area of S-type bright boulders to those of average dark boulders on the Ryugu surface. Also, many of the bright boulders are embedded in a larger substrate boulder, suggesting that they have experienced mixing and conglomeration with darker fragments on the parent body, rather than gently landing on Ryugu during or after its formation by reaccumulation. This is consistent with the hypothesis that S-type bright boulders were likely mixed during and/or before a catastrophic disruption., Comment: 19 pages, 11 figures, 3 Tables, published in Icarus, 369, 15 November, 2021, 114529

We report a chemical assessment of the explosive chamber in the projector system used during the sampling operation of the Hayabusa2 project at the surface of the C-type asteroid Ryugu. Although the explosion process was designed as a closed system, volatile combustion gases and semivolatile organics were produced together with quenched carbonaceous product. The chemical compositions of the gases, organics, and inorganics were investigated in the screening analysis. A solid-phase microextraction technique and thermal desorption coupled with gas chromatography/mass spectrometry analysis revealed that aliphatic (20n-alkanes) and aromatic ( two rings > three rings > four rings, resulting in abiogenic molecular patterns. The most intense inorganic fingerprints were due to potassium (K+) and chloride (Cl–) ions derived from the initial KTB explosive and RK ignition charge. We discuss quality control and quality assurance issues applicable to future sample processes during the Hayabusa2 project.

We report an assessment of the explosive chamber in the projector system used during the sampling operation of the Hayabusa2 project at the surface of the C-type asteroid Ryugu. Although the explosion process was designed as a closed system (cf. Sawada et al., Space Sci. Rev., 2017), volatile combustion gases and semivolatile organics were produced together with quenched carbonaceous products. The chemical compositions of the gases, organics, and inorganics were investigated in the screening analysis. A solid-phase microextraction technique and thermal desorption coupled with gas chromatography/mass spectrometry analysis revealed that aliphatic ( three rings > four rings, resulting in abiogenic molecular patterns. The most intense inorganic fingerprints were due to potassium (K + ) and chloride (Cl – ) ions derived from the initial KTB explosive and RK ignition charge. We discuss quality control and quality assurance issues applicable to future sample processes during the Hayabusa2 project.

Impact-cratering processes on small bodies are thought to be mainly controlled by the local material strength because of their low surface gravity, and craters that are as large as the parent bodies should be affected by the target curvature. Although cratering processes on planar surfaces in the strength-controlled regime have been studied extensively, the mechanism by which target curvature affects the cratering processes remains unclear. Herein, we report on a series of impact experiments that used spherical targets with various diameters. The resultant craters consisted of a deep circular pit and an irregular-shaped spall region around the pit, which is consistent with the features reported in a number of previous cratering experiments on planar surfaces. However, the volume and radius of the craters increased with the normalized curvature. The results indicate that the increase in the spall-region volume and radius mainly contributes to the increase in the whole crater volume and radius, although the volume, depth, and radius of pits remain constant with curvature. The results of our model indicate that the geometric effect due to curvature (i.e., whereby the distance from the equivalent center to the target free surface is shorter for higher curvature values) contributes to increases in the cratering efficiency. Our results suggest that the impactors that produce the largest craters (basins) on some asteroids are thus smaller than what is estimated by current scaling laws, which do not take into account the curvature effects., Accepted for publication in Icarus, 37 pages, 9 figures, 2 tables

Accepted: 2017-12-12, 資料番号: SA1170267000

Accepted: 2016-12-17, 資料番号: SA1160351000

Introduction: Although studies have shown that bystander cardiopulmonary resuscitation (CPR) in witnessed out-of-hospital cardiac arrest (OHCA) is associated with better neurological prognosis, whether bystander and Emergency Medical Service (EMS) interventions are associated with prognosis in unwitnessed OHCA patients is not fully elucidated. We aimed to investigate the prognostic importance of bystander and EMS interventions among unwitnessed OHCA patients in Japan. Methods and Results: This study was a nation-wide population-based observational study of OHCA in Japan from 2011 to 2015 based on data from the All-Japan Utstein Registry. The outcome measures were neurological outcome and survival at 30-day. The neurologically favorable outcome was defined as Glasgow-Pittsburgh cerebral performance category score 1 or 2. First, to investigate the effectiveness of bystander interventions, we included 105,655 unwitnessed cardiogenic OHCA patients (aged 18-80 years). Of these, 1,614 (1.5%) showed neurologically favorable outcome and 3,273 (3.1%) survived at 30-day. Multivariate logistic regression analysis adjusting for age, sex, geographical region, year and EMS response time showed that bystander CPR was associated with neurologically favorable outcome (adjusted odds ratio [aOR] 1.49, 95% CI 1.35-1.65, P Conclusions: Among unwitnessed OHCA patients, bystander CPR was associated with neurologically favorable prognosis. For unwitnessed OHCA patients with non-shockable rhythm, epinephrine administration was associated with survival, but advanced airway management was negatively associated with neurological outcome.

To assess the use of plasma free amino acids (PFAAs) as biomarkers for metabolic disorders, it is essential to identify genetic factors that influence PFAA concentrations. PFAA concentrations were absolutely quantified by liquid chromatography–mass spectrometry using plasma samples from 1338 Japanese individuals, and genome-wide quantitative trait locus (QTL) analysis was performed for the concentrations of 21 PFAAs. We next conducted a conditional QTL analysis using the concentration of each PFAA adjusted by the other 20 PFAAs as covariates to elucidate genetic determinants that influence PFAA concentrations. We identified eight genes that showed a significant association with PFAA concentrations, of which two, SLC7A2 and PKD1L2, were identified. SLC7A2 was associated with the plasma levels of arginine and ornithine, and PKD1L2 with the level of glycine. The significant associations of these two genes were revealed in the conditional QTL analysis, but a significant association between serine and the CPS1 gene disappeared when glycine was used as a covariate. We demonstrated that conditional QTL analysis is useful for determining the metabolic pathways predominantly used for PFAA metabolism. Our findings will help elucidate the physiological roles of genetic components that control the metabolism of amino acids.

Accepted: 2012-11-21, 資料番号: SA1004111000

In order to study the catastrophic disruption of porous bodies such as asteroids and planetesimals, we conducted several impact experiments using porous gypsum spheres (porosity: 50%). We investigated the fragment mass and velocity of disrupted gypsum spheres over a wide range of specific energies from 3 x 10^3 J/kg to 5 x 10^4 J/kg. We compared the largest fragment mass (ml/Mt) and the antipodal velocity (Va) of gypsum with those of non-porous materials such as basalt and ice. The results showed that the impact strength of gypsum was notably higher than that of the non-porous bodies; however, the fragment velocity of gypsum was slower than that of the non-porous bodies. This was because the micro-pores dispersed in the gypsum spheres caused a rapid attenuation of shock pressure in them. From these results, we expect that the collisional disruption of porous bodies could be significantly different from that of non-porous bodies.

The ALADDIN (Arrayed Large-Area Dust Detectors in INterplanetary space) made of 0.54 m2 PVDF sensors was deployed on the anti-Sun face of the thin polyimide sail membrane of the deep space solar sail spacecraft gIKAROS (Interplanetary Kitecraft Accelerated by the Radiation Of the Sun)h. It has measured micrometeoroid flux between the Earthfs orbit and Venusf orbit (i.e., 1.0 ~ 0.7 AU of heliocentric distance) for 1.5 revolutions from June 2010 until October 2011. The ALADDIN dust detector is arrayed by 8 channels of 9-20 micron-thick PVDF sensors, which are capable of detecting hypervelocity impacts of micrometeoroids at > ~ 10−12g, according to ground calibration impact experiments. The sensors filter electronic, thermal and vibration noises and can record time, peak hold value above its threshold, and relaxation duration of each impact signal. In total, its cruising measurements counted more than 3000 dust impacts after screening noise signals. The ALADDIN flux in the 2010-2011 epoch was compared with fluxes at similar mass range of micrometeoroids and in similar heliocentric distances measured by Helios in 1970fs and Galileo in 1990fs, both of which were composed of much less number of impact data. Then, it suggested enhancement of dust flux in the trailing edge of circumsolar orbits of the Earth and Venus, which are consistent with previous reports of larger dust grain enhancements observed by infrared telescopes. This also implies that the temporal flux enhancement of large micrometeoroids in the blob may have caused a cascading effect to produce smaller dust by collisions with sporadic meteoroids. Also it is apparent that the micrometeoroid flux increases by approximately one order of magnitude from 1 AU to 0.7 AU during the 2010-2011 epoch. The temporal variance of the Helios flux data in 1976-80 in the same region of 1 AU may be associated with difference of averaged solar activities during both epochs. Since the solar activity in the years 2010-2011 was around the minimum of the solar cycle, smaller micrometeoroids, which are more affected by solar radiation pressure than larger ones, may have survived longer than those in the Helios epoch, which covered from the minimum to the maximum of the solar cycle in late 1970fs.

The Hayabusa2 spacecraft returned to Earth from the asteroid 162173 Ryugu on 6 December 2020. One day after the recovery, the gas species retained in the sample container were extracted and measured on-site and stored in gas collection bottles. The container gas consists of helium and neon with an extraterrestrial ³He/⁴He and ²⁰Ne/²²Ne ratios, along with some contaminant terrestrial atmospheric gases. A mixture of solar and Earth’s atmospheric gas is the best explanation for the container gas composition. Fragmentation of Ryugu grains within the sample container is discussed on the basis of the estimated amount of indigenous He and the size distribution of the recovered Ryugu grains. This is the first successful return of gas species from a near-Earth asteroid., 「はやぶさ2」ミッションによる世界初の小惑星からのガスサンプル：リュウグウからのたまて箱. 京都大学プレスリリース. 2022-10-21.