58 research outputs found
SMN promotes mitochondrial metabolic maturation during myogenesis by regulating the MYOD-miRNA axis
脊髄性筋萎縮症における骨格筋病変の発症メカニズムの一部を解明. 京都大学プレスリリース. 2023-01-17.Pathogenesis of skeletal muscle lesions in spinal muscular atrophy. 京都大学プレスリリース. 2023-02-17.Spinal muscular atrophy (SMA) is a congenital neuromuscular disease caused by the mutation or deletion of the survival motor neuron 1 (SMN1) gene. Although the primary cause of progressive muscle atrophy in SMA has classically been considered the degeneration of motor neurons, recent studies have indicated a skeletal muscle–specific pathological phenotype such as impaired mitochondrial function and enhanced cell death. Here, we found that the down-regulation of SMN causes mitochondrial dysfunction and subsequent cell death in in vitro models of skeletal myogenesis with both a murine C2C12 cell line and human induced pluripotent stem cells. During myogenesis, SMN binds to the upstream genomic regions of MYOD1 and microRNA (miR)-1 and miR-206. Accordingly, the loss of SMN down-regulates these miRs, whereas supplementation of the miRs recovers the mitochondrial function, cell survival, and myotube formation of SMN-deficient C2C12, indicating the SMN-miR axis is essential for myogenic metabolic maturation. In addition, the introduction of the miRs into ex vivo muscle stem cells derived from Δ7-SMA mice caused myotube formation and muscle contraction. In conclusion, our data revealed novel transcriptional roles of SMN during myogenesis, providing an alternative muscle-oriented therapeutic strategy for SMA patients
A Large X-ray Flare from a Single Weak-lined T Tauri Star TWA-7 Detected with MAXI GSC
We present a large X-ray flare from a nearby weak-lined T Tauri star TWA-7
detected with the Gas Slit Camera (GSC) on the Monitor of All-sky X-ray Image
(MAXI). The GSC captured X-ray flaring from TWA-7 with a flux of
ergs cm s in 2--20 keV band during the scan
transit starting at UT 2010-09-07 18:24:30.The estimated X-ray luminosity at
the scan in the energy band is 3 ergs s,indicating that
the event is among the largest X-ray flares fromT Tauri stars.Since MAXI GSC
monitors a target only during a scan transit of about a minute per 92 min
orbital cycle, the luminosity at the flare peak might have been higher than
that detected. At the scan transit, we observed a high X-ray-to-bolometric
luminosity ratio, log = ; i.e., the
X-ray luminosity is comparable to the bolometric luminosity. Since TWA-7 has
neither an accreting disk nor a binary companion, the observed event implies
that none of those are essential to generate such big flares in T Tauri stars.Comment: 4 pages, 2 figures, 1 table accepted for publication in PAS
Brown adipose tissue dysfunction promotes heart failure via a trimethylamine N-oxide-dependent mechanism.
Low body temperature predicts a poor outcome in patients with heart failure, but the underlying pathological mechanisms and implications are largely unknown. Brown adipose tissue (BAT) was initially characterised as a thermogenic organ, and recent studies have suggested it plays a crucial role in maintaining systemic metabolic health. While these reports suggest a potential link between BAT and heart failure, the potential role of BAT dysfunction in heart failure has not been investigated. Here, we demonstrate that alteration of BAT function contributes to development of heart failure through disorientation in choline metabolism. Thoracic aortic constriction (TAC) or myocardial infarction (MI) reduced the thermogenic capacity of BAT in mice, leading to significant reduction of body temperature with cold exposure. BAT became hypoxic with TAC or MI, and hypoxic stress induced apoptosis of brown adipocytes. Enhancement of BAT function improved thermogenesis and cardiac function in TAC mice. Conversely, systolic function was impaired in a mouse model of genetic BAT dysfunction, in association with a low survival rate after TAC. Metabolomic analysis showed that reduced BAT thermogenesis was associated with elevation of plasma trimethylamine N-oxide (TMAO) levels. Administration of TMAO to mice led to significant reduction of phosphocreatine and ATP levels in cardiac tissue via suppression of mitochondrial complex IV activity. Genetic or pharmacological inhibition of flavin-containing monooxygenase reduced the plasma TMAO level in mice, and improved cardiac dysfunction in animals with left ventricular pressure overload. In patients with dilated cardiomyopathy, body temperature was low along with elevation of plasma choline and TMAO levels. These results suggest that maintenance of BAT homeostasis and reducing TMAO production could be potential next-generation therapies for heart failure.We thank Kaori Yoshida, Keiko Uchiyama, Satomi Kawai, Naomi Hatanaka, Yoko Sawaguchi, Runa Washio,
Takako Ichihashi, Nanako Koike, Keiko Uchiyama, Masaaki Nameta (Niigata University), Kaori Igarashi, Kaori
Saitoh, Keiko Endo, Hiroko Maki, Ayano Ueno, Maki Ohishi, Sanae Yamanaka, Noriko Kagata (Keio University)
for their excellent technical assistance, C. Ronald Kahn (Joslin Diabetes Center and Harvard Medical School)
for providing the BAT cell line, Evan Rosen (Harvard Medical School) for providing us Ucp-Cre mice, Kosuke
Morikawa (Kyoto University), Tomitake Tsukihara (University of Hyogo) and Shinya Yoshikawa (University of
Hyogo) for their professional opinions and suggestions. Tis work was supported by a Grant-in-Aid for Scientifc Research (A) (20H00533) from MEXT, AMED under Grant Numbers JP20ek0210114, and AMED-CREST
under Grant Number JP20gm1110012, and Moonshot Research and Development Program (21zf0127003s0201),
MEXT Supported Program for the Strategic Research Foundation at Private Universities Japan, Private University
Research Branding Project, and Leading Initiative for Excellent Young Researchers, and grants from the Takeda
Medical Research Foundation, the Vehicle Racing Commemorative Foundation, Ono Medical Research Foundation, and the Suzuken Memorial Foundation (to T.M.). Support was also provided by a Grants-in-Aid for Young
Scientists (Start-up) (26893080), and grants from the Uehara Memorial Foundation, Kowa Life Science Foundation, Manpei Suzuki Diabetes Foundation, SENSHIN Medical Research Foundation, ONO Medical Research
Foundation, Tsukada Grant for Niigata University Medical Research, Te Nakajima Foundation, SUZUKEN
memorial foundation, HOKUTO Corporation, Mochida Memorial Foundation for Medical & Pharmaceutical
Research, Grants-in-Aid for Encouragement of Young Scientists (A) (16H06244), Daiichi Sankyo Foundation of
Life Science, AMED Project for Elucidating and Controlling Mechanisms of Aging and Longevity under Grant
Number JP17gm5010002, JP18gm5010002, JP19gm5010002, JP20gm5010002, JP21gm5010002, Astellas Foundation for Research on Metabolic Disorders, Research grant from Naito Foundation, Te Japan Geriatrics Society
(to I.S.); by a Grant-in-Aid for Scientifc Research (C) (19K08974), Yujin Memorial Grant, Sakakibara Memorial
Research Grant from Te Japan Research Promotion Society for Cardiovascular Diseases, TERUMO Life Science Foundation, Kanae Foundation (to Y.Y.), JST ERATO (JPMJER1902), AMED-CREST (JP20gm1010009),
the Takeda Science Foundation, the Food Science Institute Foundation (to S.F.), and by a grant from Bourbon
(to T.M., I.S. and Y.Y.).S
Sedentary Time and All-Cause Mortality
BACKGROUND: This study aimed to determine the association between sedentary time and mortality with regard to leisure‐time physical activity with or without cardiometabolic diseases such as hypertension, dyslipidemia, and diabetes mellitus.
METHODS AND RESULTS: Using data from the J‐MICC (Japan Multi‐Institutional Collaborative Cohort) Study, 64 456 participants (29 022 men, 35 434 women) were analyzed. Hazard ratios (HRs) and 95% CIs were used to characterize the relative risk of all‐cause mortality to evaluate its association with sedentary time (categorical variables: <5, 5 to <7, 7 to <9, ≥9 h/d and 2‐hour increments in exposure) according to the self‐reported hypertension, dyslipidemia, and diabetes mellitus using a Cox proportional hazards model. A total of 2257 participants died during 7.7 years of follow‐up. The corresponding HRs for each 2‐hour increment in sedentary time among participants with all factors, no factors, hypertension, dyslipidemia, and diabetes mellitus were 1.153 (95% CI, 1.114–1.194), 1.125 (95% CI, 1.074–1.179), 1.202 (95% CI, 1.129–1.279), 1.176 (95% CI, 1.087–1.273), and 1.272 (95% CI, 1.159–1.396), respectively. Furthermore, when analyzed according to the combined different factors (hypertension, dyslipidemia, and diabetes mellitus), HRs increased with each additional factor, and participants reporting all 3 conditions had the highest HR of 1.417 (95% CI, 1.162–1.728) independently of leisure‐time metabolic equivalents.
CONCLUSIONS: The association between sedentary time and increased mortality is stronger among patients with hypertension, dyslipidemia, and diabetes mellitus regardless of leisure‐time physical activity in a large Japanese population
Peculiarly Narrow SED of GRB 090926B with MAXI and Fermi/GBM
The monitor of all-sky X-ray image (MAXI) Gas Slit Camera (GSC) on the
International Space Station (ISS) detected a gamma-ray burst (GRB) on 2009,
September 26, GRB\,090926B. This GRB had extremely hard spectra in the X-ray
energy range. Joint spectral fitting with the Gamma-ray Burst Monitor on the
Fermi Gamma-ray Space Telescope shows that this burst has peculiarly narrow
spectral energy distribution and is represented by Comptonized blackbody model.
This spectrum can be interpreted as photospheric emission from the low
baryon-load GRB fireball. Calculating the parameter of fireball, we found the
size of the base of the flow cm and Lorentz factor of the plasma , where is a ratio between the total fireball energy and
the energy in the blackbody component of the gamma-ray emission. This is
factor of a few larger, and the Lorentz factor of 110 is smaller by also factor
of a few than other bursts that have blackbody components in the spectra.Comment: 7 pages, 6 figure
The ASTRO-H X-ray Observatory
The joint JAXA/NASA ASTRO-H mission is the sixth in a series of highly
successful X-ray missions initiated by the Institute of Space and Astronautical
Science (ISAS). ASTRO-H will investigate the physics of the high-energy
universe via a suite of four instruments, covering a very wide energy range,
from 0.3 keV to 600 keV. These instruments include a high-resolution,
high-throughput spectrometer sensitive over 0.3-2 keV with high spectral
resolution of Delta E < 7 eV, enabled by a micro-calorimeter array located in
the focal plane of thin-foil X-ray optics; hard X-ray imaging spectrometers
covering 5-80 keV, located in the focal plane of multilayer-coated, focusing
hard X-ray mirrors; a wide-field imaging spectrometer sensitive over 0.4-12
keV, with an X-ray CCD camera in the focal plane of a soft X-ray telescope; and
a non-focusing Compton-camera type soft gamma-ray detector, sensitive in the
40-600 keV band. The simultaneous broad bandpass, coupled with high spectral
resolution, will enable the pursuit of a wide variety of important science
themes.Comment: 22 pages, 17 figures, Proceedings of the SPIE Astronomical
Instrumentation "Space Telescopes and Instrumentation 2012: Ultraviolet to
Gamma Ray
The Quiescent Intracluster Medium in the Core of the Perseus Cluster
Clusters of galaxies are the most massive gravitationally-bound objects in
the Universe and are still forming. They are thus important probes of
cosmological parameters and a host of astrophysical processes. Knowledge of the
dynamics of the pervasive hot gas, which dominates in mass over stars in a
cluster, is a crucial missing ingredient. It can enable new insights into
mechanical energy injection by the central supermassive black hole and the use
of hydrostatic equilibrium for the determination of cluster masses. X-rays from
the core of the Perseus cluster are emitted by the 50 million K diffuse hot
plasma filling its gravitational potential well. The Active Galactic Nucleus of
the central galaxy NGC1275 is pumping jetted energy into the surrounding
intracluster medium, creating buoyant bubbles filled with relativistic plasma.
These likely induce motions in the intracluster medium and heat the inner gas
preventing runaway radiative cooling; a process known as Active Galactic
Nucleus Feedback. Here we report on Hitomi X-ray observations of the Perseus
cluster core, which reveal a remarkably quiescent atmosphere where the gas has
a line-of-sight velocity dispersion of 164+/-10 km/s in a region 30-60 kpc from
the central nucleus. A gradient in the line-of-sight velocity of 150+/-70 km/s
is found across the 60 kpc image of the cluster core. Turbulent pressure
support in the gas is 4% or less of the thermodynamic pressure, with large
scale shear at most doubling that estimate. We infer that total cluster masses
determined from hydrostatic equilibrium in the central regions need little
correction for turbulent pressure.Comment: 31 pages, 11 Figs, published in Nature July
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