A muscle fatigue-like contractile decline was recapitulated using skeletal myotubes from Duchenne muscular dystrophy patient-derived iPSCs

デュシェンヌ型筋ジストロフィー患者由来iPS細胞を用いて、筋疲労に似た収縮力低下を培養細胞で再現する事に成功. 京都大学プレスリリース. 2021-06-07.Stopping muscles fatigue. 京都大学プレスリリース. 2021-06-21.Duchenne muscular dystrophy (DMD) is a muscle degenerating disease caused by dystrophin deficiency, for which therapeutic options are limited. To facilitate drug development, it is desirable to develop in vitro disease models that enable the evaluation of DMD declines in contractile performance. Here, we show MYOD1-induced differentiation of hiPSCs into functional skeletal myotubes in vitro with collagen gel and electrical field stimulation (EFS). Long-term EFS training (0.5 Hz, 20 V, 2 ms, continuous for 2 weeks) mimicking muscle overuse recapitulates declines in contractile performance in dystrophic myotubes. A screening of clinically relevant drugs using this model detects three compounds that ameliorate this decline. Furthermore, we validate the feasibility of adapting the model to a 96-well culture system using optogenetic technology for large-scale screening. Our results support a disease model using patient-derived iPSCs that allows for the recapitulation of the contractile pathogenesis of DMD and a screening strategy for drug development

Contribution of Majoron to Hubble tension in gauged U(1)Lμ−Lτ_{L_\mu-L_\tau} Model

In this paper, we analyze parameter regions that can alleviate the Hubble tension in the U(1)$_{L_\mu - L_\tau}$ model with the broken lepton number U(1)$_L$ symmetry. As new particles, this model has a U(1)$_{L_\mu - L_\tau}$ gauge boson $Z'$ and a Majoron $\phi$, which can affect the early universe and the effective number of neutrino species $N_{\rm eff}$. If $Z'$ and $\phi$ simultaneously exist in the early universe, $Z'\,$-$\,\phi$ interaction processes such as $Z'\nu_\alpha \leftrightarrow \phi\bar{\nu}_\beta$ occur. The comparison of $N_{\rm eff}$ between the cases with and without the $Z'\,$-$\,\phi$ interaction processes shows that these processes make a small contribution of $\mathcal{O}(10^{-4})$ to $N_{\rm eff}$, and it does not need to be considered for the alleviation of the Hubble tension. Based on these facts, we calculated $N_{\rm eff}$ for various Majoron parameters without the $Z'\,$-$\,\phi$ interaction processes to search parameters that could alleviate the Hubble tension. As a result, we found that the U(1)$_{L_\mu - L_\tau}$ gauge boson and Majoron can alleviate the Hubble tension in some parameter regions, and there is a non-trivial synergy contribution between $Z'$ and $\phi$. Moreover, the parameter region with a lighter mass $m_\phi \lesssim 2$ MeV and a larger coupling $\lambda \gtrsim 10^{-8}$ is excluded because it predicts too large $N_{\rm eff}$, i.e. $N_{\rm eff} \gtrsim 3.5$. The favored and restricted regions of the Majoron parameters depend on the $Z'$ parameters because of the presence of the $Z'$ contribution and synergy one.Comment: 24 pages, 4 figure

Role of the C-terminal extension stacked on the re-face of the isoalloxazine ring moiety of the flavin adenine dinucleotide prosthetic group in ferredoxin-NADP+ oxidoreductase from Bacillus subtilis

Ferredoxin-NADP+ oxidoreductase [EC 1.18.1.2] from Bacillus subtilis (BsFNR) is homologous to the bacterial NADPH-thioredoxin reductase, but possesses a unique C-terminal extension that covers the re-face of the isoalloxazine ring moiety of the flavin adenine dinucleotide (FAD) prosthetic group. In this report, we utilize BsFNR mutants depleted of their C-terminal residues to examine the importance of the C-terminal extension in reactions with NADPH and ferredoxin (Fd) from B. subtilis by spectroscopic and steady-state reaction analyses. The depletions of residues Y313 to K332 (whole C-terminal extension region) and S325 to K332 (His324 intact) resulted in significant increases in the catalytic efficiency with NADPH in diaphorase assay with ferricyanide, whereas Km values for ferricyanide were increased. In the cytochrome c reduction assay in the presence of B. subtilis ferredoxin, the S325-K332 depleted mutant displayed a significant decrease in the turnover rate with an Fd concentration range of 1-10 μM. The Y313-K332 depleted mutant demonstrated an increase in the rate of the direct reduction of horse heart cytochrome c in the absence of Fd. These data indicated that depletion of the C-terminal extension plays an important role in the reaction of BsFNR with ferredoxin. © 2014 Elsevier Masson SAS. All rights reserved

General Relativistic Ray-Tracing Method for Estimating the Energy and Momentum Deposition by Neutrino Pair Annihilation in Collapsars

Bearing in mind the application to the collapsar models of gamma-ray bursts (GRBs), we develop a numerical scheme and code for estimating the deposition of energy and momentum due to the neutrino pair annihilation ($\nu + {\bar \nu} \rightarrow e^{-} + e^{+}$) in the vicinity of accretion tori around a Kerr black hole. Our code is designed to solve the general relativistic neutrino transfer by a ray-tracing method. To solve the collisional Boltzmann equation in curved spacetime, we numerically integrate the so-called rendering equation along the null geodesics. For the neutrino opacity, the charged-current $\beta$-processes are taken into account, which are dominant in the vicinity of the accretion tori. The numerical accuracy of the developed code is certificated by several tests, in which we show comparisons with the corresponding analytic solutions. Based on the hydrodynamical data in our collapsar simulation, we estimate the annihilation rates in a post-processing manner. Increasing the Kerr parameter from 0 to 1, it is found that the general relativistic effect can increase the local energy deposition rate by about one order of magnitude, and the net energy deposition rate by several tens of percents. After the accretion disk settles into a stationary state (typically later than $\sim 9$ s from the onset of gravitational collapse), we point out that the neutrino-heating timescale in the vicinity of the polar funnel region can be shorter than the dynamical timescale. Our results suggest the neutrino pair annihilation has a potential importance equal to the conventional magnetohydrodynamic mechanism for igniting the GRB fireballs.Comment: 33 pages, 15 figures, accepted to the Ap

C-terminal residues of ferredoxin-NAD(P)+ reductase from Chlorobaculum tepidum are responsible for reaction dynamics in the hydride transfer and redox equilibria with NADP+/NADPH

金沢大学理工研究域物質化学系Ferredoxin-NAD(P)+ reductase ([EC 1.18.1.2], [EC 1.18.1.3]) from Chlorobaculum tepidum (CtFNR) is structurally homologous to the bacterial NADPH-thioredoxin reductase (TrxR), but possesses a unique C-terminal extension relative to TrxR that interacts with the isoalloxazine ring moiety of the flavin adenine dinucleotide prosthetic group. In this study, we introduce truncations to the C-terminal residues to examine their role in the reactions of CtFNR with NADP+ and NADPH by spectroscopic and kinetic analyses. The truncation of the residues from Tyr326 to Glu360 (the whole C-terminal extension region), from Phe337 to Glu360 (omitting Phe337 on the re-face of the isoalloxazine ring) and from Ser338 to Glu360 (leaving Phe337 intact) resulted in a blue-shift of the flavin absorption bands. The truncations caused a slight increase in the dissociation constant toward NADP+ and a slight decrease in the Michaelis constant toward NADPH in steady-state assays. Pre-steady-state studies of the redox reaction with NADPH demonstrated that deletions of Tyr326–Glu360 decreased the hydride transfer rate, and the amount of reduced enzyme increased at equilibrium relative to wild-type CtFNR. In contrast, the deletions of Phe337–Glu360 and Ser338–Glu360 resulted in only slight changes in the reaction kinetics and redox equilibrium. These results suggest that the C-terminal region of CtFNR is responsible for the formation and stability of charge-transfer complexes, leading to changes in redox properties and reactivity toward NADP+/NADPH. © 2017 Springer Science+Business Media B.V., part of Springer NatureEmbargo Period 12 month

Glycosylated porphyra-334 and palythine-threonine from the terrestrial cyanobacterium nostoc commune

Mycosporine-like amino acids (MAAs) are water-soluble UV-absorbing pigments, and structurally different MAAs have been identified in eukaryotic algae and cyanobacteria. In this study novel glycosylated MAAs were found in the terrestrial cyanobacterium Nostoc commune (N. commune). An MAA with an absorption maximum at 334 nm was identified as a hexose-bound porphyra-334 derivative with a molecular mass of 508 Da. Another MAA with an absorption maximum at 322 nm was identified as a two hexose-bound palythine-threonine derivative with a molecular mass of 612 Da. These purified MAAs have radical scavenging activities in vitro, which suggests multifunctional roles as sunscreens and antioxidants. The 612-Da MAA accounted for approximately 60% of the total MAAs and contributed approximately 20% of the total radical scavenging activities in a water extract, indicating that it is the major water-soluble UV-protectant and radical scavenger component. The hexose-bound porphyra-334 derivative and the glycosylated palythine-threonine derivatives were found in a specific genotype of N. commune, suggesting that glycosylated MAA patterns could be a chemotaxonomic marker for the characterization of the morphologically indistinguishable N. commune. The glycosylation of porphyra-334 and palythine-threonine in N. commune suggests a unique adaptation for terrestrial environments that are drastically fluctuating in comparison to stable aquatic environments. © 2013 by the authors

A marine phytoplankton (Prymnesium parvum) up-regulates ABC transporters and several other proteins to acclimatize with Fe-limitation

Iron (Fe) is one of the vital limiting factors for phytoplankton in vast regions of the contemporary oceans, notably the high nutrient low chlorophyll regions. Therefore, it is apparent to be acquainted with the Fe uptake strategy of marine phytoplankton under Fe-limited condition. In the present study, marine phytoplankton Prymnesium parvum was grown under Fe-deplete (0.0025 μM) and Fe-rich (0.05 μM) conditions, and proteomic responses of the organism to Fe conditions were compared. In sodium dodecyl sulfate (SDS) gel electrophoresis, 7 proteins (16, 18, 32, 34, 75, 82, and 116. kDa) were highly expressed under Fe-deplete condition, while one protein (23. kDa) was highly expressed under Fe-rich condition. These proteins were subjected to 2-dimensional gel electrophoresis (2-D DIGE) to differentiate individual proteins, and were identified by matrix-assisted laser desorption-ionization-time of flight-mass spectrometer (MALDI-TOF-MS) analysis. The results showed that under Fe-deplete condition P. parvum increases the biosynthesis of ATP binding cassette (ABC) transporters, flagellar associated protein (FAP), and Phosphoribosylaminoimidazole-succinocarboxamide synthase. These proteins are assumed to be involved in a number of cellular biochemical processes that facilitate Fe acquisition in phytoplankton. Under Fe-deplete condition, P. parvum increases the synthesis of ribulose biphosphate carboxylase (RuBisCo), malate dehydrogenase, and two Fe-independent oxidative stress response proteins, manganese superoxide dismutase (MnSOD) and Serine threonine kinase (STK). Thus, marine phytoplankton may change their Fe acquisition strategy by altering the biosynthesis of several proteins in order to cope with Fe-limitation. © 2013 Elsevier Ltd

Special Relativistic Simulations of Magnetically-dominated Jets in Collapsing Massive Stars

We perform a series of two-dimensional magnetohydrodynamic core-collapse simulations of rapidly rotating and strongly magnetized massive stars. To study the properties of magnetic explosions for a longer time stretch of postbounce evolution, we develop a new code under the framework of special relativity including a realistic equation of state with a multiflavor neutrino leakage scheme. Our results show the generation of the magnetically-dominated jets in the two ways. One is launched just after the core-bounce in a prompt way and another is launched at $\sim 100$ ms after the stall of the prompt shock. We find that the shock-revival occurs when the magnetic pressure becomes strong, due to the field wrapping, enough to overwhelm the ram pressure of the accreting matter. The critical toroidal magnetic fields for the magnetic shock-revival are found to be universal of $\sim 10^{15}\mathrm{G}$ behind the jets. We point out that the time difference before the shock-revival has a strong correlation with the explosions energies. Our results suggest that the magnetically dominated jets are accompanied by the formation of the magnetars. Since the jets are mildly relativistic, we speculate that they might be the origin of some observed X-ray flashes.Comment: 50 pages, 14 figures, Accepted to ApJ, A paper with high-resolution figures available at http://www-utap.phys.s.u-tokyo.ac.jp/~takiwaki/res/index-j.htm

Development of the ARICA-2 Satellite Using Spresense as an Onboard Computer

Gamma-ray bursts (GRBs) are transient astronomical phenomena that emit enormous amounts of energy in electromagnetic waves, mainly in the gamma-ray range, for several seconds to tens of seconds. GRB observations are challenging because of the difficulty in predicting the location and time of occurrence and its extremely short duration. Therefore, it is necessary to notify about the discovery in space and to conduct follow-up observations by researchers. The AGU Remote Innovative CubeSat Alert system-2 (ARICA-2) has been developed to demonstrate a new alert system using commercial satellite network services. ARICA-2 uses SONY’s Spresense as its onboard computer (OBC). We manufactured the special board to attach two Spresenses as a redundancy of the OBC system. We will present the system development of ARICA-2 using Spresense