Effect of Paraquat-Induced Oxidative Stress on Insulin Regulation of Insulin-Like Growth Factor-Binding Protein-1 Gene Expression

Oxidative stress is thought to play a role in the development of insulin resistance. In order to elucidate the molecular effect of oxidative stress on liver insulin signaling, we analyzed the effect of paraquat (1,1-dimethyl-4,4-dipyridynium; PQ)-derived oxidative stress on the expression of insulin-dependent genes and activation of liver insulin signaling pathway. Incubation of primary cultured rat hepatocytes with 2 mM PQ for 6 h impaired the suppressive effect of insulin on insulin-like growth factor-binding protein-1 (IGFBP-1) gene expression, but did not influence glucose-6-phosphatase gene expression. Insulin-dependent phosphorylation or activation of insulin receptor, insulin receptor substrate-1 and -2, phosphatidylinositol 3-kinase, Akt and forkhead in rhabdomyosarcoma were not affected by PQ pre-treatment. In contrast, PQ treatment impaired insulin-dependent phosphorylation of mammalian target of rapamycin (mTOR). These results indicate that PQ-induced oxidative stress impairs insulin-dependent mTOR activation and that this impairment probably causes inhibition of insulin-dependent repression of IGFBP-1 expression

Age-related modulation of γ-secretase activity in non-human primate brains.

Age-dependent accumulation of the amyloid-β peptide (Aβ) in the brain is a pre-condition for development of Alzheimer’s disease. A relative increase in the generation of longer Aβ species such as Aβ42 and Aβ43 is critical for Aβ deposition, but the underlying mechanism remains unresolved. Here, we performed a cell-free assay using microsome fractions of temporal cortex tissues from 42 cynomolgus monkeys and found that Aβ40-generating γ-secretase activity (γ40) decreased with age, whereas Aβ42-generating γ-secretase activity (γ42) was unaltered. In ELISAs, more than 80% of monkeys over 20-years old showed evidence of Aβ accumulation in the temporal cortex. The ratio of γ42 to γ40 increased with age and correlated with the level of accumulated Aβ. These results suggest that γ-secretase activity undergoes age-related, non-genetic modulation and that this modulation may cause Aβ accumulation in aging brains. Similar modulation may predispose aged human brains to Alzheimer’s disease

Explosive nucleosynthesis in the neutrino-driven aspherical supernova explosion of a non-rotating 15M⊙M_{\odot} star with solar metallicity

We investigate explosive nucleosynthesis in a non-rotating 15$M_\odot$ star with solar metallicity that explodes by a neutrino-heating supernova (SN) mechanism aided by both standing accretion shock instability (SASI) and convection. To trigger explosions in our two-dimensional hydrodynamic simulations, we approximate the neutrino transport with a simple light-bulb scheme and systematically change the neutrino fluxes emitted from the protoneutron star. By a post-processing calculation, we evaluate abundances and masses of the SN ejecta for nuclei with the mass number $\le 70$ employing a large nuclear reaction network. Aspherical abundance distributions, which are observed in nearby core-collapse SN remnants, are obtained for the non-rotating spherically-symmetric progenitor, due to the growth of low-mode SASI. Abundance pattern of the supernova ejecta is similar to that of the solar system for models whose masses ranges (0.4-0.5) \Ms of the ejecta from the inner region (\le 10,000\km) of the precollapse core. For the models, the explosion energies and the \nuc{Ni}{56} masses are $\simeq 10^{51} \rm erg$ and (0.05-0.06) \Ms, respectively; their estimated baryonic masses of the neutron star are comparable to the ones observed in neutron-star binaries. These findings may have little uncertainty because most of the ejecta is composed by matter that is heated via the shock wave and has relatively definite abundances. The abundance ratios for Ne, Mg, Si and Fe observed in Cygnus loop are well reproduced with the SN ejecta from an inner region of the 15\Ms progenitor.Comment: 15 pages, 1 table, 17 figures, accepted for publication in Astrophyscal Journa

Efficacy and safety of micafungin in empiric and D-index-guided early antifungal therapy for febrile neutropenia ; A subgroup analysis of the CEDMIC trial

Objectives: The D-index is defined as the area over the neutrophil curve during neutropenia. The CEDMIC trial confirmed the noninferiority of D-index-guided early antifungal therapy (DET) using micafungin to empirical antifungal therapy (EAT). In this study, we evaluated the efficacy and safety of micafungin in these settings. Methods: From the CEDMIC trial, we extracted 67 and 113 patients who received micafungin in the DET and EAT groups, respectively. Treatment success was defined as the fulfilment of all components of a five-part composite end point. Fever resolution was evaluated at seven days after the completion of therapy. Results: The proportion of high-risk treatments including induction chemotherapy for acute leukemia and allogeneic hematopoietic stem cell transplantation was significantly higher in the DET group than in the EAT group (82.1% vs. 52.2%). The efficacy of micafungin was 68.7% (95%CI: 56.2–79.4) and 79.6% (71.0–86.6) in the DET and EAT groups, respectively. When we focused on high-risk treatments, the efficacy was 69.1% (55.2–80.9%) and 78.0% (65.3–87.7%), respectively (P = 0.30). There was no significant difference in any of the 5 components between the two groups. Conclusions: The efficacy of micafungin in patients undergoing high-risk treatment was not strongly impaired in DET compared to that in EAT

Absence of in vivo selection for K13 mutations after artemether–lumefantrine treatment in Uganda

Additional file 1. Eligibility criteria for recruitment into the therapeutic efficacy study and the molecular study

Mechanical guidance of self-condensation patterns of differentiating progeny

Spatially controlled self-organization represents a major challenge for organoid engineering. We have developed a mechanically patterned hydrogel for controlling self-condensation process to generate multi-cellular organoids. We first found that local stiffening with intrinsic mechanical gradient (IG > 0.008) induced single condensates of mesenchymal myoblasts, whereas the local softening led to stochastic aggregation. Besides, we revealed the cellular mechanism of two-step self-condensation: (1) cellular adhesion and migration at the mechanical boundary and (2) cell-cell contraction driven by intercellular actin-myosin networks. Finally, human pluripotent stem cell-derived hepatic progenitors with mesenchymal/endothelial cells (i.e., liver bud organoids) experienced collective migration toward locally stiffened regions generating condensates of the concave to spherical shapes. The underlying mechanism can be explained by force competition of cell-cell and cell-hydrogel biomechanical interactions between stiff and soft regions. These insights will facilitate the rational design of culture substrates inducing symmetry breaking in self-condensation of differentiating progeny toward future organoid engineering.Matsuzaki T., Shimokawa Y., Koike H., et al. Mechanical guidance of self-condensation patterns of differentiating progeny. iScience 25, 105109 (2022); https://doi.org/10.1016/j.isci.2022.105109

Preparation of mechanically patterned hydrogels for controlling the self-condensation of cells

Synthetic protocols providing mechanical patterns to culture substrate are essential to control the self-condensation of cells for organoid engineering. Here, we present a protocol for preparing hydrogels with mechanical patterns. We describe steps for hydrogel synthesis, mechanical evaluation of the substrate, and time-lapse imaging of cell self-organization. This protocol will facilitate the rational design of culture substrates with mechanical patterns for the engineering of various functional organoids. For complete details on the use and execution of this protocol, please refer to Takebe et al. (2015) and Matsuzaki et al. (2014, 2022).Matsuzaki T., Kawano Y., Horikiri M., et al. Preparation of mechanically patterned hydrogels for controlling the self-condensation of cells. STAR Protocols 4, 102471 (2023); https://doi.org/10.1016/j.xpro.2023.102471

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