Safer Treatment of Novel Imeglimin (Twymeeg) For Elderly Female with Type 2 Diabetes (T2D)

Background: A novel oral hypoglycemic agent (OHA) would be imeglimin (Twymeeg) as tetrahydrotriazine-containing drug. Case presentation: The patient is 93-year-old female and developed appetite loss and slower vocal response in March, 2022. Result: She was transferred to our hospital, and diagnosed as T2DM with HbA1c 8.4% and small lacunar infarction in bilateral white matter by MRI. Then, imeglimin 2000mg/day was started and HbA1c was decreased to 6.2% in April, 2020. Discussion: Imeglimin has dual function for increasing insulin secretion and decreasing insulin resistance. It seems to be effective for elderly case, and will be used widely in the future

Mathematical modeling of atopic dermatitis reveals "double switch" mechanisms underlying 4 common disease phenotypes

Background: The skin barrier acts as the first line of defense against constant exposure to biological, microbial, physical and chemical environmental stressors. Dynamic interplay between defects in the skin barrier, dysfunctional immune responses, and environmental stressors are major factors in the development of atopic dermatitis (AD). A systems-biology modeling approach can yield significant insights into these complex and dynamic processes through integration of prior biological data. Objective: To develop a multi-scale mathematical model of AD pathogenesis that describes the dynamic interplay between the skin barrier, environmental stress and immune dysregulation, and use it to achieve a coherent mechanistic understanding of onset, progression and prevention of AD. Methods: We mathematically investigated synergistic effects of known genetic and environmental risk factors on the dynamic onset and progression of the AD phenotype, from a mostly asymptomatic mild phenotype to a severe treatment-resistant form. Results: Our model analysis identified a “double switch”, with two concatenated bistable switches, as a key network motif that dictates AD pathogenesis: The first switch is responsible for the reversible onset of inflammation; The second switch is triggered by long-lasting or frequent activation of the first switch, causing the irreversible onset of systemic Th2 sensitization and worsening of AD symptoms. Conclusions: Our mathematical analysis of the bistable switch predicts that genetic risk factors lower the threshold of environmental stressors to trigger systemic Th2 sensitization. This analysis predicts and explains four common clinical AD phenotypes from a mild and reversible phenotype through to severe and recalcitrant disease and provides a mechanistic explanation for clinically-demonstrated preventive effects of emollient treatments against development of AD

Molecular and functional characterization of an evolutionarily conserved CREB-binding protein in the Lymnaea CNS

In eukaryotes, CREB-binding protein (CBP), a coactivator of CREB, functions both as a platform for recruiting other components of the transcriptional machinery and as a histone acetyltransferase (HAT) that alters chromatin structure. We previously showed that the transcriptional activity of cAMP-responsive element binding protein (CREB) plays a crucial role in neuronal plasticity in the pond snail Lymnaea stagnalis. However, there is no information on the molecular structure and HAT activity of CBP in the Lymnaea central nervous system (CNS), hindering an investigation of its postulated role in long-term memory (LTM). Here, we characterize the Lymnaea CBP (LymCBP) gene and identify a conserved domain of LymCBP as a functional HAT. Like CBPs of other species, LymCBP possesses functional domains, such as the KIX domain, which is essential for interaction with CREB and was shown to regulate LTM. In-situ hybridization showed that the staining patterns of LymCBP mRNA in CNS are very similar to those of Lymnaea CREB1. A particularly strong LymCBP mRNA signal was observed in the cerebral giant cell (CGC), an identified extrinsic modulatory interneuron of the feeding circuit, the key to both appetitive and aversive LTM for taste. Biochemical experiments using the recombinant protein of the LymCBP HAT domain showed that its enzymatic activity was blocked by classical HAT inhibitors. Preincubation of the CNS with such inhibitors blocked cAMP-induced synaptic facilitation between the CGC and an identified follower motoneuron of the feeding system. Taken together, our findings suggest a role for the HAT activity of LymCBP in synaptic plasticity in the feeding circuitry

The Effect of Valproic Acid on Mesenchymal Pluripotent Cell Proliferation and Differentiation in Extracellular Matrices

Valproic acid (2-n-propylpentanoic acid, VPA) is a widely used antiepileptic and anticonvulsant drug. Previous studies have reported that VPA effects osteogenesis in vivo and in vitro, yet it remains unclear whether VPA promotes cell differentiation of osteoblasts derived from mesenchymal cells. The purpose of this study was to clarify the effect of VPA on undifferentiated pluripotent mesenchymal cell proliferation and differentiation into osteoblasts while analyzing the impact of the absence or presence of extracellular matrices (ECMs). Mouse mesenchymal cells were cultured on non-coated plastic, type I collagen-coated, and fibronectin-coated plates in the absence or presence of VPA. A cell proliferation assay was performed in which modified formazan dye content was analyzed and proliferation nuclear antigen (PCNA)-positive cells were counted at various concentrations of VPA. A high concentration of VPA did not clearly alter cell morphology, but large numbers of stress fibers were observed in these cells and the cell proliferation ratio was decreased with positive PCNA counts. In the presence of matrices, the cell proliferation ratio decreased at low VPA concentrations compared with the ratio obtained in the absence of these ECMs. On the other hand, VPA promoted osteoblastic differentiation in the presence of type I collagen. These findings indicate that for undifferentiated mesenchymal cells, VPA promotes a decrease in the cell proliferation rate in the presence of ECMs and promotes osteoblastic differentiation, both of which could provide insight into additional mechanisms of osteoblastic cell differentiation caused by VPA

Measurement of radon concentrations at Super-Kamiokande

Radioactivity from radon is a major background for observing solar neutrinos at Super-Kamiokande. In this paper, we describe the measurement of radon concentrations at Super-Kamiokande, the method of radon reduction, and the radon monitoring system. The measurement shows that the current low-energy event rate between 5.0 MeV and 6.5 MeV implies a radon concentration in the Super-Kamiokande water of less than 1.4 mBq/m$^3$.Comment: 11 pages, 4 figure

Observation of the east-west anisotropy of the atmospheric neutrino flux

The east-west anisotropy, caused by the deflection of primary cosmic rays in the Earth's magnetic field, is observed for the first time in the flux of atmospheric neutrinos. Using a 45 kt-year exposure of the Super-Kamiokande detector, 552 e-like and 633 mu-like horizontally-going events are selected in the momentum range between 400 and 3000 MeV/c. The azimuthal distribution of e-like and mu-like events agrees with the expectation from atmospheric neutrino flux calculations that account for the geomagnetic field, verifying that the geomagnetic field effects in the production of atmospheric neutrinos in the GeV energy range are well understood.Comment: 8 pages,3 figures revtex, submitted to PR

Search for Supernova Relic Neutrinos at Super-Kamiokande

A search for the relic neutrinos from all past core-collapse supernovae was conducted using 1496 days of data from the Super-Kamiokande detector. This analysis looked for electron-type anti-neutrinos that had produced a positron with an energy greater than 18 MeV. In the absence of a signal, 90% C.L. upper limits on the total flux were set for several theoretical models; these limits ranged from 20 to 130 nu_e bar cm^-2 s^-1. Additionally, an upper bound of 1.2 nu_e bar cm^-2 s^-1 was set for the supernova relic neutrino flux in the energy region E_nu > 19.3 MeV.Comment: 4 pages, 2 figures. Submitted to Physical Review Letters. New version includes corrections to Figure 1. Also, text has been shortened to conform with the space limitations of PR

Measurement of the flux and zenith-angle distribution of upward through-going muons by Super-Kamiokande

A total of 614 upward through-going muons of minimum energy 1.6 GeV are observed by Super-Kamiokande during 537 detector live days. The measured muon flux is 1.74+/-0.07(stat.)+/-0.02(sys.)x10^{-13}cm^{-2}s^{-1}sr^{-1} compared to an expected flux of 1.97+/-0.44(theo.)x10^{-13}cm^{-2}s^{-1}sr^{-1}. The absolute measured flux is in agreement with the prediction within the errors. However, the zenith angle dependence of the observed upward through-going muon flux does not agree with no-oscillation predictions. The observed distortion in shape is consistent with the \nu_\mu \nu_\tau oscillation hypothesis with \sin^22\theta > 0.4 and 1x10^{-3} < \Delta m^2 < 1x10^{-1} eV^{2} at 90% confidence level.Comment: 8 pages w/ 3 figures new version contains minor fixes, as it appears in PR

A search for periodic modulations of the solar neutrino flux in Super-Kamiokande-I

A search for periodic modulations of the solar neutrino flux was performed using the Super-Kamiokande-I data taken from May 31st, 1996 to July 15th, 2001. The detector's capability of measuring the exact time of events, combined with a relatively high yield of solar neutrino events, allows a search for short-time variations in the observed flux. We employed the Lomb test to look for periodic modulations of the observed solar neutrino flux. The obtained periodogram is consistent with statistical fluctuation and no significant periodicity was found

Measurement of a small atmospheric νμ/νe\nu_\mu/\nu_e ratio

From an exposure of 25.5~kiloton-years of the Super-Kamiokande detector, 900 muon-like and 983 electron-like single-ring atmospheric neutrino interactions were detected with momentum $p_e > 100$ MeV/$c$, $p_\mu > 200$ MeV/$c$, and with visible energy less than 1.33 GeV. Using a detailed Monte Carlo simulation, the ratio $(\mu/e)_{DATA}/(\mu/e)_{MC}$ was measured to be $0.61 \pm 0.03(stat.) \pm 0.05(sys.)$, consistent with previous results from the Kamiokande, IMB and Soudan-2 experiments, and smaller than expected from theoretical models of atmospheric neutrino production.Comment: 14 pages with 5 figure