血管内皮細胞における過酸化水素誘導のカベオリン-1リン酸化に対するケルセチンの抑制効果

Caveolin-1 is a major protein of the caveolae structure in vascular endothelial cell membrane. Phosphorylation of caveolin-1 is one of the initial events leading to exacerbation of vascular permeability caused by oxidative stress. Although quercetin is known to be an anti-atherosclerosis factor that acts as a dietary antioxidant, little is known about its role in the regulation of caveolin-1 phosphorylation. In this study, we investigated the inhibitory effect of quercetin on hydrogen peroxide-induced caveolin-1 phosphorylation in human umbilical vein endothelial cells. Quercetin inhibited caveolin-1 phosphorylation in cells pretreated with quercetin for 24 h and then exposed to hydrogen peroxide. However, quercetin 3-O-β-glucuronide, a conjugated metabolite of quercetin, did not exert this inhibitory effect. Exposure to hydrogen peroxide increased vascular permeability and reduced mRNA expression of the intercellular adhesion protein, vascular endothelial cadherin (VE-cadherin). By contrast, pretreatment with quercetin suppressed the increase in vascular permeability and decreased VE-cadherin expression. These results indicate that deconjugated quercetin can play a role in the prevention of altered vascular permeability under oxidative stress by suppressing caveolin-1 phosphorylation. Thus, dietary quercetin may be beneficial for the maintenance of endothelial cell function

High platelet reactivity is a predictor of left ventricular remodelling in patients with acute myocardial infarction

Aims Acute myocardial infarction (AMI) is associated with left ventricular remodelling (LVR), which leads to progressive heart failure. Platelets play a pivotal role in promoting systemic and cardiac inflammatory responses during the complex process of myocardial wound healing or repair following AMI. This study aimed to investigate the impact of platelet reactivity immediately after primary percutaneous coronary intervention (PCI) on LVR in AMI patients with ST-segment (STEMI) and nonST-segment elevation (NSTEMI). Methods and results This prospective, single-centre, observational study included 182 patients with AMI who underwent primary PCI (107 patient with STEMI and 75 patients with NSTEMI). Patients were administered a loading dose of aspirin plus prasugrel before the procedure, and platelet reactivity was assessed using the VerifyNow P2Y12 assay immediately after PCI. Echocardiography was performed before discharge and during the chronic phase (8 +/- 3 months after discharge). LVR was defined as a relative >= 20% increase in left ventricular end-diastolic volume index (LVEDVI). LVR in chronic phase was found in 34 patients (18.7%) whose platelet reactivity was significantly higher than those without LVR (259.6 +/- 61.5 and 213.1 +/- 74.8 P2Y12 reaction units [PRU]; P = 0.001). The occurrence of LVR did not differ between patients with STEMI and patients with NSTEMI (21.5% and 14.7%; P = 0.33). The optimal cut-off value of platelet reactivity for discriminating LVR was >= 245 PRU. LVEDVI significantly decreased at chronic phase in patients without high platelet reactivity (= d245 PRU) (P = 0.06). Multivariate logistic analysis showed that high platelet reactivity was an independent predictor of LVR after adjusting for LVEDVI before discharge (odds ratio, 4.13; 95% confidence interval, 1.85-9.79). Conclusions High platelet reactivity measured immediately after PCI was a predictor of LVR in patients with AMI during the chronic phase. The role of antiplatelet therapy on inflammation in the myocardium is a promising area for further research

A Comprehensive Study of Short Bursts from SGR 1806-20 and SGR 1900+14 Detected by HETE-2

We present the results of temporal and spectral studies of the short burst (less than a few hundred milliseconds) from the soft gamma repeaters (SGRs) 1806-20 and 1900+14 using the HETE-2 samples. In five years from 2001 to 2005, HETE-2 detected 50 bursts which were localized to SGR 1806-20 and 5 bursts which were localized to SGR 1900+14. Especially SGR 1806-20 was active in 2004, and HETE-2 localized 33 bursts in that year. The cumulative number-intensity distribution of SGR 1806-20 in 2004 is well described by a power law model with an index of -1.1+/-0.6. It is consistent with previous studies but burst data taken in other years clearly give a steeper distribution. This may suggest that more energetic bursts could occur more frequently in periods of greater activity. A power law cumulative number-intensity distribution is also known for earthquakes and solar flares. It may imply analogous triggering mechanisms. Although spectral evolution during bursts with a time scale of > 20 ms is not common in the HETE-2 sample, spectral softening due to the very rapid (< a few milliseconds) energy reinjection and cooling may not be excluded. The spectra of all short bursts are well reproduced by a two blackbody function (2BB) with temperatures ~4 and ~11 keV. From the timing analysis of the SGR 1806-20 data, a time lag of 2.2+/-0.4 ms is found between the 30-100 keV and 2-10 keV radiation bands. This may imply (1) a very rapid spectral softening and energy reinjection, (2) diffused (elongated) emission plasma along the magnetic field lines in pseudo equilibrium with multi-temperatures, or (3) a separate (located at < 700 km) emission region of softer component (say, ~4 keV) which could be reprocessed X-rays by higher energy (> 11 keV) photons from an emission region near the stellar surface.Comment: 50 pages, 14 figures, accepted for publication in PAS

Modular Invariance in Superstring on Calabi-Yau n-fold with A-D-E Singularity

We study the type II superstring theory on the background \br^{d-1,1}\times X_n, where $X_n$ is a Calabi-Yau $n$-fold ($2n+d=10$) with an isolated singularity, by making use of the holographically dual description proposed by Giveon-Kutasov-Pelc (hep-th/9907178). We compute the toroidal partition functions for each of the cases $d=6,4,2$, and obtain manifestly modular invariant solutions classified by the standard $A-D-E$ series corresponding to the type of singularities on $X_n$. Partition functions of these modular invariants all vanish due to theta function identities and are consistent with the presence of space-time supersymmetry.Comment: typos corrected, to appear in Nucl. Phys.

Differentiation of hypertrophic chondrocytes from human iPSCs for the in vitro modeling of chondrodysplasias

iPS細胞から肥大軟骨細胞への誘導法を確立し、成長板疾患の病態再現に成功. 京都大学プレスリリース. 2021-02-26.Reprogramming children's cells to study cartilage diseases. 京都大学プレスリリース. 2021-02-26.Chondrodysplasias are hereditary diseases caused by mutations in the components of growth cartilage. Although the unfolded protein response (UPR) has been identified as a key disease mechanism in mouse models, no suitable in vitro system has been reported to analyze the pathology in humans. Here, we developed a three-dimensional culture protocol to differentiate hypertrophic chondrocytes from induced pluripotent stem cells (iPSCs) and examine the phenotype caused by MATN3 and COL10A1 mutations. Intracellular MATN3 or COL10 retention resulted in increased ER stress markers and ER size in most mutants, but activation of the UPR was dependent on the mutation. Transcriptome analysis confirmed a UPR with wide-ranging changes in bone homeostasis, extracellular matrix composition, and lipid metabolism in the MATN3 T120M mutant, which further showed altered cellular morphology in iPSC-derived growth-plate-like structures in vivo. We then applied our in vitro model to drug testing, whereby trimethylamine N-oxide led to a reduction of ER stress and intracellular MATN3

N=4 Superconformal Algebra and the Entropy of HyperKahler Manifolds

We study the elliptic genera of hyperKahler manifolds using the representation theory of N=4 superconformal algebra. We consider the decomposition of the elliptic genera in terms of N=4 irreducible characters, and derive the rate of increase of the multiplicities of half-BPS representations making use of Rademacher expansion. Exponential increase of the multiplicity suggests that we can associate the notion of an entropy to the geometry of hyperKahler manifolds. In the case of symmetric products of K3 surfaces our entropy agrees with the black hole entropy of D5-D1 system.Comment: 25 pages, 1 figur

SL(2,R)/U(1) Supercoset and Elliptic Genera of Non-compact Calabi-Yau Manifolds

We first discuss the relationship between the SL(2;R)/U(1) supercoset and N=2 Liouville theory and make a precise correspondence between their representations. We shall show that the discrete unitary representations of SL(2;R)/U(1) theory correspond exactly to those massless representations of N=2 Liouville theory which are closed under modular transformations and studied in our previous work hep-th/0311141. It is known that toroidal partition functions of SL(2;R)/U(1) theory (2D Black Hole) contain two parts, continuous and discrete representations. The contribution of continuous representations is proportional to the space-time volume and is divergent in the infinite-volume limit while the part of discrete representations is volume-independent. In order to see clearly the contribution of discrete representations we consider elliptic genus which projects out the contributions of continuous representations: making use of the SL(2;R)/U(1), we compute elliptic genera for various non-compact space-times such as the conifold, ALE spaces, Calabi-Yau 3-folds with A_n singularities etc. We find that these elliptic genera in general have a complex modular property and are not Jacobi forms as opposed to the cases of compact Calabi-Yau manifolds.Comment: 39 pages, no figure; v2 references added, minor corrections; v3 typos corrected, to appear in JHEP; v4 typos corrected in eqs. (3.22) and (3.44