The Development and the Use of Experimental Animal Models to Study the Underlying Mechanisms of CA Formation

Cerebral aneurysms (CAs) have a high prevalence and can cause a lethal subarachnoid hemorrhage. Currently, CAs can only be treated with invasive surgical procedures. To unravel the underlying mechanisms of CA formation and to develop new therapeutic drugs for CAs, animal models of CA have been established, modified, and analyzed. Experimental findings from these models have clarified some of the potential mechanisms of CA formation, especially the relationship between hemodynamic stress and chronic inflammation. Increased hemodynamic stress acting at the site of bifurcation of cerebral arteries triggers an inflammatory response mediated by various proinflammatory molecules in arterial walls, inducing pathological changes in the models similar to those observed in the walls of human CAs. Findings from animal studies have provided new insights into CA formation and may contribute to the development of new therapeutic drugs for CAs

Dynamical Aspects of Large N Reduced Models

We study the large N reduced model of D-dimensional Yang-Mills theory with special attention to dynamical aspects related to the eigenvalues of the N by N matrices, which correspond to the space-time coordinates in the IIB matrix model. We first put an upper bound on the extent of space time by perturbative arguments. We perform a Monte Carlo simulation and show that the upper bound is actually saturated. The relation of our result to the SSB of the U(1)^D symmetry in the Eguchi-Kawai model is clarified. We define a quantity which represents the uncertainty of the space-time coordinates and show that it is of the same order as the extent of space time, which means that a classical space-time picture is maximally broken. We develop a 1/D expansion, which enables us to calculate correlation functions of the model analytically. The absence of an SSB of the Lorentz invariance is shown by the Monte Carlo simulation as well as by the 1/D expansion.Comment: 41 pages, LaTeX, 15 eps figures; comments added for the well-definedness of the models and for a related referenc

Critical role of TNF-alpha-TNFR1 signaling in intracranial aneurysm formation

BACKGROUND: Intracranial aneurysm (IA) is a socially important disease due to its high incidence in the general public and the severity of resultant subarachnoid hemorrhage that follows rupture. Despite the social importance of IA as a cause of subarachnoid hemorrhage, there is no medical treatment to prevent rupture, except for surgical procedures, because the mechanisms regulating IA formation are poorly understood. Therefore, these mechanisms should be elucidated to identify a therapeutic target for IA treatment. In human IAs, the presence of inflammatory responses, such as an increase of tumor necrosis factor (TNF)-alpha, have been observed, suggesting a role for inflammation in IA formation. Recent investigations using rodent models of IAs have revealed the crucial role of inflammatory responses in IA formation, supporting the results of human studies. Thus, we identified nuclear factor (NF)-kappaB as a critical mediator of inflammation regulating IA formation, by inducing downstream pro-inflammatory genes such as MCP-1, a chemoattractant for macrophages, and COX-2. In this study, we focused on TNF-alpha signaling as a potential cascade that regulates NF-kappaB-mediated IA formation. RESULTS: We first confirmed an increase in TNF-alpha content in IA walls during IA formation, as expected based on human studies. Consistently, the activity of TNF-alpha converting enzyme (TACE), an enzyme responsible for TNF-alpha release, was induced in the arterial walls after aneurysm induction in a rat model. Next, we subjected tumor necrosis factor receptor superfamily member 1a (TNFR1)-deficient mice to the IA model to clarify the contribution of TNF-alpha-TNFR1 signaling to pathogenesis, and confirmed significant suppression of IA formation in TNFR1-deficient mice. Furthermore, in the IA walls of TNFR1-deficient mice, inflammatory responses, including NF-kappaB activation, subsequent expression of MCP-1 and COX-2, and infiltration of macrophages into the IA lesion, were greatly suppressed compared with those in wild-type mice. CONCLUSIONS: In this study, using rodent models of IAs, we clarified the crucial role of TNF-alpha-TNFR1 signaling in the pathogenesis of IAs by inducing inflammatory responses, and propose this signaling as a potential therapeutic target for IA treatment

Multicanonical simulation of 3D dynamical triangulation model and a new phase structure

We apply the multicanonical technique to the three dimensional dynamical triangulation model, which is known to exhibit a first order phase transition with the Einstein-Hilbert action. We first clarify the first order nature of the phase transition with the Einstein-Hilbert action in several ways including a high precision finite size scaling analysis. We then add a new local term to the action and confirm the conjecture made through the MCRG technique that the line of the first order phase transition extends to the expanded phase diagram, ending at a point. Fractal dimension at the end point is measured to be around three up to the present size.Comment: 20 pages, latex2e(graphic package), 9 figure

Modification of cell vulnerability to oxidative stress by N-(3-oxododecanoyl)-L-homoserine-lactone, a quorum sensing molecule, in rat thymocytes

N-(3-oxododecanoyl)-L-homoserine-lactone (ODHL), a quorum sensing molecule, affects intracellular Zn2+ concentration ([Zn2+]i) and cellular levels of nonprotein thiols ([NPT]i) of rat thymic lymphocytes, both of which are assumed to affect cell vulnerability to oxidative stress. Therefore, it is interesting to examine the effects of ODHL on the cells under oxidative stress. ODHL augmented the cytotoxicity of H2O2, but not calcium ionophore A23187. ODHL potentiated the H2O2-induced elevation of [Zn2+]i, wherein, it greatly attenuated the H2O2-induced increase in intracellular Ca2+ concentration. ODHL did not affect [NPT]i in the presence of H2O2. Therefore, we conclude that the elevation of [Zn2+]i is involved in the ODHL-induced potentiation of H2O2 cytotoxicity. Our findings suggest that ODHL modifies cell vulnerability to oxidative stress in host cells

Ladder Siamese Network: a Method and Insights for Multi-level Self-Supervised Learning

Siamese-network-based self-supervised learning (SSL) suffers from slow convergence and instability in training. To alleviate this, we propose a framework to exploit intermediate self-supervisions in each stage of deep nets, called the Ladder Siamese Network. Our self-supervised losses encourage the intermediate layers to be consistent with different data augmentations to single samples, which facilitates training progress and enhances the discriminative ability of the intermediate layers themselves. While some existing work has already utilized multi-level self supervisions in SSL, ours is different in that 1) we reveal its usefulness with non-contrastive Siamese frameworks in both theoretical and empirical viewpoints, and 2) ours improves image-level classification, instance-level detection, and pixel-level segmentation simultaneously. Experiments show that the proposed framework can improve BYOL baselines by 1.0% points in ImageNet linear classification, 1.2% points in COCO detection, and 3.1% points in PASCAL VOC segmentation. In comparison with the state-of-the-art methods, our Ladder-based model achieves competitive and balanced performances in all tested benchmarks without causing large degradation in one

薬物の腎排泄および消化管吸収に及ぼすトランスポーターの影響とカニクイザルにおける低吸収性の要因

取得学位：博士(薬学)，学位授与番号：博甲第907号，学位授与年月日：平成19年3月22

Singular Vertices in the Strong Coupling Phase of Four--Dimensional Simplicial Gravity

We study four--dimensional simplicial gravity through numerical simulation with special attention to the existence of singular vertices, in the strong coupling phase, that are shared by abnormally large numbers of four--simplices. The second order phase transition from the strong coupling phase into the weak coupling phase could be understood as the disappearance of the singular vertices. We also change the topology of the universe from the sphere to the torus.Comment: 10 pages, six PostScript figures; figures are also available at http://hep-th.phys.s.u-tokyo.ac.jp/~izubuchi/paper/4dqg

Loss of maternal annexin A5 increases the likelihood of placental platelet thrombosis and foetal loss

Antiphospholipid syndrome is associated with an increased risk of thrombosis and pregnancy loss. Annexin A5 (Anxa5) is a candidate autoantigen. It is not known, however, whether endogenous Anxa5 prevents foetal loss during normal pregnancy. We found significant reductions in litter size and foetal weight in Anxa5-null mice (Anxa5-KO). These changes occurred even when only the mother was Anxa5-KO. A small amount of placental fibrin deposition was observed in the decidual tissues, but did not noticeably differ between wild-type and Anxa5-KO mice. However, immunoreactivity for integrin beta 3/CD61, a platelet marker, was demonstrated within thrombi in the arterial canals only in Anxa5-KO mothers. Subcutaneous administration of the anticoagulant heparin to pregnant Anxa5-KO mice significantly reduced pregnancy loss, suggesting that maternal Anxa5 is crucial for maintaining intact placental circulation. Hence, the presence of maternal Anxa5 minimises the risk of thrombosis in the placental circulation and reduces the risk of foetal loss