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

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

Primary arm array during directional solidification of a single-crystal binary alloy: Large-scale phase-field study

AbstractPrimary arm arrays formed during the directional solidification of a single-crystal binary alloy were investigated by performing large-scale phase-field simulations using the GPU supercomputer TSUBAME2.5 at Tokyo Institute of Technology. The primary arm array and spacing were investigated by Voronoi decomposition and Delaunay triangulation, respectively. It was concluded that a hexagonal array was dominant for both the dendrite and cell structures and that penta–hepta defects, which are typical defects in hexagonal patterns, were formed. The primary arms continuously moved such that the number of hexagons increased, and the distribution of primary arm spacing became uniform over time even after the number of primary arms was constant. The order of array was highest in the growth condition of the dendrite close to the cell-to-dendrite transition region. In addition, we proposed a realistic and accurate evaluation method of primary arm array by removing small sides from the Voronoi polygons

T cell–intrinsic prostaglandin E₂-EP2/EP4 signaling is critical in pathogenic T_H17 cell–driven inflammation

PGE2経路による病因細胞Th17の増殖機構を解明 --乾癬の慢性的な皮膚炎症を改善する新しい治療薬開発に向けて--. 京都大学プレスリリース. 2018-06-20.Background: IL-23 is the key cytokine for generation of pathogenic IL-17–producing helper T (TH17) cells, which contribute critically to autoimmune diseases. However, how IL-23 generates pathogenic TH17 cells remains to be elucidated. Objectives: We sought to examine the involvement, molecular mechanisms, and clinical implications of prostaglandin (PG) E2–EP2/EP4 signaling in induction of IL-23–driven pathogenic TH17 cells. Methods: The role of PGE2 in induction of pathogenic TH17 cells was investigated in mouse TH17 cells in culture in vitro and in an IL-23–induced psoriasis mouse model in vivo. Clinical relevance of the findings in mice was examined by using gene expression profiling of IL-23 and PGE2-EP2/EP4 signaling in psoriatic skin from patients. Results: IL-23 induces Ptgs2, encoding COX2 in TH17 cells, and produces PGE2, which acts back on the PGE receptors EP2 and EP4 in these cells and enhances IL-23–induced expression of an IL-23 receptor subunit gene, Il23r, by activating signal transducer and activator of transcription (STAT) 3, cAMP-responsive element binding protein 1, and nuclear factor κ light chain enhancer of activated B cells (NF-κB) through cyclic AMP–protein kinase A signaling. This PGE2 signaling also induces expression of various inflammation-related genes, which possibly function in TH17 cell–mediated pathology. Combined deletion of EP2 and EP4 selectively in T cells suppressed accumulation of IL-17A+ and IL-17A+IFN-γ+ pathogenic Th17 cells and abolished skin inflammation in an IL-23–induced psoriasis mouse model. Analysis of human psoriatic skin biopsy specimens shows positive correlation between PGE2 signaling and the IL-23/TH17 pathway. Conclusions: T cell–intrinsic EP2/EP4 signaling is critical in IL-23–driven generation of pathogenic TH17 cells and consequent pathogenesis in the skin

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

Diagnostic ability of contrast-enhanced computed tomography formetastatic cervical nodes in head and neck squamous cell carcinomas : significance of additional coronal reconstruction images

Purpose: To evaluate the significance of additional coronal reconstruction images in the diagnostic ability of contrastenhanced computed tomography (CECT) for metastatic cervical nodes in patients with head and neck squamous cell carcinomas (HNSCC). Material and methods: We retrospectively assessed 97 metastatic and 141 reactive histologically proven cervical nodes of 38 patients with HNSCC, who underwent CECT before neck dissection. Observer #1, an expert radiologist in head and neck imaging, and observer #2, a general radiologist, reviewed all CECT images. The observers first assessed the presence of nodal metastasis using axial CECT alone (A-CECT). Three days later, they reassessed its presence using combined axial and coronal CECT (A&C-CECT). Results: The sensitivity of A-CECT vs. A&C-CECT was 73.2% vs. 75.3% for observer #1 (p = 0.73) and 69.1% vs. 69.1% for observer #2 (p = 1.00), respectively. The specificity of A-CECT versus A&C-CECT was 92.2% vs. 97.2% for observer #1 (p < 0.05) and 92.9% vs. 95.7% for observer #2 (p = 0.22), respectively. The accuracy of A-CECT versus A&C-CECT was 84.5% vs. 88.2% for observer #1 (p < 0.05) and 83.2% vs. 85.3% for observer #2 (p = 0.30), respectively. The area under the curve (AUC) of A-CECT vs. A&C-CECT was 0.86 vs. 0.91 for observer #1 (p < 0.05) and 0.85 vs. 0.85 for observer #2 (p = 0.80), respectively. Conclusions: The specificity, accuracy, and AUC increased with the use of coronal images during the assessment by the expert radiologist. The appropriate use of coronal images allowed proper configuration recognition and improved diagnostic ability

Stargazer: Long-Term and Multiregional Measurement of Timing/ Geolocation-Based Cloaking

Malicious hosts have come to play a significant and varied role in today's cyber attacks. Some of these hosts are equipped with a technique called cloaking, which discriminates between access from potential victims and others and then returns malicious content only to potential victims. This is a serious threat because it can evade detection by security vendors and researchers and cause serious damage. As such, cloaking is being extensively investigated, especially for phishing sites. We are currently engaged in a long-term cloaking study of a broader range of threats. In the present study, we implemented Stargazer, which actively monitors malicious hosts and detects geographic and temporal cloaking, and collected 30,359,410 observations between November 2019 and February 2022 for 18,397 targets from 13 sites where our sensors are installed. Our analysis confirmed that cloaking techniques are widely abused, i.e., not only in the context of specific threats such as phishing. This includes geographic and time-based cloaking, which is difficult to detect with single-site or one-shot observations. Furthermore, we found that malicious hosts that perform cloaking include those that survive for relatively long periods of time, and those whose contents are not present in VirusTotal. This suggests that it is not easy to observe and analyze the cloaking malicious hosts with existing technologies. The results of this study have deepened our understanding of various types of cloaking, including geographic and temporal ones, and will help in the development of future cloaking detection methods

Prostaglandin E-2-EP2-NF-kappa B signaling in macrophages as a potential therapeutic target for intracranial aneurysms

Intracranial aneurysms are common but are generally untreated, and their rupture can lead to subarachnoid hemorrhage. Because of the poor prognosis associated with subarachnoid hemorrhage, preventing the progression of intracranial aneurysms is critically important. Intracranial aneurysms are caused by chronic inflammation of the arterial wall due to macrophage infiltration triggered by monocyte chemoattractant protein-1 (MCP-1), macrophage activation mediated by the transcription factor nuclear factor kappa B (NF-kappa B), and inflammatory signaling involving prostaglandin E-2 (PGE(2)) and prostaglandin E receptor subtype 2 (EP2). We correlated EP2 and cyclooxygenase-2 (COX-2) with macrophage infiltration in human intracranial aneurysm lesions. Monitoring the spatiotemporal pattern of NF-kappa B activation during intracranial aneurysm development in mice showed that NF-kappa B was first activated in macrophages in the adventitia and in endothelial cells and, subsequently, in the entire arterial wall. Mice with a macrophage-specific deletion of Ptger2 (which encodes EP2) or macrophage-specific expression of an I kappa B alpha mutant that restricts NF-kappa B activation had fewer intracranial aneurysms with reduced macrophage infiltration and NF-kappa B activation. In cultured cells, EP2 signaling cooperated with tumor necrosis factor-alpha (TNF-alpha) to activate NF-kappa B and synergistically induce the expression of proinflammatory genes, including Ptgs2 (encoding COX-2). EP2 signaling also stabilized Ccl2 (encoding MCP-1) by activating the RNA-stabilizing protein HuR. Rats administered an EP2 antagonist had reduced macrophage infiltration and intracranial aneurysm formation and progression. This signaling pathway in macrophages thus facilitates intracranial aneurysm development by amplifying inflammation in intracranial arteries. These results indicate that EP2 antagonists may therefore be a therapeutic alternative to surgery.Peer reviewe

Design, Synthesis, and Biological Applications of Boron-Containing Polyamine and Sugar Derivatives

Boron (B), an element that is present in ultratrace amounts in animal cells and tissues, is expected to be useful in many scientific fields. We have found the hydrolysis of C–B bond in phenylboronic acid-pendant cyclen (cyclen = 1,4,7,10-tetraazacyclododecane) and the full decomposition of ortho-carborane attached with cyclen and ethylenediamines in aqueous solution at neutral pH upon complexation with intracellular metals. The change in the chemical shift of the 11B signals in 11B-NMR spectra of these boron-containing metal chelators can be applied to the magnetic resonance imaging (MRI) of metal ions in solutions and in living cells