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Steel truss bridges, which are one of the bridge structures applicable to long spans, are widely used as marine bridges connecting mainland and remote island. Since such steel truss bridges are built on the sea, they are exposed to severe corrosive environment due to the influence of airborne salt. In addition, there are many parts where it is not easy to inspect to detect abnormalities, so it is more difficult to eliminate the risk of member damage in such steel truss bridges than in general bridges. On the other hand, once the marine bridges are built, they become an indispensable facility for the life of the island. Therefore, if there are no other traffic routes to access an island, the sustainability of the marine bridge is an important issue that is directly linked to the sustainability of the remote island life. When member damage occurs in a steel truss bridge, it depends on redundancy, which means the margin for the load-bearing capacity and load-bearing function, whether the damage develops into chain damage or remains limited damage. Bridges with redundancy could be restored by repairing even if the member damages occurred, because they did not develop into chain damages. In some cases, vehicles could pass through with traffic restrictions. Although redundancy is an important performance for maintaining life on remote islands that have no alternative traffic routes, there are few studies on evaluation and improvement methods of redundancy for long steel truss bridges used for marine bridges. The purpose of this study is to propose a method for improving the redundancy of long steel truss bridges, and three research subjects are set to achieve this purpose. The first study subject is the investigation of the effect of truss joint modeling on redundancy evaluation, and is the subject to appropriately evaluate the redundancy of steel truss bridges. The second is also the subject related to the redundancy evaluation of steel truss bridges, and is the development of dynamic response calculation method that considers the vibration characteristics of steel truss bridges, which are vibration systems with multiple degrees of freedom. The third study subject is a proposal for methods to improve the redundancy of long steel truss bridges. This paper consists of five chapters. Chapter 1 is an introduction, and describes the background of the research, the setting of the purpose and research subjects, and the previous studies. Chapter 2 describes the study on the modeling of the truss joint. In the analysis of healthy steel truss bridges with no member damage, the sectional forces can be calculated appropriately even with analysis modeling in which frame elements of truss members are rigidly connected at the truss joints, simply. On the other hand, in the redundancy analysis of steel truss bridges with member damages, it is shown that it is necessary to consider the shape of the gusset plates at the truss joints in analysis modeling. Chapter 3 describes the study on the calculation method of dynamic response caused by damage of truss members. There are cases where the dynamic response due to member damage is calculated in the same way as a single-degree-of-freedom vibration system. However, this study develops a dynamic response calculation method considering the vibration characteristics of long steel truss bridges by using the eigenvector of steel truss bridges with member damage. A method is proposed to set the magnitude of the eigenvector using balance equation of the work given to the steel truss bridge by the sectional force unloaded from damaged member and the strain energy stored in the steel truss bridge. In addition, a method is proposed to calculate the dynamic response by setting the range of vibration modes using the sum of effective mass ratio, and selecting the eigenvector that has the greatest effect on the dynamic response for each member. It is shown that the proposed calculation method gives redundancy evaluation closer to time-history-response analysis than the method that calculates the dynamic response in the same way as a single-degree-offreedom vibration system. Chapter 4 describes the study on redundancy improvement for a long steel truss bridge. A combination of the countermeasure against members that trigger chain damage and the countermeasure against members with insufficient load-bearing capacity is planned. Analysis clarifies that the X bracing, which is a reinforcing structure in X shape, is an efficient reinforcement that works against multiple member damage cases as the countermeasure against the trigger member of member chain damage. Also, the load-bearing capacity is verified by a loading test of specimens with reinforced structures. Since the subject bridge has 18 truss panels where X bracing can be installed, the placement patterns were examined by the optimization method. It is clarified that the weight of reinforcing material can be reduced by installing X-braces only at four truss panels in the alternating areas, rather than installing at all 18 truss panels. Chapter 5 describes the summary of this study and future developments.

Many mail filtering methods have been proposed, but they have not yet achieved perfect filtering. One of the reasons for this is the influence of modified words created by spammers to slip through the mail filtering, in which words are modified by insert symbols, spaces, HTML tags, etc. For example,“ price$ for be$t drug$! ”，“ priceC I A L I S ”， “ <font>se</font>xu<font>al</font> ”, etc. These are frequently replaced with new strings by changing the combination of symbols ,HTML tags etc. Mail filtering is a technique that captures trends in words in training mails (mails received in the past) and applies these trends to words in test mails (newly received emails). Some of the above modified words appear in both training and test mails, i.e., words that could be used as features of spam mail by using them unprocessed, while others appear only in test mails, i.e., words that have not been learned and require special processing (e.g., removal of symbols, search for similar words, etc.) for their use. However, existing methods do not make these distinctions and treat them in the same way. Therefore, in order to bring the filtering performance of the existing methods closer to perfect filtering, we developed a method in which the above modified words are separated into words that appear in both training and test mails and words that appear only in test mails, and each of these words is used for mail filtering. In this study, we treat the above modified words as ”strange words”. Typical examples of such strange words include, in addition to the above, new words included in ham mails, proper nouns used in close relationships, and abbreviations. The results of this study are as follows (1) In order to compare the filtering performance between strange words and other words, filtering experiments were conducted using existing methods with strange words, nouns, verbs, and adjectives. The results showed that the filtering performance of the strange words was the best. This means that strange words have a significant impact on the filtering performance, and we expect to improve the filtering performance of existing methods by developing a new method to utilize strange words. (2) In order to examine the breakdown of strange words, we counted the number of words that appeared in both training and test mails, and the number of words that appeared only in test mails. The results were compared with those obtained for nouns, verbs and adjectives. We found that there are a significant number of strange words that appear in both training and test mails, but only in one of the groups, i.e., ham or spam mail. Words with this appearance pattern are most useful for mail filtering. On the other hand, we found that there are many strange words that appear only in test mails, i.e., words that cannot be learned. We expect to improve the filtering performance by separating these strange words and developing a new method to use each of them. (3) For the use of strange words, we developed (A) a method for using words that appear in both training and test mails, and (B) a method for using words that appear only in test mails, respectively. (A) To examine the breakdown of strange words that appear in both training and test mails, we divided them into two categories: words that appear only in ham and spam mails, i.e., words with patterns that improve filtering performance, and words that do not, and examined their frequency of occurrence. The results showed that the words with appearance patterns that improve filtering performance tend to appear more frequently than those without such patterns. This means that by using words with a certain number of occurrences in filtering, it is possible to use more words that improve filtering performance. We developed a method to do this and conducted experiments with different threshold values to find the optimal value, and confirmed that setting the threshold around 7 improves filtering performance. (B) We compared the number of strange words that appear only in the test mails between ham and spam mails, and found that the number tends to be higher in spam mail than in ham mail. In order to utilize this difference for filtering, we proposed a method to set a uniform spam probability for strange words that appear only in the test mails, and attempted to find the optimal spam probability. As a result, setting the spam probability to 0.7 improved the filtering accuracy from 98.2% to 98.9%. By using (A) and (B) above together, both words that appear in both training and test mails and words that appear only in test mails can be used for mail filtering to increase accuracy. Mail filtering has been improved and its performance has reached its limit. In order to further improve accuracy, i.e., to approach perfect filtering, a new perspective is needed, and this paper provides one such perspective: the use of strange words. This paper is organized as follows. In Chapter 1, we review the background of mail filtering methods, discuss how spammers use strange words to slip through such filters. The purpose and structure of this paper are then presented. In Chapter 2, we will discuss related research on examples of filtering methods that have been proposed so far are given. In Chapter 3, we describe the mail datasets, word handling, and strange words used in the this paper. This is followed by an explanation of the ROC curve, which is the measure used to evaluate the filtering performance, and explanation of scatter plots and box-and-whisker plots. In Chapter 4, we compare the filtering performance between strange words and other words, and show that strange words have a significant impact on the filtering performance. Furthermore, based on the results of a breakdown of the number of strange words, we discuss the possibility of improving filtering performance by separating words that appear in both training and test mails from those that appear only in the test mails. We will work on this in the next chapters and report the results. In Chapter 5, we develop a method to use (A) above, i.e., strange words that appear in both training and test mails. From the results of counting the number of words used in the subject and body of each email, we show that the number tends to be smaller for words that degrade the filtering performance. Based on these results, we propose a method that sets a threshold for the number of words used in the subject and body of mails, and uses only those words that exceed the threshold for classification. Experiments are conducted to find the optimal value by varying the threshold, and the effect of this method on performance is reported. In Chapter 6, we develop a method to use (B) above, i.e., strange words that appear only in the test mails. We compare the number of types of these words in ham and spam mails, and show that the number tends to be larger in spam mails, and that this feature can be used as a bias for detecting spam mails. In this paper, we deal with experiments using bsfilter and develop a method to set spam probabilities uniformly for strange words that appear only in the test mails. After searching for the optimal spam probability, we report that a spam probability of 0.7 greatly improves the filtering performance. In Chapter 7, we describes the processing flow combining the methods developed in Chapter 5 and Chapter 6. The paper is then summarized, including future prospects.

To investigate whether dantrolene (DAN), cardiac ryanodine receptor (RyR2) stabilizer, improves impaired diastolic function in an early pressure-overloaded hypertrophied heart, pressure-overload hypertrophy was induced by transverse aortic constriction (TAC) in mice. Wild-type (WT) mice were divided into four groups: sham-operated mice (Sham), sham-operated mice treated with DAN (DAN+Sham), TAC mice (TAC), and TAC mice treated with DAN (DAN+TAC). The mice were then followed up for 2 weeks. Left ventricular (LV) hypertrophy was induced in TAC, but not DAN+TAC mice, 2 weeks after TAC. There were no differences in LV fractional shortening among the four groups. Catheter tip micromanometer showed that the time constant of LV pressure decay, an index of diastolic function, was significantly prolonged in TAC but not in DAN+TAC mice. Diastolic function was significantly impaired in TAC, but not in DAN+TAC mice as determined by cell shortening and Ca2+ transients. An increase in diastolic Ca2+ leakage and a decrease in calmodulin (CaM) binding affinity to RyR2 were observed in TAC mice, while diastolic Ca2+ leakage improved in DAN+TAC mice. Thus, DAN prevented the progression of hypertrophy and improved the impairment of LV relaxation by inhibiting diastolic Ca2+ leakage through RyR2 and the dissociation of CaM from RyR2.

右心室 (RV) の機能障害とそれに関連する不整脈は、肺動脈性肺高血圧症 (PAH) の予後の重要な決定要因として認識されている。今回心臓リアノジン受容体 (RyR2) の安定剤であるダントロレン (DAN) による右室心筋への直接的な薬理学的介入が、モノクロタリン (MCT) 誘発性PAHラットモデルにおいてRV機能障害および不整脈に対する保護効果を有するかどうかを調査することを目的とした。方法として雄の8週齢のSprague-Dawleyラットに、PAHの誘発のためにMCTを腹腔内投与した。カテコールアミンによる心室頻拍 (VT) の誘発も、単離された心筋細胞におけるRyR2を介したCa^{2+}放出特性に関連して評価された。RVの形態と機能に対する慢性的な圧力過負荷の独立した影響を評価するためには、肺動脈縮窄モデルも確立した。結果、MCT誘発PHAラットモデルでは、RV肥大、拡張、および機能低下が観察され、MCT誘発2か月後の生存率は0%であった。対照的に、慢性DAN治療はこれらすべてのRVパラメータを改善し、生存率を80%に増加させた。慢性的なDAN療法はまた、RyR2からのカルモジュリンの解離を防ぎ、それによってMCTによって誘発された肥大したRV心筋細胞におけるCa^{2+}スパークと自発的なCa^{2+}トランジェストを抑制した。エピネフリンは、MCT誘発性PAHのラットの50%以上でVTを誘発したが、慢性DAN治療によってVTの完全に抑制した。以上よりDANによるRyR2の安定化は、PAHに関連するRV機能障害および致命的な不整脈の発症に対する新しい治療薬としての可能性を秘めている。

Generalized pustular psoriasis (GPP) is a rare form of psoriasis, which is characterized by sudden onset of repeated erythema and pustule formation with generalized inflammation. Recent advances in molecular genetics have led to the identification of several genes associated with GPP, including IL36RN, CARD14, AP1S3, SERPINA3, and MPO. Of these, only limited cases of GPP have been reported to carry mutations in the AP1S3, SERPINA3, or MPO to date. In the present study, we investigated a Japanese patient with GPP and found a bi-allelic missense mutation c.1769G>T (p.Arg590Leu) in the MPO gene. Structural analysis predicted that the mutant MPO protein would abolish its ability to bind with heme protein. In vitro studies using cultured cells revealed that the mutant MPO was stably expressed, but completely lost its myeloperoxidase activity. Immunohistochemistry (IHC) using an anti-MPO antibody showed markedly-reduced expression of MPO protein in the patient’s skin, suggesting that the mutation would lead to an instability of the MPO protein in vivo. Finally, IHC with an anti-citrullinated Histone H3 antibody demonstrated a sparse formation of neutrophil extracellular traps within a Kogoj's spongiform pustule of the patient’s skin. Collectively, we conclude that the c.1769G>T (p.Arg590Leu) in the MPO is a complete loss-of-function mutation associated with GPP in the patient. Our data further underscore critical roles of the MPO gene in the pathogenesis of GPP.

Objective: Anastomotic leakage is a common and severe complication of esophageal reconstruction. Accordingly, there is a clinical need for novel methods to prevent it. We developed multilayered, growth factor-secreting fibroblast sheets that promote wound healing and angiogenesis. The present study aimed to assess the utility of allogenic multilayered fibroblast sheets in preventing esophageal anastomotic leakage in a rat model of esophageal reconstruction. Methods: Allogenic multilayered fibroblast sheets prepared from oral mucosal tissues were implanted at esophageal anastomotic sites. Results: The allogenic multilayered fibroblast sheet group had significantly higher burst pressure and collagen deposition compared to a control group five days postoperatively. The expression levels of collagen type I and III mRNAs around esophageal suture sites were higher in the allogenic multilayered fibroblast sheet group compared to the control group on postoperative days 0, 3, and 5. There was a trend toward lower anastomotic leakage and lower abscess scores in the allogenic multilayered fibroblast sheet group compared to the control group; however, these differences did not reach statistical significance. Allogenic multilayered fibroblast sheets completely disappeared at ten days after implantation. Further, no inflammation was observed at suture sites with implanted allogenic multilayered fibroblast sheets at five days after surgery. Conclusion: Allogenic multilayered fibroblast sheets may represent a promising method of preventing esophageal anastomotic leakage.

転写因子CCAAT/enhancer-bringing protein beta（C/EBPβ）は、IGF-binding protein-1（IGFBP-1）やprolactin（ERL）遺伝子のプロモーターおよびエンハンサー領域において、転写活性マーカーであるHistone-H3 lysine-27 アセチル化(H3K27ac)を誘導するパイオニア因子であり、ヒト子宮内膜間質細胞（ESC）の脱落膜化に貢献することを我々はこれまでに報告している。パイオニア因子の一部はヒストンアセチルトランスフェラーゼ（HAT）活性を有するコファクターと複合体を形成することで機能する。我々は、C/EBPβと共役するHATタンパクとしてp300を同定しているが、それ以外のコファクターについては不明である。Peroxisome proliferator-activated receptor gamma comma coactivator 1-α（PGC-1α）はH3K27acを制御することが知られている転写共役因子である。PGC-1αはESCでも発現しているが、脱落膜化におけるPGC-1αの機能は不明である。そこで、PGC-1αがC/EBPβの転写共役因子として働き、脱落膜化過程においてH3K27ac誘導に関与しているのではないかと考え検討した。脱落膜化を誘導するためにESCをcAMP存在上で培養した。cAMPによるIGFBP-1およびPRLの発現上昇はPGC-1αのノックダウンにより抑制された。また、cAMPはIGFBP-1およびPRLのプロモーターとエンハンサー領域に存在するC/EBPβ結合部位へのPGC-1αとp300のリクルートを増加させた。さらに、PGC-1αをノックダウンするとC/EBPβとp300に結合、およびH3K27acレベルが低下したことから、PGC-1αはこれらの領域でC/EBPβおよびp300とヒストン修飾複合体を形成することでH3K27ac誘導に関与していることが示された。さらにPGC-1αの発現制御機構を調べるために、C/EBPβを上流因子として着目した。PGC-1αのエンハンサー領域へのC/EBPβの結合はcAMPで増加した。また、これらのエンハンサーをゲノム編集により欠失させた細胞ではPGC-1αの発現が減少したことから、C/EBPβは我々が見出したエンハンサー領域に結合することでPGC-1αの発現を上昇させると考えられた。以上より、PGC-1αはC/EBPβの新規エンハンサーへの結合によって発現誘導されること、また、C/EBPβとp300と共にヒストン修飾複合体を形成して、IGFBP-1およびPRLのプロモーターとエンハンサーにエピゲノム変化を引き起こすことで脱落膜化に貢献していることがわかった。

Pandemic influenza virus A(H1N1)pdm09 infection occurred in healthy children and young adults, but asthmatic patients presented more rapid progression of respiratory distress and plastic bronchitis. To investigate the pathogenesis of worsening respiratory symptoms after A(H1N1)pdm09 infection, we focused on matrix metalloproteinase‐9 (MMP‐9) and tissue inhibitor of metalloproteinases‐1 (TIMP‐1). MMP‐9 and TIMP‐1 levels in bronchoalveolar lavage fluid and serum from mice with and without asthma were evaluated after A(H1N1)pdm09 or seasonal A(H1N1) infection. MMP‐9 levels were more elevated in Asthma/A(H1N1)pdm09‐infected mice than in non‐Asthma/A(H1N1)pdm09‐infected mice on both 3 and 7 days post‐infection. Immunohistochemical findings in this pneumonia model showed that MMP‐9 and TIMP‐1 positive cells were observed in blood vessels and bronchus of lung tissue in severe pathological findings of pneumonia with asthma. Microscopically, shedding cells and secretions were conspicuous in the trachea on days 3 and 7 postinfection, in the A(H1N1)pdm09‐infected mice with asthma. Our results suggest that MMP‐9 and TIMP‐1 expressions are related to severe pneumonia in the A(H1N1)pdm09 infection with asthma, leading to cause epithelial cell shedding.