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方法： 2010年10月から2019年9月までに山口大学医学部附属病院および川崎医科大学附属病院で画像検査を受けられた患者を後ろ向きに検討した。炭酸ガス拡張を用いたCTC直後にDCE-CTを実施した82例をCE-CTC群とした。CE-CTC群と同様のDCE-CTプロトコールで撮像されたCTC非併用のDCE-CTの症例のうち、年齢や性別をマッチさせた77例を対照群とした。CE-CTC群は男性48名、女性34名で年齢は21～85歳（平均60歳）、対照群は男性46名、女性31名で年齢は20～84歳（平均60歳）であった。 CTは多列検出器CT装置（Optima CT660 ProまたはLightSpeed Ultra 16、ともにGE社製）を用いて行った。CE-CTC群では、大腸の拡張は自動低圧炭酸ガス送出装置（HP-2®；堀井薬品工業社製）を用いて行った。 胃、肝臓（右葉、左葉）、膵尾部、門脈（PV）、脾静脈（SpV）、上腸間膜静脈（SMV）、下腸間膜静脈（IMV）のCT値を、それぞれ非造影CTと早期CTで測定した。造影CT値として、非造影CT画像とDCE-CT早期相画像のCT値（Hounsfeld unit値）の差を算出した。これらの測定は、2名の放射線科医がワークステーション（EV InsiteS；PSP社製）で各々行い、各臓器、血管の画像上に円形または楕円形の関心領域（ROI）を設定し、2人の測定した造影CT値の平均を算出した。また、肝偽病変の有無を共同で記録した。肝偽病変は、DCE-CT早期相で、肝左葉内側区の後縁または胆嚢窩の周囲にある高または低吸収領域として定義した。 Mann-Whitney U検定を用いて各臓器と血管ごとの造影CT値を比較した。また、カイ二乗検定を用いてCE-CTC群と対照群の間で肝病変の発症頻度を比較した。 結果： CE-CTC群と対照群の各臓器・血管における造影CT値の平均値の比較は表1のとおりで、CECTC群の肝実質(図1)、PV、SMV・IMV(図2)の造影CT値は、対照群に比べて有意に高かった。一方で、CE-CTC群の胃(図3）、膵尾部、SpVの造影CT値は、対照群に比べて有意に低かった。 肝偽病変は、CE-CTC群の6例（7％）において、肝左葉内側区の後縁（n＝5）または胆嚢窩周囲（n＝1）に低吸収領域として認められた（図4）が、対照群では認められなかった（p＝0.016）。表2は、CE-CTC患者で肝偽病変がある場合とない場合の肝臓の造影CT値を比較した結果で、肝偽病変のあるCE-CTC患者の肝の造影CT値は、肝偽病変のないCE-CTC患者の造影CT値よりも有意に高かった。

（目的）排卵期の黄体形成ホルモン（LH）サージは、顆粒膜細胞（GCs）において、遺伝子発現や細胞機能の急激な変化を引き起こし、黄体化を誘導する。本研究では、黄体化過程のGCsにおける遺伝子発現の経時的変化と、エピジェネティックな遺伝子発現制御機構に着目し、ゲノムワイドに黄体化過程の遺伝子発現と細胞機能変化を明らかにすること、および遺伝子発現制御や細胞機能変化とヒストン修飾H3K4me3変化の関連性を明らかにすることを目的とした。 （方法）幼若雌マウスにeCG-hCG注射による過排卵刺激を行い、hCG投与前、投与後4時間、12時間の時点でGCsを回収し、RNAシークエンスとH3K4me3抗体を用いたChIPシークエンスを行った。 （結果）RNAシークエンスにより、多数の発現変動遺伝子が同定され、遺伝子発現の時間的変化に応じて8つのパターンに分類された。多くの遺伝子は、hCG刺激後4時間で一過性に発現上昇または低下していた。これらの遺伝子群に関連する細胞機能をGene Ontology解析で調べたところ、ステロイド産生、排卵、卵丘細胞複合体の膨化、血管新生、免疫、活性酸素代謝、炎症反応、脂質代謝、オートファジーが同定された。さらに、DNA修復と細胞サイズの増大という2つの機能がこれまでに報告されていない細胞機能として同定された。ChIPシークエンスにより、黄体化過程ではゲノム全域にわたってH3K4me3が急激に変化し、遺伝子発現に関与することが示唆された。mRNA発現データとH3K4me3のデータを統合解析したところ、H3K4me3はステロイド産生、排卵、COCの拡大、血管新生、炎症反応、免疫、活性酸素代謝、脂質・糖代謝、オートファジー、細胞サイズの調節などに関与することが示唆された。 （結論）LHサージ後の黄体化過程にあるGCsにおいて、遺伝子発現はゲノムワイドに変化し、細胞機能が劇的に変化する。H3K4me3の変化は、これらの急激な遺伝子発現制御に関与し、種々の細胞機能を調節することでGCsの黄体化に寄与する可能性が示された。

新規ヒトin vitroおよびex vivo BBBモデル，in vivo モデルを用いて，NMOSDの病態生理とサトラリズマブの作用機序を，BBB破綻の点から検討した．血管内皮細胞に対するペリサイトおよびアストロサイトの足突起の接触を再現した3層共培養系を構築し，これを用いて静的in vitroモデルおよび流速負荷型ex vivoモデルを作製した．これらのBBBモデルを使用し，バリア機能の持続測定，白血球のmigration，NMO-IgGとサトラリズマブのBBB透過性を評価した．In vivo研究では，脊髄中でIL-6が著増するEAEマウスのin vivoでのBBB破綻に対して，マウスIL-6受容体抗体MR16-1が与える効果を評価した．In vitroおよびex vivoでの実験では，NMO-IgGがサトラリズマブおよびNMO-IgGの脳内透過性を亢進させること，サトラリズマブがNMO-IgGが誘導するT細胞のmigrationとBBB破綻を抑制することが示された．In vivo研究では，IL-6シグナル伝達の阻害によって，T細胞の脊髄への浸潤が抑制され，脊髄炎の発症が抑えられた．これらの結果から以下のことが示された．（1）我々が作製した，3層共培養によるin vitroおよびex vivo BBBモデルは，バリア機能，白血球のmigration，脳内移行性を評価するために理想的なBBBモデルである．（2）NMO-IgGは，バリア機能の減弱によってNMO-IgG自身の透過性を亢進し，アストロサイトからのIL-6分泌を誘導し，さらなるバリア機能の障害と細胞浸潤の制御破綻を引き起こす．（3）サトラリズマブは，NMO-IgGの共存下でBBB通過が容易となり，BBB機能障害と炎症細胞浸潤を抑制する結果，NMOSDの発症を予防する．

ラット坐骨神経結紮モデル（SNL）は最も一般的に神経障害性疼痛の実験に用いられるモデルラットであり、運動麻痺を生じないことでも知られている。神経障害性疼痛モデルの疼痛評価にはこれまでフォンフレイテスト（機械的アロディニア評価）と熱刺激回避テストが用いられてきた。しかしこれらのテストは臨床で用いられる神経学的検査とは全く異なる手法での評価である。神経障害性疼痛を有する患者では、両下肢の協調運動が乱れ，歩行時の下肢の動きに左右差を生じていることが多い。本研究において、私達はヒトと同様な疼痛行動や疼痛に伴う歩行障害などが実際には生じているのではないかと考え、三次元歩行解析を行いて本モデルの関節の動きや歩行時の動態解析を行った。今回の解析にはキネマトレーサーシステムを用いた。 機械的アロディニアに関するSNLの効果として術後１週間から８週間にわたり、回避行動閾値の47±6.1％の低下を認めた。ＳNLラットにおける股関節・膝関節・足関節のマーカーの矢状面の軌跡は歩行中に大きな変動を認めた。歩行中の不安定性を示す患側左股関節・膝関節の上下端の高低差は、SNLラットでほうが有意に大きかった。歩行パターンを示す、両足同時接地時間はSNLラットのほうが有意に長い結果であった。左右下肢の協調運動を評価するため、両下肢の歩行周期時間も計測した。歩行周期の左右差を示す左右比は、コントロール群のラットでは1.0±0.08と左右差がほぼないのに比較し、SNLラットでは0.62±0.15と有意に左右下肢の歩行周期が異なることが示唆された。 フォンフレイテストや熱刺激回避テストは臨床現場で使用されることのない疼痛機能評価であるが、こうした新しい三次元歩行動態解析技術を用いることができれば、神経障害性疼痛患者における疼痛行動も、定量的かつ数値化して示すことが可能になる可能性について示すことができた。従来の神経障害性疼痛モデルにおける、疼痛機能評価に関する臨床と実験モデルの大きなかけ離れについての問題点を解決し、将来的にはヒトでの機能評価にも応用できる新しい三次元歩行動態解析技術について報告し、実際のラット坐骨神経結紮モデルでのデータを示した。

オメガ3長鎖多価不飽和脂肪酸(ω-3)は海産魚や魚油に含まれる必須脂肪酸で、抗炎症効果を有することから非感染性ぶどう膜炎の有効な治療になる可能性がある。多くのぶどう膜炎でみられる獲得免疫による炎症反応は、樹状細胞（DC）、マクロファージ、およびBリンパ球を含む抗原提示細胞(APC)による抗原提示から開始され、炎症のトリガーとして重要である。これまでに我々はω-3長鎖多価不飽和脂肪酸（LCPUFA）が、実験的自己免疫性ぶどう膜炎モデル（EAU）の眼炎症を抑制することを示した。今回、ω-3によるEAUの抗炎症効果に対する APCの関与を検討し、その作用機構について解析した。 C57BL/6マウスに等カロリーに調整したω-3もしくはω-6を含有した餌で給餌し、安楽死後に回収した脾臓細胞をマイトマイシンC処理してAPCを調整した。これらをEAU誘導したマウスから単離したCD4陽性T細胞と共培養し、種々の炎症性サイトカインの発現量および3H-チミジン取り込み量を指標とした増殖能を評価した。次にω-3群のAPCをDC、マクロファージ、B細胞を含む残りの細胞群（B細胞他）に分離し、ω-3の炎症作用を担当する細胞を探索した。続いて、ω-3で賦活化したDCによる抗炎症効果を検討するため、ω-3群のDCを単離し、EAUを誘導したマウスにAdoptive transfer(養子細胞移植)し、臨床および組織学的スコアを評価した。最後にω-3がDCに直接作用して抗炎症効果を発揮するか否かを検討した。 C57BL/6由来DCとBALB/c由来CD4陽性T細胞を混合培養して混合リンパ球反応MLR(mixed lymphocyte reaction)を誘導した培養系に、代表的なω-3脂肪酸であるDHAおよびEPAを投与し、T細胞増殖能を評価した。 ω-3群のAPCは、ω-6群に比較してIFN-γ、IL-17の発現量およびT細胞増殖能を有意に低下した。その抗炎症効果はAPCから単離したマクロファージやB細胞他ではみられず、DCのみで保存された。さらに、ω-3群のDCをAdoptive transferしたEAUマウスでは、炎症スコアが有意に低下した。DHA・EPAで賦活化したDCはMLRによるT細胞増殖能を有意に抑制した。 以上より、ω-3の経口摂取によるEAUの眼炎症抑制効果は、APC、特にDCを介在して発揮されることが示された。

近年、イヌ・ネコ・フェレットといった様々な動物が愛玩動物として飼育されており、ヒトと同様に多様な感染症に罹ることが知られている。愛玩動物における感染症の治療法や診断法を確立することはOne Healthの観点でも重要で、ヒトの健康の維持に直結するような公衆衛生上重要な課題である。ネコヘルペスウイルス1（FHV-1）は猫ウイルス性鼻気管炎の原因となるヘルペスウイルスとして知られ、上部呼吸器症状や流産などを引き起こす。インフルエンザAウイルス（IAV）は人において呼吸器症状を引き起こす季節性のウイルスとして知られ、イヌ・ネコ・ブタといった様々な動物に感染することが知られている。季節性のIAV以外にも、動物の体内で生まれる遺伝子再集合体のパンデミックも問題となる。本研究では、愛玩動物に感染が認められる上記の2種類のウイルスを解析し、FHV-1の新規治療薬の提案とIAVの診断法の確立を目的とし、全2章で構成された。

Many infrastructures constructed in the period of high economic growth are currently deteriorated and need renewal / repair. Considering the future situation, new-build infrastructures should be more durable, so the use of high-strength materials capable of reducing maintenance and management costs is preferable. A suitable construction material for the future situation is an ultra-high-strength fiber-reinforced concrete (UFC). General UFCs are cured under high temperature (at 90℃ for 48 hours). Most UFC members are often made in precast-concrete factories with dedicated curing facilities. A UFC manufacturable at general ready-mixed concrete plants has been required for various constructions using cast-in-placed concrete. The study focused on the mixture design and the manufacturing method of UFC without heat-curing. The targeted strength of the UFC was 200 N/mm^2 at the concrete age of 28 days. To achieve the required performance for UFC, the experimental study was designed and conducted. The thesis consists of seven chapters, and the content of each chapter is as follows: Chapter 1 "Introduction" shows the social concern in Japan, such as the present conditions of infrastructures. In addition, the chapter summarizes the transition of high strength concrete and fiber-reinforced concrete. The research background and the purpose of this study are described in this chapter. Chapter 2 "Previous studies" shows the review of previous studies dealing with investigations on UFC. In addition, the chapter clarifies the problem of UFC manufacturing by referring to the previous studies. Chapter 3 "Mixture design", the materials and mixture proportions required for the UHPC manufacturable under ambient temperature conditions were investigated. Five types of cement and four types of powder materials were tested, as well as the fine aggregate needed to achieve proper fluidity, fiber dispersibility and strength. To achieve the appropriate flowability and adequate strength, the cement having low C_3A and high C_3S was suitable for the UHPC manufacturable at ambient temperatures. Furthermore, the mortar with W/B of 21% achieved 200 N/mm^2 at 28 days, so it can be designed as the maximum W/B for the UFC. The test result confirmed that allowable fine aggregate volume was lower than 600 kg/m^3 to obtain proper dispersion of steel fibers. Chapter 4 "Material properties and durability of hardened UFC", the hardening material properties and durability of the UFC designed in Chapter 2 were examined. The result confirmed that the UFC achieved 196 N/mm^2 at the age of 28 days. The UFC exhibited an excellent cracking strength and tensile strength which were almost equivalent strength of the conventional UFC. In addition, the UFC indicated excellent resistances to various degradation effects, such as neutralization, freezing and thawing, permeability of chloride ions, and sulfate attack. On the other hand, the UFC had low resistance to sulfuric acid and large autogenous shrinkage strain. The properties should be considered in the application of prestressed concrete owing to the loss of prestress. Chapter 5 "Manufacturing method in RMC plant" reports the manufacturing methods at the ready-mixed concrete (RMC) plant. The result confirmed that UFC can be manufactured at a general RMC plant, the equipment although mixing time varies owing to the mixer capacity. In addition, the mixing methods of steel fibers were compared. Owing to the high viscosity of the UFC, undischarged UFC from the truck was approximately 190 L, which was extremely higher than ordinary concrete (80 L). The compressive strength of UFC using several types of fine aggregate were examined. The result suggested that the evaluation of the properties of fine aggregates in the UFC is necessary for the practical use. Chapter 6 "Practical applications of UFC" verifies the applicability of UFC of at sites. The result confirmed that the mixing-load increased in proportion to the mixing volume, the maximum mixing volume was identified as 80% of the capacity of mixer. The results showed that the UFC made in a RMC plant indicated stable fresh and strength properties for a few months. Furthermore, the production of UFC with onboard mixers was tested. The result confirmed that the method reduced the material-loss during transportation. The surface-finish of UFC was also evaluated by comparing the results obtained from a soil hardness tester. Moreover, the heat curing conditions of UFC were investigated. The result confirmed that the highest temperature and the curing time for the heat curing were lower and shorter than the standard heat curing (at 90℃ for 48 hours), respectively. Chapter 7 "Conclusions" presents the remarkable conclusions in this study and further research for the practical application of the UFC.

It is important to anticipate problems such as a large amount of spring water that occurs during shafts construction and maintenance problems such as concentration of lining cracks after shafts construction in advance, and to carry out construction in a rational manner. Crack tensor from the rock mass information (cracks, strength) obtained by the construction of the shafts of the Horonobe Underground Research Laboratory of the JAEA, aiming at the selection of support and the implementation of spring water countermeasures. Based on the theory, the research results were summarized with the aim of evaluating the water hydraulic conductivity of the rock mass during shafts construction and the deteriorated condition of the lining after shafts construction, and establishing a simple prediction method for these. Chapter 1 summarizes the current state of rock mass geological observation and lining maintenance in the shafts, the water permeability coefficient of the rock mass, and the past domestic and overseas studies on the deterioration state of the lining, and the hydraulic conductivity of the rock mass using the rock mass information. The purpose of this study was clarified with the task of evaluating the deterioration state of the lining and establishing these simple prediction methods. In Chapter 2, crack tensor theory and stereology (statistical geometry) are used using information (length, direction, opening width) of rock cracks during shafts construction. By applying the concept, the three-dimensional permeable tensor was estimated accurately. Then, when the hydraulic conductivity obtained from the three-dimensional hydraulic tensor and the hydraulic conductivity based on the result of the in-situ permeability test using the deep borehole near the shafts were compared, it was clarified that they were in good agreement. A high correlation was obtained between the crack frequency obtained by dividing the total length of the cracks obtained in the shafts construction by the evcavation surface area and the hydraulic conductivity obtained from the three-dimensional hydraulic tensor. Therefore, we proposed a method to easily predict the hydraulic conductivity of rock from the frequency of cracks. The obtained prediction formula targets the depth at which three cross sections orthogonal to each other can be obtained on the rock crack observation surface, but the prediction formula was also obtained at a depth where three cross sections orthogonal to each other cannot be obtained. Comparing the hydraulic conductivity of the rock mass and the hydraulic conductivity based on the in-situ permeability test results, it was clarified that they are in good agreement. In Chapter 3, the orientation dependence of the earth pressure is recognized in the underground environment of the Horonobe Underground Research Center, and it is the major principal stress direction in the shafts of the underground Laboratory. Cracks have occurred on the lining wall surface in the east-west direction. However, the lining cracks in the shafts at that point may depend not only on the orientation dependence of the ground pressure, but also on the rock cracks on the back surface of the lining, the ground cover and the rock strength. If a prediction formula for predicting lining deterioration can be created in consideration, it will be useful information for countermeasures during construction, and based on the crack tensor calculated based on the information on cracks, from the rock crack tensor and rock strength. I proposed a method to estimate the deterioration condition of the lining. The estimated value of the crack tensor regarding the deterioration of the lining using the obtained prediction formula and the measured value calculated from the information of the lining crack, assuming that the margin of error due to the relative error is 0.1, the estimated value and the measured value are well one. Im adei t clear that Ia md oing it. In Chapter 4, aiming at selection of rational support for shafts extension of underground Research Laboratory planned in the future and implementation of spring water countermeasures. Ip roposed ac onstruction management system that applies the crack tensor prediction method for rock hydraulic conductivity during shafts construction and deterioration of lining after shafts construction. In the future, in order to select more rational support and implement measures against spring water, the rock mass information (cracks and rock mass strength) acquired during shafts construction will be obtained using the prediction formulas established in Chapters 2 and 3. By predicting the hydraulic conductivity of the rock and the crack tensor related to the deterioration of the lining, and reflecting it in the measures against spring water in the rock mass and the measures against the deformation of the lining, it can be expected to contribute to the reduction of maintenance costs. Chapter 5 summarizes the research results in each chapter and raises future issues for conclusion.

Rapid population growth and economic progress over the past decades have triggered a sharp increase in the global demand for fossil fuels thereby resulting in an energy crisis. The problem may be alleviated by upgrading and producing gaseous energy, but one of the major challenges associated with gaseous energy is to separate it effectively from other less desirable gases. Thus, energy-saving and high-efficiency separation technology is needed. In the past three decades, gas separation membranes, including polymeric membranes and inorganic membranes, have attracted much attention due to their advantages in terms of energy efficiency, operational simplicity, cost competitiveness, and small footprint. Although polymeric membranes have been utilized in practical gas separation, their separation performance is not sufficient for widespread practical application. Carbon molecular sieve (CMS) membranes, one of the inorganic porous membranes, can be prepared by pyrolyzing polymeric precursors.Their pore structures provide molecular sieving ability and possess good thermal and chemical resistance. Especially, the separation properties of the CMS membranes for a variety of gas pairs have exceeded the upper bound of polymeric membranes. These characteristics have made them attractive candidates for gas separation. The pore structures, separation properties, and transport mechanism of the CMS membranes depend critically on the type of the polymeric precursors, pyrolysis conditions and pre- and post-treatments. Thus, in this thesis, I prepared CMS membranes derived from different polymeric precursors and investigated the effect of pyrolysis conditions and post-treatment on the gas permeation properties. In Chapter 2, toluene vapor addition was performed for the first time during the pyrolysis process to prepare highly selective CMS membranes. Adding toluene vapor in the pyrolysis process was a simple method to improve the selectivity compared with the traditional chemical vapor deposition post-treatment technique. Additionally, the use of toluene can avoid the high transportation costs of gaseous hydrocarbons. The results indicated that toluene vapor addition increased selectivities of the H2-related gas pairs compared with CMS membranes without toluene vapor addition. This could not be realized simply by increasing the pyrolysis temperature without toluene vapor addition. The CMS membrane with toluene vapor addition also showed higher permeance with a moderate selectivity compared with the CMS membrane with gaseous hydrocarbon addition reported in the literature. Furthermore, the gas permeance and selectivity could be readily controlled by adjusting the pyrolysis temperature and duration of the addition. The optimal preparation conditions of the CMS membrane with toluene vapor addition depend on the targeted gas pair to be separated. This study indicated that adding liquid hydrocarbon vapor in the pyrolysis process can be a simple and effective method for preparing highly selective CMS membranes. In Chapter 3, the mechanism of achieving high selectivity for the CMS membranes prepared by adding toluene vapor was further investigated. The physical and chemical properties of CMS membrane with adding toluene vapor were characterized using some sophisticated characterization techniques. It was found that toluene vapor addition formed carbon deposition on the outer surface region of the CMS membrane, which agreed with the previous report. The gas adsorption experiment suggested that toluene vapor addition also resulted in the loss and the narrowing of ultramicroporosity. Additionally, I preliminary analyzed the mechanism of achieving high selectivity for the CMS membrane with toluene vapor addition. In Chapter 4, a novel porous carbon fiber (PCF) was investigated to prepare supported CMS membranes derived from wood tar solution, as the development of wood tar-derived CMS membranes has been limited by the availability of porous supports in recent years. Moreover, the CMS membranes supported on commercially available porous ceramic tubes were also prepared under the same conditions for comparison purposes. The PCF consisted of interconnected pore structures, which provide additional paths and channels for gas transport, whereas the porous structure of the ceramic support consisted of voids between the alumina particles. It was found that for both supports, 70 wt% wood tar solution was the optimal solution for preparation of CMS membranes. The PCF-supported CMS membranes exhibited higher gas permeance and selectivity than the NA3-supported membranes. Furthermore, a series of PCF-supported CMS membranes from 70 wt% wood tar solution were prepared at different pyrolysis temperatures, the membrane pyrolyzed at 600 °C exhibited the highest H2 selectivity. This study demonstrated that PCF can be used for supported CMS membranes derived from wood tar solution. Additionally, PCF is also a promising support for the supported CMS membranes derived from other polymeric precursors. Finally, Chapter 5 summarized the main contents of this thesis.

The role of optimization can be found in almost all aspects of human life. Optimization is common in but not limited to the fields of engineering, economics, design, and planning. Although the optimization problems to be solved change, the optimization goal never changes. That is to find effective solutions efficiently. In modern optimization studies, the metaheuristic algorithm has been one of the most interesting methods, considering the demands of a reasonable computational time. Many metaheuristic algorithms have been introduced. However, based on the number of tentative solutions used in the search process, metaheuristic algorithms can be categorized into (1) population-based or (2) single-trajectory-based algorithms. The searching with singletrajectory-based metaheuristic algorithms manipulates and modifies a single solution point in every iteration. In contrast, the population-based metaheuristic algorithms combine a set of solution points to create new solutions in every iteration. A metaheuristic algorithm usually consists of two components, i.e., exploration and exploitation. Exploration means searching for solutions in the global space. In contrast, exploitation means searching for a solution by focusing on a small area or an area near an already known solution. The single-trajectory-based metaheuristic algorithm is exploitation-oriented. On the other side, the population-based metaheuristic algorithm is exploration-oriented because of searching by many points distributed on all search spaces. Balance settings between exploration and exploitation are needed to produce good solutions. In fact, most population-based algorithms will encounter decreasing in exploration and become too exploitation-oriented as the iteration increase. Any metaheuristic algorithm applies parameters to control the behavior. However, the parameters usually do not provide a good intuition of the rate of exploration and exploitation. Hence, reaching a balance between them is hard to predict just by the algorithm parameters. This dissertation proposes a conceptual design combining the spy algorithm and B-VNS. The spy algorithm is a population-based metaheuristic algorithm that mimics the strategy of a group of spies, the spy ring. The spy algorithm is a new concept with the main idea to ensure the benefit of exploration and exploitation, and cooperative and non-cooperative searches always exist. This goal is implemented by utilizing three kinds of dedicated search operators and regulating them in a fixed portion. The occurrences of exploration and exploitation are controlled by algorithm parameters. Thus, the spy algorithm parameters provide good before-running intuition to easier reach the balance between exploration and exploitation. The spy algorithm is first designed to be used in the continuous optimization model. The spy algorithm was compared to the genetic algorithm, improved harmony search, and particle swarm optimization on a set of non-convex functions by aiming at accuracy, the ability to detect many global optimum points, and computation time. The Kruskal-Wallis tests, followed by Games—Howell post hoc comparison tests, were conducted using a. for the comparison. The statistical analysis results show that the spy algorithm outperformed the other algorithms by providing the best accuracy and detecting more global optimum points within less computation time. Furthermore, those results indicate that the spy algorithm is more robust and faster than other algorithms tested. On the other hand, the B-VNS algorithm is a modification of the variable neighborhood search (VNS) algorithm. The benefit of VNS comes from its thorough search while avoiding the local optimum trap by moving to the neighboring point called shaking. The local search after shaking is another benefit of VNS that makes VNS a prominent algorithm. However, the thorough search has the drawback of long computation time. This dissertation introduces a modified neighborhood structure to reduce the computation times. The main idea is to apply the binomial distribution to create the neighboring point. As a result, the neighborhood distance has a random pattern. However, it follows a binomial distribution instead of a strictly monotonic increase like in VNS. The B-VNS is a modification of VNS and is classified as a single solution-based algorithm. The B-VNS is intended to solve combinatorial optimization problems, particularly the quadratic unconstrained binary optimization (QUBO) problems categorized as NP-hard problems. The B-VNS and VNS algorithms were tested on standard QUBO problems from Glover and Beasley, on standard max-cut problems from Helmberg-Rendl, and those proposed by Burer, Monteiro, and Zhang. Finally, Mann-Whitney tests were conducted using a. to compare the performance of the two algorithms statistically. It was shown that the B-VNS and VNS algorithms are able to provide good solutions, but the B-VNS algorithm runs substantially faster. Furthermore, the B-VNS algorithm performed better in all of the max-cut problems regardless of problem size and in QUBO problems with sizes less than The spy algorithms and B-VNS have different designs in the process and the domain of the solved problems. However, considering the benefit of the spy algorithm and B-VNS, their combination has the potential to provide good results. Conceptually, the spy algorithm can be seen as the first step of B-VNS. Conversely, B-VNS can be considered an additional refinement for the spy algorithm.

Political connections are considered a valuable resource in not only high-corruption countries but also low-corruption countries. This dissertation investigates the relationship between political connections and Sharia compliance, aiming to deepen understanding of the nature of political connections, as Sharia compliance prohibits engaging in corruption. Specifically, I analyze whether: 1) political connections and Sharia compliance affect merger and acquisition (M&A) performance; 2) connections to politicians affect the market response to firms' inclusion in or exclusion from the Indonesia Sharia Stock Index (ISSI); 3) political connections and Sharia compliance have been valuable during the COVID-19 pandemic; and 4) political connections affect firms' environmental performance. This dissertation comprises six chapters. Chapters 1 and 6 respectively introduce and conclude this dissertation. The remaining four chapters (i.e., Chapters 2-5) are essays on the empirical relationship between political connections and Sharia compliance. In Chapter 2, I study the impact of political connections and Sharia compliance on M&A performance, focusing on M&A deals in Indonesia during 2010-2016. I find that while political connections can improve market reactions to M&A announcements, Sharia compliance has a positive but insignificant impact on M&A performance. I further find that there is a substitution relationship between Sharia compliance and political connections: Sharia -compliant firms with political connections have poorer M&A performance than non-Sharia-compliant firms with political connections. Chapter 3 examines market responses to firms' addition to and removal from the ISSI and how political connections influence those market responses. I employ two kinds of analysis. First, using the event-study methodology, I measure abnormal returns surrounding the announcement of each firm's addition to or removal from the ISSI. Second, to more precisely identify the relationship between political connections and Sharia compliance, I use a pooled regression analysis. The results show that neither addition to nor removal from the ISSI produces abnormal returns for Indonesian firms, indicating that investors are little concerned with ISSI reconstitutions. Furthermore, political connections increase firms' value before inclusion in the ISSI, but the benefits of these connections are lost after their addition to the index. Chapter 4 offers novel evidence by investigating the value of political connections and Sharia compliance during the COVID-19 pandemic. I use the event-study methodology to measure the stock market reaction to the COVID-19 pandemic, and conduct a pooled regression analysis to more precisely identify the value of political connections and Sharia compliance during the pandemic. I find that a stock market anomaly occurred during the COVID-19 pandemic in Indonesia, in that the pandemic had a positive impact on the stock market. I also find that there was value for firms in being Sharia-compliant during the pandemic when the government announced tax incentives for firms. In Chapter 5, I investigate the relationship between political connections and the environmental performance of Sharia -compliant firms. I use a unique sample of firms covered by Indonesia's Program for Pollution Control Evaluation and Rating during 2013-2019. I find that political connections are less (more) valuable for Sharia-compliant firms (non-Sharia-compliant firms) m enhancing their environmental performance.

Some textbooks of formal languages and automata theory implicitly state the structural equality of the binary n-dimensional de Bruijn graph and the state diagram of minimum state deterministic finite automaton which accepts regular language (0+1)*1(0+1)^{n-1}. Although the isomorphism in binary case is relatively easy to prove, it is desirable to rigorously prove such an isomorphism in general k-ary case. To achieve this purpose, the author introduces a new computational model, called "colored finite automata (CFA)," and give a certain characterization of the general k-ary de Bruijn graphs by regular languages. The second purpose of this study is to investigate the potential of this automaton with multi-colored accepting states. By the way, when CFA is nondeterministic (NCFA), it is desirable that the colors of accepting states are unmixed (i.e., there are no inputs that are accepted with differently colored accepting states) in order to pursuit the accurate identification. Thus, the author proposes the three decision problems (Unmixedness Verification problem, Unmixedness Partitioning problem, and Unmixedness Extension problem) concerning unmixedness and show that UV, UP, and UE problems are shown to be NLOG-complete, P, and NP-complete, respectively. The author also illustrates the applications of colored finite automata, e.g. to existing regular expression engines and model checking tools for the purpose of improvement of their efficiency and conveniency. Next, the author introduces "colored pushdown automaton (CPDA)" which is an ordinary pushdown automaton with colored accepting states. It is shown that while the computational complexity of the above-mentioned UV, UP, and UE problems of CPDA are all undecidable, restriction of CPDA are all undecidable, restriction of CPDAs to unambiguous ones simplifies some problems of them to the permanently true problems. In this way, the concept of colored accepting states can be applied to a wide range of automata that have a set of accepting states and expected to be useful in a wide range of theoretical and practical field of automata applications in the future.