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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.
Creators : Temma Seiya Dissertation Number : 創科博甲第126号 Degree Names : 博士(理学) Date Granted : 2023-10-11 Degree Grantors : Yamaguchi University
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.
Creators : Tajima Keiji Dissertation Number : 創科博乙第9号 Degree Names : 博士(工学) Date Granted : 2023-11-08 Degree Grantors : Yamaguchi University
Creators : 小林 由貴 Dissertation Number : 医博乙第1109号 Degree Names : 博士(医学) Date Granted : 2023-11-08 Degree Grantors : Yamaguchi University
The development and implementation of industrial policy are essential in shaping a country’s economic landscape. It promotes industrialization, which, in turn, generates employment opportunities, enhances productivity, and diversifies the economy. the present dissertation studies the subject of industrial policy, with a particular emphasis on resource allocation and computable general equilibrium in Ghana. Chapter 2 delves into the concept of industrial policy and its implementation in Africa in general, and Ghana, in particular. First, we examine Ghana’s past experience with industrial policy implementation and the reasons for its inability to attain the desired outcomes. Subsequently, in response to the call for a return to industrial policy, we argue in favor of a renewed implementation of industrial policy in Ghana. We posit that the likelihood of success is significantly higher with the benefit of better institutions. Chapter 3 examines the subjects of firm-level productivity, productivity distribution, and resource allocation. In the first instance, we decompose labor productivity in Ghana and draw the conclusion that within-sector resource allocation primarily drives productivity growth, with structural change playing a limited role. Next, we analyze the gross allocative effect, finding evidence that resources are migrating toward sectors of lower productivity. Finally, we also examine productivity distribution through the lens of the power law distribution, establishing that firms involved in international trade exhibit higher levels of aggregation. Thus, allocating resources to such firms leads to greater productivity, thereby minimizing resource misallocation. Chapter 4 presents a dynamic recursive computable general equilibrium for Ghana, employing a Social Account Matrix (SAM) with 2015 as the benchmark year, and we conclude this chapter with a brief analysis of SAM. Chapter 5 examines several possible simulation scenarios. We build our simulations around two industrial policy strategies: labor-intensive and capital-intensive, furthermore our simulation is informed by Ghana’s industrial policy plan. We analyze various policies such as efficiency improvement, trade protection, free trade, and taxation policy. We conclude that capital-intensive industrialization would work better under a free trade policy. Moreover, we discovered that the cost of protecting labor-intensive industries is less than the cost of safeguarding capital-intensive industries. We conclude the dissertation with a discussion of the implications of our findings. we aim to provide a comprehensive discussion of the implications of our findings, as well as acknowledge the limitations of our study and propose potential avenues for further research. By doing so, we hope to contribute to the existing body of knowledge in our field and inspire future researchers to expand upon our work.
Creators : Borges Jorge Tavares Dissertation Number : 東アジア博甲第167号 Degree Names : 博士(学術) Date Granted : 2023-09-26 Degree Grantors : Yamaguchi University
Creators : 孫 森 Dissertation Number : 東アジア博甲第166号 Degree Names : 博士(学術) Date Granted : 2023-09-26 Degree Grantors : Yamaguchi University
Creators : YANG XIAODONG Dissertation Number : 創科博甲第125号 Degree Names : 博士(工学) Date Granted : 2023-09-26 Degree Grantors : Yamaguchi University
Creators : Sawayama Saki Dissertation Number : 創科博甲第124号 Degree Names : 博士(工学) Date Granted : 2023-09-26 Degree Grantors : Yamaguchi University
Since social infrastructure, which was intensively developed during the high economic growth period,will deteriorate all at once in the future, maintenance and management of facilities will be an issue in thefuture. Currently, facility inspection records are based on paperbased forms, and are not premised onautomatic processing by computer. The authors have developed the “Smart Chosa” and realized a databaseof facility inspections and a GIS System. The Smart Chosa was able to record the location of the inspectionphoto on a two dimensional map, but because it was necessary to approach the deformed part when takingthe inspection photo, it was not possible to grasp the position, direction, and size of the entire facility.Therefore, we applied 3D GIS to Smart Chosa for sabo dams, created a 3D model from photographs takenon site, and conducted research to manage inspection results on the 3D model. This study summarizes the results of research on management of inspection photographs on a 3D GISin order to improve the efficiency of management of inspection photographs of sabo facilities. This thesisconsists of 6 chapters, and the main content of each chapter is as follow. [Chapter 1: Introduction] In this chapter, the current status and issues of the maintenance and management of socialinfrastructure in Japan were summarized. Utilization of 3D models for maintenance and management ofcivil engineering facilities, high-precision positioning used for alignment of 3D models, efficientinspection of concrete structures, and existing research trends on iPhone LiDAR applications wereorganized. On that basis, the purpose and points of focus of this research were organized, and the structureand outline of this paper were described. [Chapter 2: Comparison of 3D models and examination of application to sabo facilities maintenance management system] In this chapter, three types of models, a BIM/CIM model, a 3D point cloud model, and a 3D surfacemodel, are compared and examined as 3D models to be applied to the maintenance management system.The problem setting in this chapter is the selection of a 3D model to be used in this system. The constraintis that the Sabo dams including the existing dam can be modeled in 3D. At present, there are few BIM/CIMmodels for sabo dams, so when applying to existing sabo dams, we believe that a 3D surface model thatcan be created by SfM/MVS technology from photographs taken by UAVs will be useful. The 3D modelin the research was a 3D surface model. Knowledge about the 3D model that can be applied to the sabo facility maintenance managementsystem and knowledge for utilizing the 3D model in the 3D GIS were obtained. [Chapter 3: Performance evaluation of RTK receiver used for Sabo facility investigation support system] In this chapter, a survey of high-precision positioning technology necessary for positioning 3D modelsof sabo dams and inspection photos on a 3D GIS, and evaluation of positioning performance in sabo damsand surrounding forests are conducted. The problem setting in this chapter is whether or not locationinformation can be acquired during surveys of Sabo facilities, and accuracy verification. The constraintis that real-time high-precision positioning is required using inexpensive and small devices inenvironments that are unfavorable for satellite positioning (such as sabo dams and forests). It was confirmed that the multi-band receiver whose performance was evaluated has a horizontalvariation of 22 mm (2DRMS) even in a poor environment where about 70% of the sky directly below thesabo dam is covered. It was confirmed that the method can be applied to aligning 3D models ofphotographs. [Chapter 4: Investigation of image synthesis for creation of sabo dams inspection image] In this chapter, as a basic examination of 3D model creation, the image synthesis method is organized.The problem setting in this chapter is normalization and image combination necessary for synthesizinginspection photographs (2D). The constraint is that the inspection photography equipment is a smartphonefor field survey. In the feature point detection method for image synthesis, we compared two types offeature amounts, SIFT feature amount and AKAZE feature amount, and confirmed the accuracy byexperiments. In addition, RANSAC was used as an outlier removal method. By combining these methods,we performed image synthesis using multiple photographs of the concrete surface of the sabo dam. [Chapter 5: 3D model creation by SfM/MVS and application to 3D GIS] The problem setting in this chapter is a superimposed display of a 3D Sabo dam model and inspectionphotographs. The constraint is that the equipment that can be used to create a 3D model of inspectionphotographs is limited to equipment (compact and lightweight) that can be brought by local workers. Inthis chapter, we first present an overview of the "smart chosa" system that expands the scope of applicationfrom 2D to 3D in this research. After that, we investigated SfM/MVS processing to create a 3D surfacemodel. By creating a 3D model of the sabo dam and a 3D model of inspection photos by SfM/MVSprocessing, and importing them into a 3D GIS, we succeeded in superimposing the sabo dam andinspection photos on a 3D map. In addition, we examined a method of creating a 3D surface model using the iPhone LiDARapplication that can perform 3D measurement using the LiDAR function installed from iPhone12Pro. Wecompared the 3D model created with the iPhone LiDAR app and the 3D model created using MetaShape,a software that implements SfM/MVS processing, and confirmed the image resolution and positionalaccuracy for use as inspection photographs. In order to incorporate the created 3D model into 3D GISsoftware, we examined a method for matching the orientation and position, and actually superimposedthe 3D model of the sabo dam and the 3D model of the inspection photograph on the 3D GIS. I haveconfirmed that it is possible. [Chapter 6: Summary] In this chapter, a summary of the results obtained in Chapters 2 to 5 and future issues were discussed. The result of this research is a visualization method that makes it easy for people other than fieldinvestigators to understand the situation of the site by importing 3D surface models acquired by variousmethods into 3D GIS. 3D surface models include SfM models created from photos taken with aUAV/smartphone, SfM models created from photos taken with a handheld RTK rover, and 3D modelscreated with the iPhone LiDAR app. By using this method, it is possible to grasp the deformation position and deformation direction of thesabo dam in 3D space, and by superimposing the photographs of each inspection, it is possible to graspthe change over time.
Creators : 山野 亨 Dissertation Number : 創科博甲第123号 Degree Names : 博士(工学) Date Granted : 2023-09-26 Degree Grantors : Yamaguchi University
Japan's declining birthrate and aging population are difficult to resolve in the short term, and the working-age population, which refers to the population aged 15 to 65, continues to decline. On the other hand, mental illness patients are increasing in the working age population. The medical side, which is responsible for treatment, is required to improve efficiency by reforming the way doctors work. Therefore, expectations are placed on psychotherapy performed at home for the purpose of effective treatment of the working-age population. In this study, neurofeedback, which is one of the psychological therapies, was taken up, and applied equipment development and verification were carried out for its implementation at home. In this study, as a preclinical stage, measures were verified based on measurements of general cooperators. Neurofeedback (NFB) is considered to be one of psychotherapy using electroencephalogram signals, and is a psychotherapy that visualizes one's own electroencephalogram and self-controls the visualized electroencephalogram. It is attracting attention because it is a non-drug therapy and provides neuromodulation. NFB is being investigated for many clinical applications. The target diseases are diverse, including chronic pain, ADHD, depression, and mood disorders. However, we believe that there are four tasks to ensure the effectiveness of this therapy. Task 1 is overcoming the difficulty of installing electroencephalogram electrodes. NFB is considered to be a therapy that affects the plasticity of the cranial nerves, and is a therapy that actively promotes the development of neural networks, and is expected to be highly effective if the training frequency is high. It is necessary to be able to perform it at home, and it is required that electroencephalogram electrodes can be easily installed. Therefore, we made a prototype of an electroencephalogram headset with bipolar gel electrodes, and as a result of trial verification with children, we were able to confirm the electroencephalogram signals of 30 people aged 5 to 20 years old. Analysis of the recorded electroencephalogram revealed an age-dependent left-brain tendency in β waves, etc., confirming consistency with previous findings. Task 2 is determining the brain wave derivation part of the NFB training target. For electroencephalography, lead electrodes are usually placed in the scalp, but it is difficult to place the electrodes in the scalp by yourself. There is a need to consider forehead derivation for easy EEG electrode placement at home. There are regional differences in EEG waveforms within the forehead, and it is necessary to select the most appropriate extraction site. For NFB, we explored the optimal site based on the correlation with the top of the head, which is usually the electroencephalogram derivation position. Next, we performed an EEG network analysis at the time of NFB using the EEG derived from the top of the head and the EEG derived from the optimal forehead region, and analyzed the difference in the brain network during NFB due to the difference in the derivation region. For the second task, we explored the optimal site for deriving brain waves from the forehead, and proved that NFB from the brain waves derived from this site works on the same network as NFB from the brain waves derived from the top of the head. Task 3 is a method of selecting an electroencephalogram frequency band to be derived and self-controlled in NFB therapy (training target electroencephalogram frequency band). In previous studies, the EEG frequencies targeted for NFB therapy are diverse and not standardized. Even for the same disease, various electroencephalogram frequency bands are selected and NFB is performed. A personalized frequency band decision is made according to the patient's pathology and condition. In order to make the frequency band determination method more logical, we thought it necessary to determine the electroencephalogram frequency for therapy from the comparison of the basic rhythms of healthy subjects and patients. In this study, we created an electroencephalogram basic rhythm evaluation program and collected electroencephalogram basic rhythm data from randomly selected subjects. The electroencephalogram basic rhythm evaluation program consists of 7 stages. Eyes open stage, Eyes closed stage, 0Back stage, Rest1 stage, 2Back stage, Rest2 stage, Healing Picture stage. Changes in brain waves occur due to external stimuli such as eye opening and eye closing, concentration, and relaxation. An electroencephalogram basic rhythm evaluation program was created considering multiple stimuli that affect electroencephalogram dynamics. The usefulness of this program was confirmed as a preliminary examination of the dominant fluctuation region and network analysis by topographic analysis during the execution of the electroencephalogram basic rhythm evaluation program. EEG basic rhythm brain standard program electroencephalogram measurements were carried out for 89 subjects recruited from the general public, and a database was created. Using the forehead optimally measured parts (left and right) obtained in Task 2 as electroencephalogram derivation parts, a significant difference test was performed for each electroencephalogram frequency band Power value and content rate of each stage of the electroencephalogram basic rhythm evaluation program. The α Power value increased 2.52 times when the eyes were closed, and the θ Power value increased 1.67 times during 2 Back compared to 0 Back. We examined the possibility of clinical application by analyzing the correlation between the score of the questionnaire used in clinical diagnosis and the electroencephalogram component. The questionnaires used were mainly CSI (CENTRAL SENSITIZATION INVENTORY), and POMS2 (Profile of Mood States 2). Task 4 is NFB scoring. Continuation of psychotherapy requires a score as a reward to be visualized. We compared the two scores, the time ratio score and the amplitude ratio score, analyzed the correlation between the questionnaire used in task 3 and the two scores, and examined the optimal score. In results, the frequency band that correlates better with psychological activity during NFB was suggested SMR. Some of the psychological scales included the data probably above the general average level, which might have provided hypotheses at the preclinical stage. 4 tasks were conducted to demonstrate the technical requirements and effectiveness evaluation for the practical application of cognitive psychological training NFB, which is expected to be used with high frequency at home for children to working-age adults. The technological requirements and effectiveness evaluation for the practical application of NFB are presented. This research attempted four tasks and realized the possibility of frequent NFB training at home for patients from children to productive age. As a preclinical stage, it was a study within a range that can be resolved as a stage of policy verification based on the general participant study. In the future, the efficacy of this study will be further evaluated by comparing it with clinical data in the area of mental illness such as depression and developmental disorders, including chronic pain. In the future, the effectiveness of this study will be further evaluated by comparison with clinical data in the area of chronic pain and other mental illnesses such as depression and developmental disorders.
Creators : Oda Kazuyuki Dissertation Number : 創科博甲第122号 Degree Names : 博士(工学) Date Granted : 2023-09-26 Degree Grantors : Yamaguchi University
Open source software (OSS) are adopted as embedded systems, server usage, and so on because of quick delivery, cost reduction, and standardization of systems. Therefore, OSS is often used not only for the personal use but also for the commercial use. Many OSS have been developed under the peculiar development style known as the bazaar method. According to this method, many faults are detected and fixed by developers around the world, and the fixed result will be reflected in the next release. Also, many OSS are developed and managed by using the fault big data recorded on the bug tracking systems. Then, many OSS are developed and maintained by several developers with many OSS users. According to the results of the 2022 Open Source Security and Risk Analysis (OSSRA), OSS is an essential part of proprietary software, e.g., the source code containing OSS is 97%, all source code using OSS is 78%. On the other hand, OSS has issues from various perspectives. Therefore, OSS users need to decide on whether they should use OSS with consideration of each issue. In addition, the managers of open source projects need to manage their projects appropriately because OSS has a large impact on software around the world. This thesis focuses on the following three issues among many ones. We examine a method for OSS users and open source project managers to evaluate the stability of open source projects. 1. Selection evaluation and licensing: Methods for OSS users to make selections from the many OSS available situation, 2. Vulnerability support: Predicted fault fix priority for the reported OSS, 3. Maintenance and quality assurance: Prediction of appropriate OSS version upgrade timing, considering the development effort required after OSS upgrade by OSS users. In “1. Selection evaluation and licensing,” we attempt to derive the OSS-oriented EVM by applying the earned value management (EVM) to several open source projects. The EVM is one of the project management methodologies for measuring the project performance and progress. In order to derive the OSS-oriented EVM, we apply the stochastic models based on software reliability growth model (SRGM) considering the uncertainty for the development environment in open source projects. We also improve the method of deriving effort in open source projects. In case of applying the existing method of deriving effort in open source projects, it is not possible to derive some indices in the OSS-oriented EVM. Thus, we resolve this issue. The derived OSSoriented EVM helps OSS users and open source project managers to evaluate the stability of their current projects. It is an important to use the decision-making tool regarding their decisions and projects of OSS. From a different perspective, we also evaluate the stability of the project in terms of the speed of fault fixing by predicting the time transition of fixing the OSS faults reported in the future. 2. In “Vulnerability support”, in terms of open source project managers, we create metrics to detect faults with a high fix priority and predicted a long time for fixing. In addition, we try to improve the detection accuracy of the proposed metrics by learning not only the specific version but also the bug report data of the past version by using the random forest considering the characteristic similarities of bugs fix among different versions. This allows the project managers to identify the faults that should be prioritized for fixing when a large number of faults are reported, and facilitates project operations. In “3. Maintenance and quality assurance”, as an optimum maintenance problem, we predict the appropriate OSS version-up timing considering the maintenance effort required by OSS users after upgrading the OSS. It is dangerous in terms of the vulnerability to continue using the specified version of OSS ignoring the End of Life. Therefore, we should upgrade the version periodically. However, the maintenance cost increase with the version upgrade frequently. Then, we find the optimum maintenance time by minimizing the total expected software maintenance effort in terms of OSS users. In particular, we attempt to reflect the progress of open source projects by using the OSS-oriented EVM in deriving the optimal maintenance time. In conclusion, we found that there is the applicability as the stability evaluation of open source projects from three perspectives. Particularly, the OSS-oriented EVM discussed in “1. Selection evaluation and licensing” can contribute to the visualization of maintenance effort in open source projects. The proposed method will potentially contribute to the development of OSS in the future.
Creators : Sone Hironobu Dissertation Number : 創科博甲第121号 Degree Names : 博士(工学) Date Granted : 2023-09-26 Degree Grantors : Yamaguchi University
Hyperspectral (HS) imaging can capture the detailed spectral signature of each spatial location of a scene and leads to better understanding of different material characteristics than traditional imaging systems. However, existing HS sensors can only provide low spatial resolution images at a video rate in practice. Thus reconstructing high-resolution HS (HR-HS) image via fusing a low-resolution HS (LR-HS) image and a high-resolution RGB (HR-RGB) image with image processing and machine learning technique, called as hyperspectral image super resolution (HSI SR), has attracted a lot of attention. Existing methods for HSI SR are mainly categorized into two research directions: mathematical model based method and deep learning based method. Mathematical model based methods generally formulate the degradation procedure of the observed LR-HS and HR-RGB images with a mathematical model and employ an optimization strategy for solving. Due to the ill-posed essence of the fusion problem, most works leverage the hand-crafted prior to model the underlying structure of the latent HR-HS image, and pursue a more robust solution of the HR-HS image. Recently, deep learning-based approaches have evolved for HS image reconstruction, and current efforts mainly concentrated on designing more complicated and deeper network architectures to pursue better performance. Although impressive reconstruction results can be achieved compared with the mathematical model based methods, the existing deep learning methods have the following three limitations. 1) They are usually implemented in a fully supervised manner, and require a large-scale external dataset including the degraded observations: the LR-HS/HR-RGB images and their corresponding HR-HS ground-truth image, which are difficult to be collected especially in the HSI SR task. 2) They aim to learn a common model from training triplets, and are undoubtedly insufficient to model abundant image priors for various HR-HS images with rich contents, where the spatial structures and spectral characteristics have considerable difference. 3) They generally assume that the spatial and spectral degradation procedures for capturing the LR-HS and HR-RGB images are fixed and known, and then synthesize the training triplets to learn the reconstruction model, which would produce very poor recovering performance for the observations with different degradation procedures. To overcome the above limitations, our research focuses on proposing the unsupervised learning-based framework for HSI SR to learn the specific prior of an under-studying scene without any external dataset. To deal with the observed images captured under different degradation procedures, we further automatically learn the spatial blurring kernel and the camera spectral response function (CSF) related to the specific observations, and incorporate them with the above unsupervised framework to build a high-generalized blind unsupervised HSI SR paradigm. Moreover, Motivated by the fact that the cross-scale pattern recurrence in the natural images may frequently exist, we synthesize the pseudo training triplets from the degraded versions of the LR-HS and HR-RGB observations and themself, and conduct supervised and unsupervised internal learning to obtain a specific model for the HSI SR, dubbed as generalized internal learning. Overall, the main contributions of this dissertation are three-fold and summarized as follows: 1. A deep unsupervised fusion-learning framework for HSI SR is proposed. Inspired by the insights that the convolution neural networks themself possess large amounts of image low-level statistics (priors) and can more easy to generate the image with regular spatial structure and spectral pattern than noisy data, this study proposes an unsupervised framework to automatically generating the target HS image with the LR-HS and HR-RGB observations only without any external training database. Specifically, we explore two paradigms for the HS image generation: 1) learn the HR-HS target using a randomly sampled noise as the input of the generative network from data generation view; 2) reconstructing the target using the fused context of the LR-HS and HR-RGB observations as the input of the generative network from a self-supervised learning view. Both paradigms can automatically model the specific priors of the under-studying scene by optimizing the parameters of the generative network instead of the raw HR-HS target. Concretely, we employ an encoder-decoder architecture to configure our generative network, and generate the target HR-HS image from the noise or the fused context input. We assume that the spatial and spectral degradation procedures for the under-studying LR-HS and HR-RGB observation are known, and then can produce the approximated version of the observations by degrading the generated HR-HS image, which can intuitively used to obtain the reconstruction errors of the observation as the loss function for network training. Our unsupervised learning framework can not only model the specific prior of the under-studying scene to reconstruct a plausible HR-HS estimation without any external dataset but also be easy to be adapted to the observations captured under various imaging conditions, which can be naively realized by changing the degradation operations in our framework. 2. A novel blind learning method for unsupervised HSI SR is proposed. As described in the above deep unsupervised framework for HSI SR that the spatial and spectral degradation procedures are required to be known. However, different optical designs of the HS imaging devices and the RGB camera would cause various degradation processes such as the spatial blurring kernels for capturing LRHS images and the camera spectral response functions (CSF) in the RGB sensors, and it is difficult to get the detailed knowledge for general users. Moreover, the concrete computation in the degradation procedures would be further distorted under various imaging conditions. Then, in real applications, it is hard to have the known degradation knowledge for each under-studying scene. To handle the above issue, this study exploits a novel parallel blind unsupervised approach by automatically and jointly learning the degradation parameters and the generative network. Specifically, according to the unknown components, we propose three ways to solve different problems: 1) a spatial-blind method to automatically learn the spatial blurring kernel in the capture of the LR-HS observation with the known CSF of the RGB sensor; 2) a spectral-blind method to automatically learn the CSF transformation matrix in the capture of the HR-RGB observation with known burring kernel in the HS imaging device; 3) a complete-blind method to simultaneously learn both spatial blurring kernel and CSF matrix. Based on our previously proposed unsupervised framework, we particularly design the special convolution layers for parallelly realizing the spatial and spectral degradation procedures, where the layer parameters are treated as the weights of the blurring kernel and the CSF matrix for being automatically learned. The spatial degradation procedure is implemented by a depthwise convolution layer, where the kernels for different spectral channel are imposed as the same and the stride parameter is set as the expanding scale factor, while the spectral degradation procedure is achieved with a pointwise convolution layer with the output channel 3 to produce the approximated HR-RGB image. With the learnable implementation of the degradation procedure, we construct an end-toend framework to jointly learn the specific prior of the target HR-HS images and the degradation knowledge, and build a high-generalized HSI SR system. Moreover, the proposed framework can be unified for realizing different versions of blind HSI SR by fixing the parameters of the implemented convolution as the known blurring kernel or the CSF, and is highly adapted to arbitrary observation for HSI SR. 3. A generalized internal learning method for HSI SR is proposed. Motivated by the fact that natural images have strong internal data repetition and the crossscale internal recurrence, we further synthesize labeled training triplets using the LR-HS and HR-RGB observation only, and incorporate them with the un-labeled observation as the training data to conduct both supervised and unsupervised learning for constructing a more robust image-specific CNN model of the under-studying HR-HS data. Specifically, we downsample the observed LR-HS and HR-RGB image to their son versions, and produce the training triplets with the LR-HS/HR-RGB sons and the LR-HS observation, where the relation among them would be same as among the LR-HS/HR-RGB observations and the HR-HS target despite of the difference in resolutions. With the synthesized training samples, it is possible to train a image-specific CNN model to achieve the HR-HS target with the observation as input, dubbed as internal learning. However, the synthesized labeled training samples usually have small amounts especially for a large spatial expanding factor, and the further down-sampling on the LR-HS observation would bring severe spectral mixing of the surrounding pixels causing the deviation of the spectral mixing levels at the training phase and test phase. Therefore, these limitations possibly degrade the super-resolved performance with the naive internal learning. To mitigate the above limitations, we incorporate the naive internal learning with our selfsupervised learning method for unsupervised HSI SR, and present a generalized internal learning method to achieve more robust HR-HS image reconstruction.
Creators : LIU ZHE Dissertation Number : 創科博甲第120号 Degree Names : 博士(理学) Date Granted : 2023-09-26 Degree Grantors : Yamaguchi University
Creators : 加計 悟 Dissertation Number : 共獣博乙第3号 Degree Names : 博士(獣医学) Date Granted : 2023-09-26 Degree Grantors : Yamaguchi University
Creators : 後藤 奈穂 Dissertation Number : 医博甲第1686号 Degree Names : 博士(保健学) Date Granted : 2023-09-26
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.
Creators : 鬼束 真美 Dissertation Number : 医博甲第1685号 Degree Names : 博士(医学) Date Granted : 2023-09-26 Degree Grantors : Yamaguchi University
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.
Creators : 山本 直宗 Dissertation Number : 医博甲第1684号 Degree Names : 博士(医学) Date Granted : 2023-09-26 Degree Grantors : Yamaguchi University
【背景】結腸直腸癌(colorectal cancer:CRC)の予後については、腫瘍の特性だけでなく、宿主の免疫反応も重要な因子となる。我々は宿主の免疫反応として全身および腫瘍微小環境(tumor microenvironment: TME)の炎症性サイトカイン発現に注目し、これらを評価することにより、免疫抑制状態と患者の予後との関係を検討した。 【方法】 切除可能CRC患者209名において、術前に採取した血清サンプルを用いてサイトカイン濃度(IL-1β、IL-6、IL-8、TNF-α)を電気化学発光法により測定し、予後との関連を検討した。また切除切片における腫瘍組織でのサイトカイン発現を腫瘍細胞、間質細胞に分けて免疫組織化学的に評価した。さらに、切除したCRC患者10例において、新鮮な切除切片から抽出した腫瘍浸潤細胞を用いたマスサイトメトリーによるシングルセル解析を行った。 【結果】 無再発生存期間において、血清IL-1β、IL-8、TNF-α濃度の高低では有意な関係を認めなかったが、血清IL-6高値群で有意に予後不良であった。また血中IL-6濃度上昇は腫瘍組織中の間質細胞におけるIL-6高発現と関連していた。シングルセル解析の結果、腫瘍浸潤免疫細胞のうちIL-6+細胞は主に骨髄球系細胞で構成され、リンパ球系細胞ではIL-6発現をほとんど認めなかった。またIL-6高発現群では、CD33+HLADR-骨髄由来抑制細胞(myeloid-derived suppressor cell: MDSC)およびCD4+FOXP3highCD45RA-エフェクター型抑制性T細胞(effector regulatory T cell: eTregの割合がIL-6低発現群に比べ有意に高かった。さらに、MDSCにおけるIL-10+細胞の割合、eTregにおけるIL-10+細胞またはCTLA-4+細胞の割合は、IL-6高発現群で有意に高かった。 【結論】血清IL-6濃度の上昇は間質細胞のIL-6発現と関連し、予後不良であった。腫瘍浸潤免疫細胞におけるIL-6高発現は、TMEにおけるMDSCやeTreg等の免疫抑制性細胞の蓄積と関連し、その機能性マーカーの上昇も認めた。これらIL-6を介した抑制性免疫機構がCRC患者の予後不良の一因となっている可能性がある。
Creators : 山本 常則 Dissertation Number : 医博甲第1683号 Degree Names : 博士(医学) Date Granted : 2023-09-26 Degree Grantors : Yamaguchi University
【背景】インターロイキン(IL)-33は, 宿主防御, 神経損傷, 炎症などに重要なIL-33/ST2シグナル経路を誘導する. 一方, IL-33のデコイ受容体である可溶性ST2(sST2)は, IL-33/ST2シグナル経路を抑制する. sST2は種々の神経疾患患者の血清中で増加するが, 低酸素性虚血性脳症(Hypoxic-ischemic encephalopathy; HIE)では知られていない. 【目的】本研究の目的は, HIEにおける血清中のIL-33, 及びsST2濃度を測定し, HIE重症度と神経学的予後との関連性を検討することである. 【対象と方法】2017年1月から2022年4月の期間に, 山口大学医学部附属病院総合周産期母子医療センターに入院した, 在胎期間36週以上, かつ出生体重1,800g以上の新生児を対象とし, HIE群23名, 対照群16名を本研究に登録した. HIEの重症度はSarnat分類により軽症, 中等症, 重症に分類し, 生後6時間以内, 及び1-2, 3, 7日目の血清IL-33及びsST2濃度を測定した. プロトン磁気共鳴スペクトロスコピーによりHIE群の基底核におけるlactate/N-acetylaspartate(Lac/NAA)比を算出し, 退院後の神経学的後遺症の有無を追跡調査した. 【結果】血清中IL-33濃度は各群で差を認めなかった. 一方, 中等症及び重症HIE群の血清sST2濃度は, 対照群に比し著明に高値で, HIE重症度と相関して高値であった. 血清中sST2濃度はLac/NAA比と有意な正の相関を示し(相関係数=0.527, P=0.024), 神経学的後遺症を来したHIE児では予後良好の児に比し, sST2濃度及びLac/NAA比が有意に高かった(それぞれP=0.020, <0.001).【結論】血清sST2濃度はHIEの重症度および神経学的予後予測に有用である可能性が示唆された.
Creators : 濱野 弘樹 Dissertation Number : 医博甲第1682号 Degree Names : 博士(医学) Date Granted : 2023-09-26 Degree Grantors : Yamaguchi University
キメラ抗原受容体(CAR)-T細胞療法は造血器腫瘍において優れた抗腫瘍効果を示している一方、固形がんにおいては臨床応用がまだなされていない。臨床応用におけるハードルとなっている理由の一つとして、固形がんでは適切なCAR ターゲットが欠如しているということにある。GM2 は糖鎖にシアル酸を有するスフィンゴ糖脂質の一群であるガングリオシドの一つであり、様々なタイプの固形がんにおいて過剰発現している。本研究では、我々が以前に開発したインターロイキン7(IL-7)/ケモカインリガンド19(CCL19)産生型ヒトCAR-T細胞システムを用いて、GM2が固形腫瘍に対するCART細胞療法のターゲットとなりうるかという点についてヒト肺小細胞がん異種移植マウスモデルを用いて探究した。IL-7/CCL19 産生型抗GM2 CAR-T細胞治療を行ったところ、GM2 陽性腫瘍の完全な退縮が観察され、腫瘍内部への豊富なT 細胞浸潤や長期のメモリー応答形成も観察されたが、有害事象は認めなかった。加えて、臨床においてCAR-T 細胞使用時に問題となるサイトカイン放出症候群や神経毒性をコントロールする方法として、ガンシクロビル(GCV)投与によりアポトーシスが誘導される自殺システムである単純ヘルペスウイルス-チミジンキナーゼ(HSV-TK)をCAR-T細胞に遺伝子導入した。HSV-TK発現IL-7/CCL19産生型抗GM2 CAR-T細胞は、in vivoにおいてGCV投与により効果的に除去された。以上より、我々の研究はIL-7/CCL19産生型ヒト抗GM2CAR-T細胞のGM2陽性固形がん治療への臨床応用における安全性を実証し、その有望な治療効果を明らかにした。
Creators : 佐々木 貴宏 Dissertation Number : 医博甲第1681号 Degree Names : 博士(医学) Date Granted : 2023-09-26 Degree Grantors : Yamaguchi University
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.
Creators : CHANG YAOWEI Dissertation Number : 医博甲第1680号 Degree Names : 博士(医学) Date Granted : 2023-09-26 Degree Grantors : Yamaguchi University
ダントロレン(DAN)はRyR2のN末端ドメインLeu601-Cys620に直接結合し、RyR2の4量体構造を安定化させることにより、RyR2からの拡張期Ca2+漏出を防ぐ。以前我々は、RyR2へのCaM高親和性KIマウス(V3599K)を用いて、横行大動脈縮窄(TAC)による圧過負荷誘発性心肥大マウスモデルにおいてRyR2からのCaM解離を抑制することで、Ca2+漏出を防ぎ、左室リモデリングを抑制することを報告した。そこで本研究では、横行大動脈縮窄(TAC)による圧負荷誘発性心肥大マウスモデルにおいてダントロレンの慢性投与がCaMとRyR2の結合親和性を遺伝的に強化した場合と同様の機序で左室リモデリングを抑制するかを調べた。横行大動脈縮窄(TAC)による圧負荷誘発性心肥大マウスモデルを作成した。野生型マウスを、Sham群、TAC群、TAC-DAN群(ダントロレン20mg/kg/day腹腔内投与)の3群に割り付けた。ShamまたはTAC手術から8週後の生存率、心機能および組織評価、単離心筋細胞を用いたCa2+ハンドリング、RyR2-CaM結合性の評価を行った。TAC-DAN群はTAC群と比較し、TAC手術から8週後の生存率は良好であった(TAC群 49% vs TAC-DAN群83%)。また、心エコーと心筋組織においては、TAC群で認めた左室リモデリングは、TAC-DAN群で抑制された。TAC手術から8週後の単離心筋細胞ではTAC群で拡張期Ca2+スパーク頻度の増加およびRyR2-CaM結合親和性の低下を認めたが、TAC-DAN群ではそれが抑制された。我々の研究はダントロレンの慢性投与によりRyR2を安定化させ、RyR2からのCaM解離を抑制することで、RyR2からの拡張期Ca2+漏出を防ぎ、左室リモデリングが抑制され、予後が改善することを示した。
Creators : 矢野 泰健 Dissertation Number : 医博甲第1679号 Degree Names : 博士(医学) Date Granted : 2023-09-26 Degree Grantors : Yamaguchi University
Creators : 濱田 和希 Dissertation Number : 医博甲第1678号 Degree Names : 博士(医学) Date Granted : 2023-09-26 Degree Grantors : Yamaguchi University
Creators : 岡田 真理子 Dissertation Number : 医博甲第1677号 Degree Names : 博士(医学) Date Granted : 2023-09-26 Degree Grantors : Yamaguchi University
膵β細胞量の進行性の減少が糖尿病の発症・進展に関与する。糖尿病病態では、インスリン作用不足による高血糖に対する代償的なインスリン産生の増加や脂質異常のためにβ細胞において小胞体ストレスが亢進する。一方、セリン・スレオニンキナーゼGsk-3 はPI3/Akt により抑制され、Gsk-3 の活性制御障害がβ細胞不全と小胞体ストレス関連β細胞死に関連する。しかし、Gsk-3 を介した細胞障害の分子機構は十分に解明されていない。本研究では、Gsk-3 を介する小胞体ストレス応答調節と膵β細胞アポトーシス誘導の関連について検討を行った。方法:マウス単離膵ランゲルハンス氏島(ラ氏島)およびマウス膵β細胞株で薬理学的に小胞体ストレスを誘導した。Ins2 遺伝子に変異を持ち、変異インスリンの蓄積により小胞体ストレスが亢進しβ細胞死を来すAkita mouse 由来の膵β細胞株を遺伝的小胞体ストレスのモデルとして用いた。低分子化合物、あるいは酵素不活性型Gsk-3βの導入によりGsk-3 活性を阻害した。結果:小胞体ストレス下ではGsk-3 を抑制するAkt の活性が減弱しGsk-3 が活性化した。Gsk-3 はATF4 のSer214 リン酸化を介してATF4 とSCF-βTrCP の結合とそれに続くATF4 のユビキチン化、蛋白分解を促進する。したがって、Gsk-3 の抑制によりATF4 の分解速度が低下し、ATF4 蛋白質量が増加することが明らかになった。このとき、β細胞のアポトーシスが減弱することを確認した。この抗アポトーシス効果はdominant negative-ATF4 導入あるいはATF4 ノックダウンにより有意に減弱した。Gsk-3 抑制によるアポトーシス抑制のメカニズムについて、ATF4 の転写標的であるGADD34 および4E-BP1 の発現増強を介した全般的な蛋白翻訳の動態との関連が考えられた。さらに、Akita mouse 由来の膵β細胞株でもGsk-3 活性阻害によるアポトーシス抑制が確認され、これにはATF4 の発現増強と全般的な蛋白翻訳抑制が関連した。以上の結果より、インスリンシグナルとストレス応答のクロストークが明らかになり、Gsk-3/ATF4 経路が糖尿病におけるβ細胞保護の治療標的となる可能性が示唆された。
Creators : 永尾 優子 Dissertation Number : 医博乙第1108号 Degree Names : 博士(医学) Date Granted : 2023-07-05 Degree Grantors : Yamaguchi University
目的:アルコール使用障害(Alcohol use disorder: AUD)は治療後も再発率が高く再発を予測する患者の要因は確立されていない。AUDでは衝動制御障害、実行機能障害および意思決定障害が報告されているため、本研究ではそれらを用いてAUDの予後予測因子を前方視的に明らかにすることを目的とした。 方法:20歳から70歳までの入院中のAUD患者41名を対象とした。入院中に、①情動顔go/no-go課題(衝動制御課題)および言語流暢性課題(実行機能課題)中の脳血流活性化の指標である酸素化ヘモグロビン積分値を機能的近赤外分光法(functional nearinfrared spectroscopy: fNIRS)を用いて測定し、さらに②不確実な状況下でのリスク選好課題(意思決定)を行った。退院後6ヶ月の再発の有無を主要アウトカムとした。 結果:退院後、24名(58.5%)が断酒を継続し、17名(41.5%)が再飲酒した。断酒群に比べて再飲酒群では、①情動顔go/no go課題における右前頭側頭領域の活性化が有意に低下し、②意思決定課題では有意にリスク追及的であった。断酒群でのみ、右前頭側頭領域の活性と渇望尺度の間に負の相関が観察された。さらに、退院後6ヶ月の飲酒の有無を従属変数とし、年齢、AUD重症度、発症年齢、右前頭葉領域の酸素化ヘモグロビン積分値及び意思決定課題でのリスク選好の5つの独立変数を用いた2項ロジスティック回帰分析を行い、各独立因子の再発への影響を検討した結果、右前頭側頭領域の酸素化ヘモグロビン積分値が小さいほど(オッズ比=0.161、p=0.013)、またリスク追及傾向が強いほど(オッズ比=7.04、p=0.033)再発リスクが増加することが示された。 結論:右前頭側頭領域の情動刺激に対する脳血流活性化の低下と、リスク追及傾向が、AUDにおける退院6か月後の再発を予測し得る可能性が示された。
Creators : 佐々木 順 Dissertation Number : 医博乙第1107号 Degree Names : 博士(医学) Date Granted : 2023-05-17 Degree Grantors : Yamaguchi University
本論文は,申請者が山口大学大学院東アジア研究科在学中において進めてきた,遠隔教育支援環境における授業と学習活動の支援に関する研究をまとめたものである. 人口減少社会の到来により,特に地方において,適正規模での学校運営が難しい小規模の学校が増加傾向にある.小規模校では,きめ細やかな指導等が行える一方で,人間関係が固定化しがちであったり,多様な意見や考え方に触れることが少なくなったりなど,教育上の課題を抱えている.その解決策の1つとして,複数校の児童生徒が1つの学校に集まって合同授業が実施されているが,時間的・金銭的な問題などから実施回数が制限されるケースが多い.この合同授業を補う形で,日進月歩の勢いで進歩しているICT技術を活用した遠隔合同授業の取組みが期待され,教育実践が進められてきている. 一方,小学校や中学校だけでなく,大学などの高等教育機関においてもICTを活用した遠隔教育は進められてきている.さらに,新型コロナウィルス感染症のパンデミックを契機に,小学校・中学校・高校や高等教育機関だけでなく,塾など様々な場でオンライン授業あるいはオンライン学習といった遠隔教育の取り組みも行われてきている. しかしながら,オンライン授業や遠隔合同授業を実践する上では,環境整備面や授業実施面などで課題が存在する.特に,授業実施時における教員の作業負荷が非常に高いことが問題であり,オンライン授業や遠隔合同授業の特性や授業プロセスを踏まえた仕組みの構築や機能の開発が必要となる.さらに,オンライン授業や遠隔合同授業における学習者個人あるいはグループによる学習活動や,教員による教授活動や学習者グループの活動支援のプロセスを分析した上で,その状況に応じた支援手法を検討し,学習支援機能やその機能と連動した授業支援機能を遠隔教育支援ツール・アプリとして提供することが必要となる. そこで本研究では,高校・大学などにおけるオンライン授業や小学校・中学校の小規模校における遠隔合同授業といった遠隔教育を対象にして,校種やICT活用能力に応じた機能や画面に切り替えることができる設計思想を持った,課題解決的な学習が展開される際の学習者の学習活動と教員の教授活動を支援するための遠隔教育支援環境を設計して開発することを目的にする. 本論文では,本研究の目的を達成させるために,以下に示す5つの調査・研究・開発の成果がまとめられている. (1) 遠隔教育の支援環境に関する研究動向の調査 (2) 遠隔教育を支援する環境・機能についての整理と必要機能の提案 (3) 「クラス(学級)」と「個」をつなぐ遠隔教育支援環境「つながる授業アプリ」の開発と評価 (4) 「比べる」協働的思考活動支援機能の開発と評価 (5) グループ学習活動・対話状況確認支援機能とグループ活動状況管理機能の開発と評価 (1)では,遠隔教育に関する研究動向を調査した.これらの整理・分類などを踏まえ,遠隔教育における学習環境,学習支援機能,授業支援機能の研究に対する本研究の位置づけを行った. (2)では,遠隔教育をICTで支援する環境について説明した.さらに,2つのつながり(「クラス(学級)」と「個」)を保障する遠隔教育システムと協働学習支援システムに必要な機能を整理した. (3)では,遠隔教育システムと協働学習支援システムの両方の機能を併せ持つ遠隔教育支援環境「つながる授業アプリ」を設計・開発した.さらに,「つながる授業アプリ」のの有用性を評価し,基本機能を完成させた. (4)では,遠隔合同授業における小学生を対象として,より深い学びを実感できることを目的として,グループ活動時の思考に必要なプロセスを整理し,最も基本的な思考活動の1つである「比較思考」を協働的に進めることができる支援を「つながる授業アプリ」の拡張機能として実装した.「比べる」協働的思考活動支援機能は,「比べる」思考手順を1スライドずつ学習者間の協働的な思考手順として提示して,思考活動プロセスをガイドする仕組みである.さらに,開発した支援機能についてその有用性を評価した. (5)では,大学の遠隔教育を対象にして,グループ学習活動における学習者の対話内容の確認や振り返り,教員による見とりを支援する目的として,対話音声データ(バーバル情報)とノート記述データ(ノンバーバル情報)を活用した活動状況・対話状況の可視化機能を「つながる授業アプリ」の拡張機能として実装した.さらに,教員の見とり支援としてグループ活動状況管理機能も拡張機能として実装し,これらの機能の有用性を評価した. 以上により,オンライン授業が展開でき,学習者の個別学習やグループ学習の活動支援や教員の見とり支援が可能な「つながる授業アプリ」の開発・授業実践を通して,遠隔教育において必要な学習環境の要素機能,学習支援・授業支援の機能を確認することができた.
Creators : 横山 誠 Dissertation Number : 東アジア博甲第165号 Degree Names : 博士(学術) Date Granted : 2023-03-16 Degree Grantors : Yamaguchi University
Creators : 植田 隆博 Dissertation Number : 東アジア博甲第164号 Degree Names : 博士(学術) Date Granted : 2023-03-16 Degree Grantors : Yamaguchi University
This dissertation focuses on the experiences of a group of Japanese university students who participated in a short-term study abroad program in the Philippines. While the main objective of the four-week sojourn was to improve the participants’ English language skills, I explored the effects of the trip holistically as a qualitative case study to examine the unique learning context of studying English in the Philippines, a relatively new phenomenon that has developed from the turn of the 21st century. The primary form of data I used was interview responses obtained from 14 focal participants among a larger cohort of 103 students who traveled together in the summer of 2018. The target students were mostly low to intermediate level (CEFR A2 to B1) before departure and returned at a marginally higher benchmark (CEFR B1 average) according to standardized testing scores. More importantly, most students did not have extensive international experience prior to the sojourn, and overall they expressed a more open stance to using English for communication after the trip. In this case and context, positive affective development occurred due to intensive one-on-one instruction with Filipino teachers who interacted with the Japanese students in a warm, friendly, and supportive manner. This learning situation is characteristically different from North American and other Western contexts typically associated with English learning, and with its relative ease of access geographically and financially, offers a practical alternative to Japanese students unable to study abroad otherwise. The results of this study indicate how Japanese learners of English adopt subtle changes in outlook through short-term study abroad programs in diversifying contexts. This research contributes significantly to the field of language learning in study abroad by documenting the perspectives of learners from Japan traveling within Asia. Study abroad itself is a relatively new area of inquiry which has focused predominantly on Western learners and contexts. Existing research on Japanese learners tends to concern privileged, advanced-level learners whose experiences may seem removed from the ordinary lives of students attending university in rural areas or those who do not consider themselves academically or socioeconomically exceptional. Furthermore, the amount of existing research on short-term study abroad is severely limited and does not thoroughly account for the experiences of Japanese learners of English in the Philippines, a study abroad destination which has gained substantial popularity but remains underrepresented. Accounting for the social, cultural, and ideological circumstances of learning in a non-native English speaking context in Asia allows for a more nuanced interpretation of how monolingual Japanese speakers first encounter English as an international language. I collected data in multiple forms to document the complexity of the case. As the participants’ English teacher and chaperone to the Philippines, I was immersed in the learning contexts in the students’ home country as well as abroad. Semi-structured interviews before and after the study abroad experience were conducted in the informants’ native language. Written questionnaires were administered to the larger cohort of students who traveled together to obtain a more general assessment of students’ impressions regarding the study abroad experience. Standardized test scores were accessed for reference. These multiple data sources were drawn on to illustrate the changes observed in the perspectives of the focal informants. While the learning experiences of each informant were unique, I identified common themes among the ways students collectively changed their attitudes and beliefs toward English and language learning through their participation in the short-term study abroad program. First, the learners in this study increased their self-confidence and motivation to learn English and overcame their fear, anxiety, and inhibition toward using English to varying degrees. Second, they expanded their interests in learning about other languages and cultures while becoming more aware of the boundaries of their own culture. Third, their perceived communicative ability in English improved, which they found was not the same as having to perform well on standardized English tests. Fourth, participants’ sense of success in improving their English language proficiency was less certain, reflecting their divergent test score gains on standardized exams. These reported changes in perspective were not lifechanging transformations of learners’ social identities, but their previously constructed views of language, culture, communication, and learning were evidently affected. The qualitative effects of study abroad experienced by the informants of this study cannot be assessed adequately with the language proficiency tests highly regarded in mainstream Japanese society. Language ideologies prevalent in the participants’ home and host contexts for learning need to be considered in order to explain why the changes occurred. The learners in this study initially had an additional affective barrier toward communication in intercultural contexts because they could not take advantage of the widespread use of English as a lingua franca without first making efforts to use English itself. Since they were used to monolingual discourses in Japan, the idea of using English as a lingua franca, not only as a “perfect” native language, had to be presented to them in a reallife situation. The study abroad experience nudged learners toward using English in ways that reflect the Global Englishes paradigm. These slight shifts in mindset are indicative of attitudinal changes gradually taking place within Japan and are not restricted to individuals who identify with international communities.
Creators : 池田 理紗 Dissertation Number : 東アジア博甲第163号 Degree Names : 博士(学術) Date Granted : 2023-03-16 Degree Grantors : Yamaguchi University
Creators : 松尾 朗 Dissertation Number : 東アジア博甲第162号 Degree Names : 博士(学術) Date Granted : 2023-03-16 Degree Grantors : Yamaguchi University
Creators : 張 学盼 Dissertation Number : 東アジア博甲第161号 Degree Names : 博士(学術) Date Granted : 2023-03-16 Degree Grantors : Yamaguchi University
Creators : 小村 有紀 Dissertation Number : 東アジア博甲第160号 Degree Names : 博士(学術) Date Granted : 2023-03-16 Degree Grantors : Yamaguchi University
Not only taste but also flavor has a significant impact on the "deliciousness" of food as perceived by people. Flavor characteristics of food have a significant impact on its palatability and influence the qualitative value of the food itself. In this study, the molecular mechanisms of biosynthesis of flavor compounds derived from amino acids in soybean (Glycine max) and fatty acids in mushrooms were elucidated. In Chapter 1, I identified the characteristic aromatic properties of soybean due to sulfur-containing amino acids. Several soybean germplasms, such as Nishiyamahitashi 98-5 (NH) among local varieties in Nagano Prefecture, have an intense seaweed-like flavor after cooking because of their high seed S-methylmethionine (SMM) content. In this study, I compared the amounts of amino acids in the phloem sap, leaves, pods, and seeds between NH and the common soybean cultivar Fukuyutaka. This revealed a comparably higher SMM content alongside a higher free L-methionine (L-Met) content in NH seeds, suggesting that the SMM-hyperaccumulation phenotype of NH soybean was related to L-Met metabolism in seeds. To investigate the molecular mechanism behind SMM hyperaccumulation, I examined the phenotype-associated gene locus in NH plants. Analyses of the quantitative trait loci in segregated offspring of the cross between NH and the common soybean cultivar Williams 82 indicated that one locus on chromosome 10 explains 71.4% of SMM hyperaccumulation. Subsequent fine-mapping revealed that a transposon of about 6 kbp insertion into the intron of a gene, Glyma.10g172700, is associated with the SMM-hyperaccumulation phenotype. The Glyma.10g172700-encoded recombinant protein showed Met-γ-lyase (MGL) activity in vitro, and the transposon-insertion mutation in NH efficiently suppressed Glyma.10g172700 expression in developing seeds. Exogenous administration of L-Met to sections of developing soybean seeds resulted in transient increases in L-Met levels, followed by continuous increases in SMM concentrations, which was likely caused by L-Met methyltransferase activity in the seeds. Accordingly, I propose that the SMM-hyperaccumulation phenotype is caused by suppressed MGL expression in developing soybean seeds, resulting in transient accumulation of L-Met, which is converted into SMM to avoid the harmful effects caused by excess free L-Met. In Chapter 2, I studied the biosynthesis mechanism of 1-octen-3-ol, the main volatile component of mushrooms. 1-Octen-3-ol is a volatile oxylipin found ubiquitously in Basidiomycota and Ascomycota. As 1-octen-3-ol attracts mosquitoes and flies, its involvement in emitter–receiver ecological communication has been proposed. Although the biosynthetic pathway to form 1-octen-3-ol from linoleic acid through linoleic acid 10(S)-hydroperoxide has been proposed in mushrooms, the enzymes involved in this pathway have not been identified. I determined that the Coprinopsis cinerea dioxygenase 1 and 2 (CcDOX1 and CcDOX2) genes in the mushroom C. cinerea contains an N-terminal cyclooxygenase-like heme peroxidase domain and a C-terminal cytochrome P450-related domain. Through analysis of products formed from linoleic acid by the recombinant CcDOX1 and CcDOX2 proteins, I found that CcDOX1 preferentially catalyzes to form the 10(S)-hydroperoxide of linoleic acid (10S-HPODE), meanwhile CcDOX2 form the 8-hydroperoxide of linoleic acid. Moreover, disruption of Ccdox1 in C. cinerea (ΔCcdox1) mycelia suppressed 1-octen-3-ol synthesis. Administration of the 10S-HPODE to the microsome fraction prepared from mycelia resulted in the efficient production of 1-octen-3-ol. Together, these results indicate that CcDOX1 is essential for the biosynthesis of 1-octen-3-ol as the oxygenase that forms 10S-HPODE, followed by the cleavage enzyme. I studied physiological and ecological significance of 1-octen-3-ol of mushroom. ΔCcdox1 was less attractive to fruit fly larvae, while the feeding behavior of fungus gnats on ΔCcdox1 mycelia showed little difference from that on the mycelia of the wild-type strain. The proliferation of fungivorous nematodes on ΔCcdox1 mycelia was similar to or slightly worse than that on wild-type mycelia. Thus, 1-octen-3-ol seems to be an attractive compound for some animals that interact with mushrooms.
Creators : 手嶋 琢 Dissertation Number : 創科博甲第119号 Degree Names : 博士(生命科学) Date Granted : 2023-03-16 Degree Grantors : Yamaguchi University
Creators : 山田 耕輝 Dissertation Number : 創科博甲第118号 Degree Names : 博士(学術) Date Granted : 2023-03-16 Degree Grantors : Yamaguchi University
Creators : 三谷 龍祐 Dissertation Number : 創科博甲第117号 Degree Names : 博士(工学) Date Granted : 2023-03-16 Degree Grantors : Yamaguchi University
Indonesia has extreme risk of natural disasters because of its position at the confluence of four tectonic plates: the Asian Continent, the Australian Continent, the Indian Ocean, and the Pacific Ocean. The volcano eruption is one of the geological disasters that frequently occur in this country. Mount Merapi is Indonesia’s most active volcano and is famous worldwide. The evacuation crisis in 2010, the last major eruption, led to many fatalities for humans and cattle. Nowadays, the local government developed the "sister village" strategy for mitigation. That means cooperation within or between the local community has been constructed to provide shelter, logistics, and other disaster-related services. In this scenario, the meeting area and shelter have been coordinated. However, people's behavior has not been fully considered yet in the vulnerability assessment and government's contingency plan. On the other hand, evacuation issues in a volcanic disaster such as difficulty in expecting evacuation period, aging population, missed communication and risk perception, limited private vehicles in the community, and limited evacuation transport and supporters by the government need to be addressed for better mitigation. This situation led some people to walk to the meeting area, and low walking speeds by vulnerable persons may increase the risk and delay during an emergency. The objective of this study is to find the effectiveness of the evacuation process, especially for the vulnerable community in the Mount Merapi area. Especially, this study purposes to develop a “mutual assistance” model for vulnerable people in the affected regencies with the people’s behavior and vehicle ownership as a viewpoint. The first goal is an assessment of the mutual assistance strategy and social vulnerability index (SoVI) of pedestrian evacuation. I conducted the surveys and then analyzed the data using a multicriteria method to obtain the SoVI values for communities. The second goal is the development of the assembly model to support safer and faster evacuation for vulnerable people. The AnyLogic software was selected for model simulation using input parameters from field surveys. In conducting a survey, I measured the walking speed directly of the evacuation drills in four affected regencies. I also investigated the people’s behavior and eruption characteristics using an interview process with stakeholders and group discussions with local communities. After that, I used the multicriteria method and focused on two factors, social and age structure (young, vulnerable, and mutual assistance between them), and risk perception (work, rain, night, alert, and evacuation map). The index reflects the distribution of actual walking speed, mutual assistance, and the government's plan. The result showed that mutual assistance groups have a higher walking speed than vulnerable people but lower than young people. Mutual assistance coordination is crucial to support the vulnerable in shorter evacuation times. The social and age structure of the social vulnerability index has a stronger risk influence than the perception factor in the evacuation process. The successful evacuation of vulnerable people during emergencies is a significant challenge. In this study, a mutual assistance strategy is proposed to support vulnerable people by evacuating them with young people. This strategy was simulated using AnyLogic software with the agent-based model concept. Pedestrians and vehicles played the roles of significant agents in this experiment. Evacuation departure rate, actual walking speed, group size, route, and coordination were crucial agent parameters. Residents’ attitudes, distribution of each agent, and actual walking speed were obtained from surveys. Then, I developed three scenarios and three models for the evacuation process. Scenarios considered traffic conditions of evacuation routes and models represented behavior approach. The results revealed that this mutual assistance model is effective for the rapid evacuation and risk reduction of vulnerable communities where successful evacuation rates have improved. As for mutual assistance behavior, Model 3, where young people are matched with vulnerable people in advance, has shown better results than Model 2. Additionally, Scenario C, where pedestrians have separate lanes from vehicles during the evacuation process, has resulted in more number of vulnerable people reaching the shelter than Scenario B in Model 3. The highest arrival rate was obtained by the combination of scenario C and Model 3. These findings are a novelty in the volcano context and reflect all categories of vulnerable behavior involving the elderly, disabled, children, and pregnant mothers. The model will benefit disaster management studies and authorities’ policies for sustainable evacuation planning and aging population mitigation.
Creators : Faizul Chasanah Dissertation Number : 創科博甲第116号 Degree Names : 博士(工学) Date Granted : 2023-03-16 Degree Grantors : Yamaguchi University
Population growth drives the demand for energy, which is the most pressing human need today. It puts pressure on other related sectors and increases wastewater production, which is a big problem in some countries that is inaccessible to available wastewater treatment facilities. Concerning the SDGs 2030 target, which mentions integrated sectors to deal with environmental issues, energy and water as a part of the water-energy-food nexus have a high linkage to build substantial economic and ecological benefits. Therefore, they have become the core attention of the world at this moment. To deal with the problem solving mentioned above, nowadays, an alternative energy converter integrated wastewater treatment has been massively developed to achieve green label production of products. Many countries, favoured by their scientists and practitioners, compete to find technology that is a user-friendly, eco-friendly, back-to-nature concept, inexpensive and can be accepted in any society stratifications. However, there is an available standalone converter technology known as conventional technology, which is a disintegrated system with no added value. This challenge opens an opportunity to develop a fully integrated system with any advantages. One of the promising technologies needed for solving the environmental problem and simultaneously producing other benefits for human living is a part of the bioelectrochemistry system (BES), which is microbial fuel cell (MFC). It could be easily assisted with the available conventional wastewater treatment, and it gives more benefits not only in energy production but also for remediating the environment through the superior biocatalyst, named electroactive bacteria (EAB), which has the availability to reduce organic and inorganic matter and generating electricity. However, factors affecting MFC have been a drawback in their field application that must be concerned extensively. Therefore, this study accommodates to investigation more in order to get an optimum condition in operation so that the technology could be widely used properly on the full scale. The disadvantages of the air–cathode single-chamber microbial fuel cell (AC-SCMFC) performance can be caused by numerous factors, and retention time (RT) is one such factor. It is difficult to conclude the ideal RT run for the specific tests under the same conditions. To determine the optimum RT for various types of microbial fuel cell (MFC), an AC-SCMFC batch-mode reactor was carried out by comparing different types and concentrations of substrates based on the main parameters of organic removal and power generation. The AC-SCMFC reactor was designed for the effective working volume of 500 mL and operated for 52 d in batch mode with factors being significantly correlated with the performance of the MFC reactor, which were two different substrates, sucrose and acetate, and three different chemical oxygen demand (COD) levels of 400; 1000, and 2500 mg/L (low, medium, and high, respectively) equipped with two graphene nanoplatelets (GNPs)-based electrodes connected to 100 Ω resistance and plugged onto a ii data logger. The results of this study indicated a significant pattern at the medium level, at which the optimum RT of sucrose was achieved at 24 h and that of acetate at 48 h. In comparison, the performances pattern at low and high levels of both substrates was insignificant to determine the optimum RT. For further application, the recommended RT for both substrates at any concentration is 24 h due to high overall performance, and the optimum RT established in this study could be applied to all types of MFC research, particularly in oxidizable or biodegradable organic ranges, which ensures high performance. One of the important factors in enhancing the performance of microbial fuel cells (MFCs) is reactor design and configuration. Therefore, this study was conducted to evaluate the regressors and their operating parameters affecting the double anode chamber–designed dual-chamber microbial fuel cell (DAC-DCMFC) performance. Its primary design consists of two anode chamber compartments equipped with a separator and cathode chamber. The DAC-DCMFCs were parallelly operated over 8 days (60 days after the acclimation period). They were intermittently pump-fed with the different organic loading rates (OLRs), using chemically enriched sucrose as artificial wastewater. The applied OLRs were adjusted at low, medium, and high ranges from 0.4 kg.m-3.d-1 to 2.5 kg.m-3.d-1. The reactor types were type 1 and type 2 with different cathode materials. The pH, temperature, oxidation-reduction potential (ORP), optical density 600 (OD600), chemical oxygen demand (COD), and total organic carbon (TOC) were measured, using standard analytical instruments. In general, the power production achieved a maximum of 866 ± 44 mW/m2, with a volumetric power density of 5.15 ± 0.26 W/m3 and coulombic efficiency of 84%. Two-stage COD and TOC removal at medium OLR achieved a range of 60–80%. Medium OLR is the recommended level to enhance power production and organic removal in DAC-DCMFC. The separated anode chambers into two parts in a dual anode chamber microbial fuel cell adjusted by various organic loadings expressed a preferable comprehension of the integrated MFCs for wastewater treatment. With respect to both studies, RT influences the design and configuration of MFCs, particularly in this regard, modified anode compartment of DCMFCs adapted to the range of oxidizable or biodegradable organics and reactor components towards control and dependent variables provide the simultaneous performance of DCMFCs in organic removal and power generation. In addition, DAC-DCMFC offers an opportunity to achieve optimal conditions in concurrent MFC-assisted wastewater treatment. Therefore, this study is one step closer to understanding the operating conditions comprehensively, which are the dominant factors affecting performance.
Creators : Ganjar Samudro Dissertation Number : 創科博甲第115号 Degree Names : 博士(学術) Date Granted : 2023-03-16 Degree Grantors : Yamaguchi University
Access to clean water has been crucial global problem, especially with climate change, increasing population, and industrial activities. As one of Malaysia’s leading economic activities, the Oil and Gas Industry generates a massive amount of wastewater called Produced Water (PW). Dissolved organics in produced water, such as organic acids and phenolic compounds, are concerning due to the possibility that they can be toxic, non-biodegradable, and have bioaccumulation properties. Conventional treatments such as adsorption, incineration, and biological treatment seem to have difficulties treating these dilute but toxic components in an economical and environmentally friendly manner. Regulations on wastewater management has also been stricter around the globe. Therefore, there is a need on a new water treatment method to treat the diluted organics in a large volume of wastewater. Membrane technology has been of interest in the water treatment technologies’ industrial and research scenes. It offers simpler configuration and maintenance. However, the application is limited by the reduction of performance over time due to fouling phenomena. Photocatalyst offer an effective method to decompose organics in an environmentally friendly manner. This study researched on photocatalytic removal of diluted organic in water and potential of biofouling reduction by deposition of AgTiO2 coating on membrane surface. In Chapter 1: Introduction, the research background and purpose of this research were discussed. At the end of this chapter, the thesis framework was shown. In Chapter 2: Preparation and characterization of TiO2 and AgTiO2 coatings; the method to prepare AgTiO2 coatings on membrane support were explained. The prepared membranes were characterized with XPS, SEM, TEM, and ICP analysis to understand the prepared coatings. Results shows that the concentration of silver deposited on the membrane can be control by the concentration of silver in the precursor (silver acetate solution) used during the photochemical deposition step. Via XPS, it was found that the state of silver prepared through this method is oxide state. In Chapter 3: Removal of dissolved organic pollutants in water by photooxidation, the photocatalytic performance of prepared membranes was studied. Decomposition of diluted formic acid was performed under UV-light, and the concentration was evaluated using UVspectrophotometer. AgTiO2 membranes show better photocatalytic activity then TiO2 membrane. The concentration of silver on the membrane was found to influence its photocatalytic performance. In relation to PW application which commonly contain high salts, influence of salt types; NaCl, MgSO4, MgCl2 and K2SO4 and concentration were studied. All salts were found to inhibit the membranes’ photocatalytic performance. In Chapter 4: Antibacterial activity of AgTiO2 membranes, the antibacterial activity towards E. coli by prepared AgTiO2 membranes were investigated. Silver dissolution from membrane was found to be significantly increased in the presence of NaCl as compared to only water. Comparing membrane with lower Ag deposition, and around 20 times higher deposition, the silver dissolution from these membranes reached almost the same value after some time. However, as the amount of silver deposited on the membrane was higher, the antibacterial performance show around four times higher than the lower silver membrane. Based on other tests performed, it was concluded that there are potential of contribution from the silver oxide deposited on the membrane surface on the antibacterial activity of the AgTiO2 membranes In Chapter 5: Antibacterial activity in filtration system, prepared AgTiO2 membrane was used to filter E. coli suspension in water. E. coli growth was found to be inhibited by short contact with silver on the coated membrane. Finally, Chapter 6: Conclusion, the thesis was summarized, and future works were proposed.
Creators : Azzah Nazihah binti che abdul rahim Dissertation Number : 創科博甲第114号 Degree Names : 博士(工学) Date Granted : 2023-03-16 Degree Grantors : Yamaguchi University
Creators : 田上 聖人 Dissertation Number : 創科博甲第113号 Degree Names : 博士(工学) Date Granted : 2023-03-16 Degree Grantors : Yamaguchi University
Creators : 志村 直紀 Dissertation Number : 創科博甲第112号 Degree Names : 博士(工学) Date Granted : 2023-03-16 Degree Grantors : Yamaguchi University
In recent years, many reports have been made of damage to reservoir embankments due to frequent heavy rains and earthquakes. “Internal erosion” is the phenomenon in which soil particles move through the pore spaces of embankments and flow out of them because of long-term seepage in the soil structures of reservoirs and river embankments. Internal erosion is classified according to the scale and form of the erosion. “Suffusion” is the phenomenon in which only the fine-grained soil particles move through the pore spaces formed by the coarse-grained soil particles. Suffusion is known to cause an increase in hydraulic conductivity and a decrease in soil bearing capacity. However, the mechanisms and causes of the occurrence and progression of this phenomenon, as well as its effect on soil structures, have not been fully elucidated. Therefore, the purpose of this study was to clarify the effect of suffusion on the strength properties of reservoir embankments as well as the mechanism of the progression of suffusion, focusing on the particle size of the eroded soil particles. In Chapter 1, the background of the study and the classification of internal erosion were provided. In Chapter 2, the mechanism of suffusion and its effect on geomaterials, which have been clarified in previous studies, were described. In Chapter 3, the effect of suffusion on the strength properties was firstly investigated by means of soil samples used for the reservoir embankments which were determined to be at risk of suffusion based on an internal stability evaluation. A triaxial compression testing system was established to simulate the suffusion inside each specimen. In the testing system’s apparatus, only the fine particles were able to be discharged from the specimen through a sieve by supplying water. The results showed that changes in the peak and residual strength occurred independent of changes in the void ratio due to suffusion, and that the strength properties differed depending on the presence or absence of suffusion, even when the void ratio was the same as that before shearing. However, since the amount of erosion was small (less than 0.7% of the total), it is considered that the change in strength was influenced by the fine soil particles that moved through the specimen but remained in the specimen without finally flowing out of it. In Chapter 4, in order to define the mechanism of small-scale internal erosion, a method was devised to examine the temporal changes in the size of the discharged soil particles, focusing on the relationship between the concentration and the turbidity of the drainage. The above method was also applied to the drainage obtained by seepage with suffusion in Chapter 3. As a result, the erosion rates were found to correlate with the particle size of the discharged particles. In Chapter 5, a one-dimensional water-passing experiment with suffusion was conducted to investigate in detail the relationship among the flow rate, soil particle discharge, and turbidity of the drainage. The particle size composition of the discharged soil, which varied with the progress of suffusion, was examined using the method described in Chapter 4. The results showed that, under all conditions, the soil particles with smaller diameters were selected from among those that were able to pass through the wire mesh at the outlet boundary and then discharged. It was also found that the particle size composition of the discharged soil changed with time as the suffusion progressed, and that this trend varied greatly depending on the saturation degree of each specimen before the start of permeation. After the completion of the experiment, the particle size composition of the soil samples showed that not only the distribution of the erodible component in the height direction, but also the particle size composition of the erodible component itself became heterogeneous, suggesting that soil particles with smaller particle sizes moved longer distances through the pores. Furthermore, the effect of overburden pressure on the behavior of suffusion under constant hydraulic gradient conditions was explored, and it was revealed that higher overburden pressure resulted in less frequent suffusion when the hydraulic gradient was large. The particle size composition of the discharged soil was examined, and no difference was found among the various levels of overburden pressure. In addition, the progression of suffusion was investigated under a fluctuating hydraulic gradient. The suffusion continued even after 30 cycles of hydraulic gradient variation. The particle size composition of the discharged soil particles showed that the small soil particles, that flow easily, had already been discharged when the specimen was first subjected to permeation force, and that the soil particles discharged by the change in hydraulic gradient were relatively large in diameter. The particle size of the soil particles discharged by suffusion were seen to depend on the conditions surrounding the occurrence of suffusion and the time of the progression. In studies on suffusion, the particle size composition of the soil discharged by suffusion is a significant factor that changes over time and can be used to evaluate the degree of the progression of suffusion.
Creators : 石丸 太一 Dissertation Number : 創科博甲第111号 Degree Names : 博士(工学) Date Granted : 2023-03-16 Degree Grantors : Yamaguchi University
Creators : 萩原 綾 Dissertation Number : 創科博甲第110号 Degree Names : 博士(工学) Date Granted : 2023-03-16 Degree Grantors : Yamaguchi University
Creators : 依田 真由子 Dissertation Number : 創科博甲第109号 Degree Names : 博士(工学) Date Granted : 2023-03-16 Degree Grantors : Yamaguchi University
Creators : Hua Zhudi Dissertation Number : 創科博甲第108号 Degree Names : 博士(工学) Date Granted : 2023-03-16 Degree Grantors : Yamaguchi University
Sleep is an essential physiological process for the human body. People spend about one-third of their lives sleeping. Both sleep duration and sleep quality are important to human health. Sleep quality describes how restful and restorative the sleep process is. Over 80 sleep disorders are known to affect sleep quality. Among them, sleep-related breathing disorder (SRBD) is the second factor. Sleep-related breathing disorders are sleep disorders in which breathing abnormalities occur during sleep. Abnormal snoring and respiratory arrest or abnormally low breathing during sleep reduce oxygen levels in the blood, increasing the risk of depression, cardiovascular disease, stroke and even death. Therefore, monitoring and analysis of respiration during sleep is gaining increasing importance in healthcare. Polysomnography (PSG) is considered the gold standard for diagnosing sleep disorders, but PSG is usually performed in an unfamiliar sleep laboratory under the supervision of a medical technician and is often worn with many sensors that interfere with sleep. It is often the case. This research group is developing a breathing sound measurement system that constantly monitors the quality of sleep in general home environment. This system can easily measure breath sounds during sleep all night with high accuracy without disturbing sleep. The purpose of this research is to develop a technique to classify patterns of breathing sounds and to analyze the quality of breathing in order to more accurately analyze the state of sleep from breath sound information. There are various patterns of sleep breath sounds, such as normal breath sounds and snoring, and abnormal breath sounds and snoring. To develop a method to classify these patterns, to develop an algorithm to calculate ventilation from breath sounds, to estimate the sleep apnea index (AHI), and to assess the quality of breathing during sleep. try. Specifically, the temporal feature waveform (TCW) is calculated after partly removing the noise of the breathing sounds of sleep with a band-pass filter. Based on the time feature waveform, a respiratory signal effective for analysis is extracted from low-level signals and phase-divided into a respiratory phase and an apnea or low signal. Mel-frequency cepstrum coefficients (MFCC) are then obtained for the respiratory phases, and an agglomerative hierarchical clustering (AHC) algorithm is applied to distinguish between normal/abnormal breathing, normal/abnormal snoring, and normal/abnormal breathing. , tossing and turning, etc., which are less relevant to breathing. The categorized breathing patterns are analyzed every 30 seconds and the relative tidal volume of the breath is calculated. In addition to verifying the effectiveness and accuracy of the technology and analysis method proposed in this study, a method of estimating the apnea syndrome index (AHI) and converting the ventilation volume into high, medium, and low levels, We propose a method to evaluate the quality of breathing in a patient and verify its effectiveness. This paper consists of six chapters, including an introduction and conclusion. Chapter 1 introduces the background and overview of this research. Chapter 2 describes a signal-processing technique for analyzing breath sounds during sleep and a method for classifying breathing patterns. Breathing sound data during sleep often includes disturbed breathing due to bruxism or body movement, ambient environmental noise, etc. In this chapter, the Time Characteristic Waveform (TCW) and the Characteristic Moment Waveform (CMW) are calculated for respiratory sound signals that have undergone preprocessing, such as filtering noise to preprocess the respiratory sounds, and the segmentation of inspiration and expiration is performed. The Mel-Frequency Cepstrum Coefficients (MFCC) are obtained for each respiratory cycle and applied as a feature vector to the Agglomerative Hierarchical Clustering (AHC) algorithm. This method is used to classify ordinary respiratory signals (normal and abnormal breathing, normal and abnormal snoring) from signals less relevant to respiration, such as tossing and turning and environmental noise. In Chapter 3, using the technology described in Chapter 2, breathing sound data during sleep are classified into apnea, hypopnea, normal breathing, abnormal breathing, normal snoring, and abnormal breathing for each 30-second frame. In addition, we describe a method for classifying events such as no snoring and rolling over and determining the respiratory state. In Chapter 4, we propose a method for estimating the apnea-hypopnea Apnea-Hypopnea Index (AHI) for classified abnormal breath sounds and low-level breath sound signals, compare it with the diagnostic results of PSG, and examine its validity. And verify usefulness. Chapter 5 describes a method for estimating ventilation volume from breath sounds. Because normal breath sounds are correlated with ventilation, this study used a quantitative approach to calculate normal breathing and normal snoring and a qualitative method to calculate apnea/hypopnea and abnormal breath sounds. We will propose and compare it with the diagnosis result of PSG and verify its validity. In Chapter 6, as an application development, an example of applying the breathing sound classification method proposed in this study to heart sound analysis is presented. Finally, we will explain the construction of a data collection distribution system for sharing auscultation data collected at different facilities and hospitals using blockchain technology. Chapter 7 presents the conclusions and prospects of this study.
Creators : Wang Lurui Dissertation Number : 創科博甲第107号 Degree Names : 博士(工学) Date Granted : 2023-03-16 Degree Grantors : Yamaguchi University
Innovation is the practical implementation of ideas that result in the introduction of new goods or services or the improvement in them (Schumpter, 1983). Innovation is closely related to invention as innovation is more on involving the practical implementation of a new or improved invention to make a meaningful impact in a market or society (Schumpter, 1939). On the other hand, innovative design is a process of identifying, pinpointing, and understanding the needs of the user or audience (Shaulis, 2021). Previously, Dixon (1966) defined innovative design as any design that is: new or different, or elegant or uses new ideas, or is an improvement over its peers. Once the market need has been identified, a solution can then be designed. In our proposed innovative design method, we introduced and investigated a method that is able to be applied in designing an intergrated system that could be a valuable solution to the society. This method starts with directly observe activities of things and real people in real trouble in the real field. Then, we think about the value of "I wish there were such things as…", visualize the story, draw a clear sketch to accomplish the story concretely. Next, we solidify the functions and specifications while investigating needs and competition. Then, we create a prototype that able to show and test your ideas, demonstrate to the people who need it, let them experience it, and gain feedback. Lastly, we evaluate the value of product design and development and plan methods for implementing it as an organization, and plan ways to improve and expand globally. All of the steps in this method are important for innovative design, however, in this research this time we focused on co-designing value, big idea, and considering as integrated steps for identifying latent needs of the consumers. It is because identifying needs is an important part in the product development process. Latent needs are those that many consumers recognize as important in a final product but unable to articulate in advance (Ulrich, 2015). The latent needs addressed in this study was focusing on identifying consumer requirements in product development in the innovative design method. The challenge in identifying latent needs is finding the method to elicit from consumers the needs which are not addressed by any inventors yet in the present market but would delight the consumers if delivered tomorrow. The purpose of this study is to propose and verify the method in the elicitation of latent needs from consumer needs by introducing a working prototype to the consumers, interviewing, and analyzing responses from the consumers. This research was conducted during the year the start of the COVID-19 pandemic. As the pandemic spread, most countries were forced to go into lockdown or declare an emergency state. The school was closed and business organizations needed to switch to working from home to prevent the spread. The parents were unable to work from home efficiently as they were worried their children will involve in dangerous incidents if the children were left by themselves. Based on this situation, this study was conducted in finding the latent needs of the parents, childcare workers, and children in order to assist them in going through their problems during this COVID-19 pandemic. The working prototype was used as material to prepare presentation slides for the consumers' interviews. The first presentation slides were focused on the background problems and ideas for the solutions while the second presentation slides provided consumers with a prototype and story of the product that was believed would be one of the solutions to the problems. Interviews were conducted after both slide presentations. Consumers' responses were obtained and interpreted into consumers' needs in terms of product functions. In the first study, consumers' interpreted needs from Problem-based interviews and Prototype and Story-based interviews were compared. Based on the results, latent needs interpreted from interviewees' responses and the categories of the needs obtained from the Prototype-based interviews are more than from the Problem-based interview. The latent needs that we were able to obtain from this research were for example, “The device is able to detect small changes in a child while watching he/she sleeping” which could lead into the prevention of unwanted incident such as sudden infant death syndrome (SIDS). This supports our assumption that showing working prototype-based materials with story descriptions can be effective in uncovering potential latent needs. In the second study, it is assumed that experience, empathy, and knowledge of working prototype is essential elements in product development, therefore, new additional guidelines which are “to write a statement with empathy”, “to write a statement as a designer”, and “to write a statement as someone with experience” were proposed during consumers' needs interpretation to see whether these new guidelines will influence the process of identifying latent needs of consumers. From the result, it is concluded that the number of interpreted needs increased when we applied the new proposed guideline. Although the number is small, the needs might not be interpreted if the new guidelines were not considered. We were also able to obtain a few important latent needs when we applied these new guidelines. A latent need collected from applying the guideline "to write a statement as someone with experience" is “The device is not for teaching love and humanity but for monitoring by watching facial expression, posture, and vital signals such as temperature and heart rate”. We could conclude that including these guidelines upon interpreting raw data from the consumers’ interviews might lead into discovering important and critical latent needs of the consumers. In the third study, a quantitative evaluation method for identifying latent needs was introduced. The consumers' interpreted needs were rated according to a basis of rating from the three perspectives of importance, latent-ness, and technological feasibility. The Degree of Latent Needs (DLN) was calculated by multiplying these three metrics. Based on the result for the average and variance of DLN mean value for each evaluator which is sufficiently small, it indicates that the basis of rating for three metrics of the DLN is effective. The results also indicate that the 20 highest DLN points of the interpreted needs contain attractive features in terms of design. However, we had gotten some pushback on the average of each interpreted need and its variance which indicates opposing opinions among evaluators. As it is possible that attractive needs are hidden and may lead to the discovery of latent needs through individual pinpoint interviews, the interviews with the minority evaluators were conducted. The interview results indicate that the latent needs with low DLN rates but valuable might be able to be discovered by conducting follow-up interviews such as “The device is able to recognize items (food or not) that a child wants to put in the mouth”. From the results in all three studies, we could conclude that a number of important latent needs are able to be elicited from consumers’ needs by applying the proposed method. In our fourth study, a decision-making method based on the patent analysis between the conceptual design stage and the prototyping stage in the innovative design method was introduced. Conducting a patent strategy was assumed to support how to select the right concept precisely. In this study, by conducting a patent search in this stage by the designer who understood best the product functions and working principles, a supporting method was introduced to assist the designer in their decision-making process. Based on the result, the method was able to observe whether there are dominating companies or not for our concept design. If there is a dominating company, the possibility of not being able to produce our concept becomes bigger. This method may be applied as an indicator to support decisionmaking in the concept design stage in the innovative design method, whether to proceed with the concept design or not and to reduce the possibility of product failure in the future. From the results of all the studies, we could conclude that these above methods may be applied as assistive tools to support designers’ understanding of consumers’ requirements and selecting the right concept design.
Creators : Nurhayati Binti Md Issa Dissertation Number : 創科博甲第106号 Degree Names : 博士(工学) Date Granted : 2023-03-16 Degree Grantors : Yamaguchi University
Creators : 星長 翔太 Dissertation Number : 創科博甲第105号 Degree Names : 博士(理学) Date Granted : 2023-03-16 Degree Grantors : Yamaguchi University
Creators : Wu Zhenyuan Dissertation Number : 創科博甲第104号 Degree Names : 博士(理学) Date Granted : 2023-03-03 Degree Grantors : Yamaguchi University
Creators : Sarikavak Yasin Dissertation Number : 創科博乙第8号 Degree Names : 博士(学術) Date Granted : 2023-03-03 Degree Grantors : Yamaguchi University
Creators : 𡧃津⽊ 真⼀ Dissertation Number : 獣博甲第455号 Degree Names : 博士(獣医学) Date Granted : 2023-03-16 Degree Grantors : Yamaguchi University
Aldosterone is a steroid hormone synthesized in the adrenal cortex and is part of the renin-angiotensin-aldosterone system (RAAS). It accelerates renal sodium retention and elimination of potassium through its action on the mineralocorticoid receptor (MR), and has a major role in regulating body fluid volume and blood pressure. Excessive secretion of aldosterone and activation of the MR cause cardiovascular inflammation, fibrosis and remodeling, and tubulointerstitial fibrosis and glomerular injury in the kidney. There are several reports on plasma aldosterone concentration (PAC) in healthy, chronic kidney disease (CKD), systemic hypertension, and chronic heart failure in cats and dogs. Measurement of urinary aldosterone/creatinine ratio has also been reported in cats and dogs. However, it has been suggested that measuring aldosterone in feline urine using the available methodology has limited or no utility in investigating feline hypertension associated with CKD. It may be important to evaluate PAC in cats and dogs with CKD associated with the activation of RAAS. On the other hand, angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers suppress the RAAS during hypertensive, renal, and cardiac diseases in cats. The Randomized Aldactone Evaluation Study in humans showed that the aldosterone antagonist, spironolactone, reduced the mortality of patients with chronic heart failure who received ACEI and loop diuretics. Spironolactone also reportedly reduced the mortality rate in cats with congestive heart failure secondary to cardiomyopathy. Another selective aldosterone antagonist, eplerenone, not only antagonizes MR but also blocks the nongenomic effects of aldosterone in vascular tissues not susceptible to spironolactone. These effects of eplerenone may be more effective than spironolactone in treating hypertension due to vasoconstriction. Although eplerenone reduces mortality and hospitalization in human patients with chronic heart failure, there are no available reports on eplerenone’s use in feline practice. Since elevated PAC is a risk factor for kidney injury in humans, and MR antagonists are beneficial in rodent models of CKD and human patients, it was hypothesized that if an elevated PAC is detectable in the early stages of the disease in cats, the use of eplerenone may prolong lifespan. However, the relationship between PAC and the survival time in cats and dogs with CKD has not been investigated. Therefore, this study aimed to investigate PAC in cats and dogs with CKD, and evaluate the influence of high PAC on the survival time of CKD animals and the effect of treatment with eplerenone in CKD cats with high PAC. In chapter 1, PAC in cats with CKD was investigated retrospectively, and the survival time of cats with high PAC was evaluated. Furthermore, the effect of treatment with eplerenone on survival time in CKD cats with high PAC was examined prospectively. The eplerenone study was conducted including both cats with CKD only and CKD cats complicated cardiac disease or systemic hypertension. The PAC was measured retrospectively in blood samples obtained from 156 client-owned cats that visited a veterinary hospital. The cats were designated into 2 groups: clinically healthy (n = 101) and CKD (n = 55). The PAC was measured by solid-phase radioimmunoassay. Median (minimum–maximum) PAC in healthy cats was 97 (10–416) pg/mL and the upper limit (95th percentile) was 243 pg/mL. In the CKD group, PAC [126 (10–981) pg/mL] was significantly higher than in the clinically healthy group. In the CKD group as classified by the International Renal Interest Society (IRIS) stage, the PACs were higher in IRIS stage 2 than in the healthy group. Similarly, PACs in IRIS stage 3 and 4 cats were higher than in the healthy group. In cats with CKD, the survival time of those with high PAC (n = 16) (> 243 pg/mL) was significantly shorter than that of those (n = 39) with normal PAC. In cats with high PAC and CKD, eplerenone administration (2.5 to 5 mg/kg body weight; n = 8) prolonged significantly the survival compared to cats not receiving eplerenone (n = 18). These results indicated that PAC could be a prognostic marker of CKD in cats and that eplerenone may prolong the survival in cats with CKD and high PAC complicated with cardiac disease or hypertension. In chapter 2, PAC in dogs with CKD was investigated retrospectively, and the survival time of CKD dogs with high PAC was evaluated. PAC was measured in blood samples obtained from 145 client-owned dogs. The dogs were divided into two groups: clinically healthy (n = 106) and CKD (n = 39). In clinically healthy group, median (minimum–maximum) PAC was 56 (10–250) pg/mL, and the upper limit (95th percentile) was 182 pg/mL. PAC (median 69 pg/mL; range 10–553 pg/mL) in CKD group was significantly higher than in the healthy group. In the CKD group as classified by IRIS stage, PAC (median 97 pg/mL) in IRIS stage 2 and 3 was significantly higher than in the healthy group. A significant positive correlation between PAC and IRIS stage was observed in CKD dogs, suggesting that the lower survival rate in high PAC group may be related to severity of CKD. In dogs with CKD, the survival time of those with high PAC (n = 10) (> 182 pg/mL) was significantly shorter than that of those with normal PAC (n = 24). These results suggested that high PAC might indicate shorter survival time in dogs with CKD. In conclusion, this study revealed that both cats and dogs with CKD had significantly higher PAC than clinically healthy animals. In CKD, the survival time of cats and dogs with high PAC was significantly shorter than those with normal PAC. The use of eplerenone also significantly prolonged the survival of cats with high PAC in CKD complicated with cardiac disease or hypertension. This study proposes PAC as a prognostic marker of cats or dogs with CKD. Eplerenone may be useful in prolonging cats’ survival with high PAC in CKD complicated with cardiac disease or hypertension. However, further study on PAC level in CKD progression and treatment response in a larger population may be required. This study provided new information on the relationship between PAC and the survival of cats or dogs with CKD, and the effect of eplerenone treatment for the survival time of cats with high PAC and CKD.
Creators : 甲斐 みちの Dissertation Number : 獣博甲第454号 Degree Names : 博士(獣医学) Date Granted : 2023-03-16 Degree Grantors : Yamaguchi University
Creators : 日高 千春 Dissertation Number : 獣博甲第453号 Degree Names : 博士(獣医学) Date Granted : 2023-03-16 Degree Grantors : Yamaguchi University
Creators : 井中 賢吾 Dissertation Number : 共獣博甲第11号 Degree Names : 博士(獣医学) Date Granted : 2023-03-16 Degree Grantors : Yamaguchi University
Creators : Leni Maylina Dissertation Number : 共獣博甲第10号 Degree Names : 博士(獣医学) Date Granted : 2023-03-16 Degree Grantors : Yamaguchi University
Creators : 松本 苑子 Dissertation Number : 共獣博甲第9号 Degree Names : 博士(獣医学) Date Granted : 2023-03-16 Degree Grantors : Yamaguchi University
The objective of Chapter 1 of the present study was to evaluate the effect of heat-killed Lactobacillus sakei HS-1 (HK-LS HS-1) on the health and fecal bacteriological change of suckling Japanese Black calves as a supplement in milk replacers. To this end, they were randomly assigned to an HK-LS HS-1 supplement or a control without HK-LS HS-1 group in milk replacers. HK-LS HS-1 was administered from separation day to 3 weeks. Blood and fecal samples were examined. The result is glucose and vitamin A levels on day 7 were significantly higher in the supplement group than in the control group. No significant differences were observed in haptoglobin or serum amyloid A between the groups. The number of Escherichia coli in feces was lower in the control group than in the supplement group on day 21. No difference was observed in the number of Bifidobacteria, but that of lactic acid bacteria was significantly higher in the supplement group on day 21. The number of medications administered was significantly lower in the supplement group than in the control group during the experimental period. The results indicated that HK-LS HS-1 is potentially beneficial for improving intestinal microbes and reducing the number of medical treatments. In the second study, we evaluated the effects of supplementing cattle feed with difructose anhydride III (DFA III) by measuring urinary sterigmatocystin (STC) concentrations using 20 Japanese Black cattle aged 9–10 months from one herd. DFA III was supplemented for 2 weeks for 10 animals, and non-treated animals served as controls. STC concentration in the dietary feed was 0.06 mg kg−1(mixture of roughage and concentrate) at the beginning of the study (Day 0). The urine STC concentration was measured using liquid chromatography with tandem mass spectrometry 1 d prior to DFA 2 III administration, 9 and 14 d thereafter, and 9 d following supplementation cessation, concomitant with the measurement of serum amyloid A (SAA). The number of heifers in which STC was detected in the urine was low in the DFA III group compared to that in the control group on Day 9. After 9 d following supplementation cessation (Day 23), STC concentrations were significantly lower (P = 0.032) in the DFA III group than in the control group, although there was no difference in the number of heifers in which urinary STC was detected or in SAA concentrations between the two groups. Our findings demonstrate the effect of DFA III on reducing the urinary concentration of STC in Japanese Black cattle.
Creators : 笹崎 直哉 Dissertation Number : 共獣博甲第8号 Degree Names : 博士(獣医学) Date Granted : 2023-03-16 Degree Grantors : Yamaguchi University
Creators : Imron Rosyadi Dissertation Number : 共獣博甲第7号 Degree Names : 博士(獣医学) Date Granted : 2023-03-16 Degree Grantors : Yamaguchi University
Creators : 大智 宏祐 Dissertation Number : 共獣博乙第2号 Degree Names : 博士(獣医学) Date Granted : 2023-03-16 Degree Grantors : Yamaguchi University
Creators : 宮本 いずみ Dissertation Number : 医博甲第1676号 Degree Names : 博士(保健学) Date Granted : 2023-03-16 Degree Grantors : Yamaguchi University
間葉系幹細胞(MSC)は、再生医療において有用な細胞である。MSCの培養工程の初期に、組織から抽出した単核球を培養容器に播種し、MSCの単離を行う。単離工程において、単核球の播種密度を最適化することで、単離後のMSCの収量や分化能が向上することが報告されている。しかし、単核球の播種密度がMSCの品質に影響する機構は明らかになっていない。 我々はその機構を明らかにする為、ヒト骨髄単核球を様々な播種密度(4.0×104、1.25×105、2.5×105、6.3×105、1.25×106cells/cm2)で培養し、単核球の播種密度とMSCのコロニー形成過程との関係を解析した。播種密度が高い条件(6.3×105、1.25×106cells/cm2)では、培養容器に接着したMSC同士の距離が小さく、互いの増殖スペースが制限される為、早期に高密度に達した。一方、低い播種密度(4.0×104、1.25×105 cells/cm2)では、MSCは単一細胞由来のコロニーを形成し、コロニーの直径や密度は様々な形態を示した。コロニーを継時観察したところ、高い増殖能力を持つMSCは、培養時間の経過に伴い、全体におけるその割合が増加した。それに対して、増殖能力が低いMSCは肥大化し、老化が進行した。老化細胞は剥離処理の時間を調整することで除去できることを見出した。単核球の播種密度が低い条件で、上記機構により、増殖能が高いMSCの純度が向上することが明らかになった。この機構をもとに単離工程のパラメータを最適化し、得られたMSCの増殖能と分化能を評価した。単核球の播種密度が高い条件(1.25×106cells/cm2)と比較し、最適化した条件(播種密度:1.25×105cells/cm2)から得られたMSCは、高い増殖能を示し、骨以外の脂肪や軟骨への分化能が有意に上昇した。 本研究により、高品質なMSCの純度を向上させる方法として、(1)単一細胞由来のコロニーを形成させる為に単核球の播種密度を最適化すること、(2)高い増殖能を持つMSCの割合を増やす為に培養期間を調整すること、(3)老化細胞を除去できる剥離処理の時間を設定することを提案する。
Creators : 永井 寛之 Dissertation Number : 医博甲第1675号 Degree Names : 博士(保健学) Date Granted : 2023-03-16 Degree Grantors : Yamaguchi University
方法: 本研究は圧縮センシングを用いた自由呼吸下での多相ダイナミックEOB-MRIを撮像された96人の患者を対象とした。多相ダイナミック撮像として自由呼吸下で11秒毎に1相を5分間、脂肪抑制T1強調画像を撮像し、単純1相と造影28相を撮像した。造影剤投与後20分後に肝細胞相を撮像し、30相目とした。ROI: region of intensityを肝右葉に2つ、左葉に1つを脈管を避けながら可能な限り大きく設定した。3つのROIの信号強度の平均値をそれぞれの時相の信号強度とした。 以下の増強効果のパラメータについて評価した。 CER (contrast enhancement ratio) CERy-x: (SIy -SIx)/SIx (x相目からy相目)とし、 CER4-pre:動脈相 CER7-5:門脈相から動脈相にかけて CER7-pre:門脈相 CER28-pre:5分早期肝細胞相 CER28-7:門脈相から5分早期肝細胞相 CERHBP-pre:20分肝細胞相 GRL (gradient of regression line):回帰曲線の傾き GRLy-x: x相目からy相目とし、 GRL4-2:動脈相での傾き GRL7-4 :門脈相での傾き GRL 7-2 :動脈相、門脈相にかけての傾き GRL 28-7:門脈相から早期肝細胞相での傾き 先行研究によると、肝実質の線維化の重症度(F0-F2 vs F3-F4)に基づいてCERHBP-preでcut off値を0.703として肝細胞相での増強効果がinsufficient HBP enhancement groupとsufficient HBP enhancement groupに分けれるとしている。CERHBP-pre<0.703またはCERHBP-pre>0.703により患者を2群に分け、CERy-x、GRLy-xについて検討した。 上記に加えて年齢、性別、総ビリルビン、プロトロンビン時間、アルブミン、eGFRについても、この2群間で比較した(ウィルコクソンの順位和検定)。 肝細胞相の増強効果に対する影響の大きさを調べるためにノンパラメトリック検定も用いられた(スピアマンの順位相関係数)。 結果: 動脈相(CER4-pre、GRL4-2)に関する結果として、これらはsufficient HBP enhancement groupがinsufficient HBP enhancement groupの間に有意差を認めなかった。 動脈門脈相(1相目~7相目)に関する結果としては、CER7-preはsufficient HBP enhancement groupがinsufficient HBP enhancement groupより有意に高い値となった(0.55 vs 0.44, p<0.001)。CER4-pre、GRL4-2、Gradient7-4、Gradient7-2では2群間に有意差は見られなかった。 5分後の早期肝細胞相(1相目~28相目)に関する結果としては、CER28-pre、CER28-7、GRL28-7においてsufficient HBP enhancement groupがinsufficient HBP enhancement groupより有意に高い値となった(0.64 vs 0.47, 0.10 vs 0.03, 1.27 vs 0.27、すべてp<0.001)。 血液データ(総ビリルビン、プロトロビン時間、アルブミン、eGFR)においても2群間で有意差が認められた(p=0.004-0.049)。CER7-pre、CER28-pre、CER28-7、GRL28-7の各パラメータは血液データのパラメータよりも相関係数が高かった。 CER28-preが最も相関係数が高かった(0.838)。 考察: 動脈相では2群間(sufficient HBP enhancement groupとinsufficient HBP enhancement group)に有意差を認めず、門脈相のパラメータでは有意差が見られた。機序としては推測になってしまうが、肝の線維化の進行に伴い門脈血流は低下しやすいが、動脈血流は比較的保たれることが原因であろうか。 また、肝細胞相の信号強度は、血液データなどによって得られた肝機能を示す数値と相関することはこれまでにも報告されてきた。肝機能が良好であるほど、肝細胞がEOBを取り込みやすいためとされる。 本研究では腎機能と肝細胞相の信号強度とにも相関が見られたが、腎機能が低い症例の方がより肝排泄の割合が増えるからと思われた。 本研究のように、ダイナミック撮像中に得られるパラメータが肝細胞相における肝実質の信号強度と相関することを報告した研究はこれまでになかった。 CER7-pre、CER28-pre、CER28-7、GRL28-7の各パラメータは、いずれも血液データのパラメータよりも相関係数が高かった。 本研究のようにダイナミック撮像中に得られたパラメータを用いれば、血液データよりも高い精度で肝実質の信号強度を予測することができる。 これにより、肝細胞相の撮像タイミングを症例により短縮できることが期待される。 結語: 圧縮センシングを用いた自由呼吸下でのEOB-MRIのダイナミック撮像おいて、肝実質の信号強度の変化を連続データとして捉えることにより得られたパラメータは、肝細胞相での肝実質の信号強度と強い相関を示す。これにより、肝細胞相の撮像タイミングを症例により短縮できることが期待される。
Creators : 田邊 雅也 Dissertation Number : 医博甲第1674号 Degree Names : 博士(医学) Date Granted : 2023-03-16 Degree Grantors : Yamaguchi University
背景:糖尿病患者における聴覚障害の有病率は有意に高く、その予防法の開発が望まれている。 目的:本研究では、糖尿病マウスに対するエイコサペンタエン酸(EPA)投与による早期難聴の予防効果を検討した。 方法:糖尿病モデルとしてTSOD(Tsumura, Suzuki, Obese Diabetes)マウスを、コントロールとしてTSNO(Tsumura, Suzuki, Non Obesity)マウスを使用した。TSNO群とTSOD(EPA-)群(ひまわり油投与)、TSOD(EPA+)群(EPA投与)の3 群に分けた。聴性脳幹反応(ABR)を測定し、蝸牛を組織学的に評価した。 結果:TSOD(EPA+)群はTSOD(EPA-)群に比べ、閾値の上昇が小さい傾向を認めた。TSOD(EPA+)群では、生後11 ヶ月から14 ヶ月にかけて、4kHzでのABR 閾値がTSOD(EPA-)群よりも有意に低かった。TSOD(EPA-)群では、血管条の毛細血管内腔の狭小化と蝸牛軸における血管壁の肥厚が観察された。 結論:TSOD マウスに対するEPA 投与による蝸牛血管の動脈硬化の抑制は、加齢に伴う早期難聴を抑制することが示唆された。
Creators : 松浦 貴文 Dissertation Number : 医博甲第1673号 Degree Names : 博士(医学) Date Granted : 2023-03-16 Degree Grantors : Yamaguchi University
角膜の剛性を表す生体力学的指標の一つとして角膜ヒステリシス(CH)があり,CHは眼圧(IOP)や中心角膜厚(CCT)などの影響を受け,眼球全体の剛性も反映することから,CH低下が緑内障の進行リスクとして注目される。一方で,硝子体は眼球を外力から保護する緩衝材としての作用があり,眼球の剛性に影響するが,硝子体とCHとの関連は明らかになっていない。本研究では硝子体切除がCHに与える影響を評価することを目的に,白内障単独手術と白内障手術併施硝子体切除術の術後早期のCHを比較した。白内障手術(PEA+IOL)を施行した18例20眼(PEA+IOL群),黄斑上膜あるいは黄斑円孔に対してPEA+IOL併施の経毛様体扁平部硝子体切除術(PPV)を施行した27例28眼(PPV triple群)を対象とした。術前,術後2週,術後3か月のCH,IOP,CCTおよびCHとCCTの相関関係について後ろ向きに検討した。CHは術前,術後2週,術後3か月で,PEA+IOL群において11.1±1.1mmHg,10.4±1.1 mmHg,11.0±1.0 mmHgであり,PPV triple群において11.0±1.4mmHg,9.8±1.4 mmHg,10.6±1.6 mmHgであった。CHはPEA+IOL群で術前後に有意差は認めなかったが,PPV triple群の術後2週で有意に低下していた。IOPおよびCCTは両群とも術前後に有意な変化は認めなかった。PEA+IOL群の全時点とPPV triple群の術前にはCHとCCTの正の相関関係を認めたが,PPV triple群の術後には相関関係を認めなかった。以上より,PPV triple手術ではIOPやCCT以外による要因で術後にCHが低下することが示され,硝子体切除が眼球の剛性変化をもたらしCH低下に寄与した可能性が考えられた。CHの低下は,外力や眼圧の影響を受けやすい眼球構造であると言えることから,PPV 術後のCH評価は眼圧管理の指標や緑内障の発症,進行リスクを反映する可能性がある。
Creators : 太田 真実 Dissertation Number : 医博甲第1672号 Degree Names : 博士(医学) Date Granted : 2023-03-16 Degree Grantors : Yamaguchi University
本研究では、特定の遺伝子型と表現型との関連を明らかにするために、EDAR遺伝子の潜性(劣性)変異に着目し、その特徴を詳細に検討した。具体的には、過去にEDARのDD内に同定された潜性(劣性)遺伝形式を示す4 種類のミスセンス変異(p.R358Q、p.G382S、p.I388T、p.T403M)について、培養細胞での過剰発現系で一連の解析を実施した。これらの変異の中で、p.R358QはEDARADDとの結合能を失い、下流のNF-κB活性を低下させることが知られており、機能喪失の陽性対照として用いた。 まず、細胞溶解液を用いたwestern blot法では、p.R358Qおよびp.T403M変異型EDAR蛋白は野生型EDAR蛋白よりも発現量が減衰し、より大きい分子量を示した。一方で、p.G382Sおよびp.I388T変異型EDAR蛋白は野生型EDAR蛋白と同様の発現パターンを示した。また、各EDAR蛋白の細胞内での局在を解析するために実施した蛍光免疫染色法では、野生型EDAR蛋白と同様にp.G382Sおよびp.I388T変異型EDAR蛋白は細胞質内に局在が認められたが、p.R358Qとp.T403M変異型EDAR蛋白は細胞膜に発現していた。これらの結果から、変異型蛋白間で発現パターンが異なることが示された。続いて行ったNF-κBレポーターアッセイでは、すべての変異型EDAR蛋白がNF-κBの活性化を抑制したが、p.R358Qとp.T403M変異型EDAR蛋白に比べ、p.G382Sとp.I388T変異型EDAR蛋白による抑制効果は軽微であった。EDARとEDARADDの結合を検討した共免疫沈降法では、p.R358Qとp.T403M変異型EDAR蛋白はEDARADDとの結合能を完全に喪失していたが、p.G382Sとp.I388T変異型EDAR蛋白は、ある程度結合能を維持した。これらの解析で、p.G382S変異型EDARの機能喪失の程度は最も軽度と考えられた。 過去の研究で、野生型EDARはTRAF6とは直接結合しないことが報告されており、本研究で実施した野生型EDARとTRAF6間の共免疫沈降法でも同様の結果が得られた。しかしながら、驚くべきことに、本研究で解析した全ての変異型EDAR蛋白はTRAF6と直接結合する性質を示した。 培養細胞での過剰発現系においては、機序は不明だがEDAR蛋白を含む種々のTNF受容体が細胞質内に発現する傾向を示すことが知られていたことから、p.R358Qおよびp.T403M変異型EDAR蛋白の細胞膜への局在は異常な発現パターンと考えられる。NF-κBレポーターアッセイおよび共免疫沈降法の結果から、各変異型EDAR蛋白とEDARADDの親和性はNF-κB活性低下の程度と強く相関することが示唆された。今回解析した4 種類のミスセンス変異は、いずれもEDARの機能や構造に重大な影響を与えると複数のデータベースで推測されていたが、各データベースのスコアは4つの変異の間で非常に類似していた。すなわち、現在の予測ツールの解析能力には限界があり、本研究のように実際に発現・機能解析を行う重要性がハイライトされたといえる。 4種類の変異型EDAR蛋白に共通する唯一の現象は、野生型EDAR蛋白がEDARADDを介して間接的にTRAF6と相互作用するのに対し、TRAF6と直接結合することである。これは、変異型EDAR蛋白がEDAR、DARADD、TRAF6からなる正しい蛋白複合体を形成できないことを示唆しており、EDAR遺伝子変異に起因するHEDの鍵となっている可能性があるが、本現象の病的意義を解明するためには今後のさらなる検討を要する。 本研究で得られた結果に基づき、各変異を機能喪失の度合いで評価した。R358QとT403Mを「重度」、p.I388Tを「中等度」、p.G382Sを「軽度」とした。各変異を報告した文献に提示されていた表現型と比較検討した結果、EDAR遺伝子変異の機能喪失の程度がHEDの重症度と相関している可能性が示唆された。
Creators : 八木 献 Dissertation Number : 医博甲第1671号 Degree Names : 博士(医学) Date Granted : 2023-03-16 Degree Grantors : Yamaguchi University
自動車事故に際しシートベルトに沿って生じる帯状の皮下出血斑はシートベルト兆候(seat belt sign:SBS)と呼ばれている。特に腹部SBS が上前腸骨棘(anterior superior iliac spine:ASIS)よりも上方に位置する場合、腹部臓器損傷の危険性が高い。本研究の目的は、腹部SBS 位置に関連するシートベルト腹部部分(ラップベルト)の位置に影響を与える因子について解析することである。本研究は、健康な成人100名(男性50名、女性50名)の身体所見と、カーシート座位時のラップベルト位置との関係を前向きに検討したものである。身体所見は、年齢、身長、Body Mass Index(BMI)、腹囲を測定した。それぞれ平均年齢37.9歳、平均身長164.9cm、平均BMI 23.9kg/m2、平均腹囲83.4cmであった。X線学的所見は、腰椎前弯(lumbar lordosis:LL)、仙骨傾斜(sacral slope:SS)を測定し、ラップベルト位置は運転席側のラップベルトの中央とASIS相当の位置に鉛テープでマーキングすることで計測した。側面X線撮影を行い、ASISから中央マーカーまでの水平距離(X値)、垂直距離(Z値)を計測した。ラップベルト角度は、2つのマーカーの上端を結ぶ直線と水平線とのなす角度を計測することで求めた。これらの身体所見とX線学的所見との関係を統計学的に解析した。X値とZ値は体重(X値r = 0.73、Z値r = 0.56)、BMI(X値r = 0.77、Z値r = 0.56)、腹囲(X値r = 0.74、Z値r = 0.52)と正の相関があり、ラップベルト角度は体重(r = -0.33)、BMI(r = -0.35)、腹囲(r = -0.37)と負の相関があった。これらの結果からは、BMIの高い乗員ではラップベルトがASISより高い位置にあるため、シートベルト損傷を引き起こす可能性が高い。この解析は、より安全なシートベルトの開発に役立つと思われる。
Creators : 山縣 大樹 Dissertation Number : 医博甲第1670号 Degree Names : 博士(医学) Date Granted : 2023-03-16 Degree Grantors : Yamaguchi University
人工股関節全置換術(Total hip arthroplasty, 以下THA)においてカップ設置角度、カップ設置位置は脱臼の予防、外転筋レバーアームの再建、腸腰筋インピンジメント予防などの点で重要性はますます高くなっている。これまで後方アプローチでのComputed Tomography(CT)-based navigation使用によるcup 設置の正確性に関する報告は多数あるが、仰臥位前方アプローチ(Direct anterior approach、以下DAA)での報告は少なく、また術中イメージを使用した設置精度との比較をした報告はない。今回DAAでのTHAにおけるCT-based navigationを使用したカップ設置精度を検討した。DAAによるTHAを施行した156例171股における、カップ設置精度について、術中mechanical cup alignment guide使用群(MG群63股)、術中fluoroscopy使用群(FS群58股)、CT-based navigation使用群(CTN群50股)の3群について比較した。検討項目は、Lewinneckのsafe zone内のカップ設置割合(%)、カップ外転角(radiographic inclination、以下RI)、カップ前捻角(radiographic anteversion、以下RA)、カップの骨頭中心位置(上下、前後、内外)に関して、術前計画と術後設置角度、位置を比較し、その絶対値誤差をそれぞれ3群にて検討した。術後2週で全例CT検査を実施し、三次元解析ソフトにて誤差を抽出した。Lewinneckのsafe zone内の設置割合は、MG群80.9%(55/63)、FS群81%(47/58)、CTN 群100%(50/50)で、CTN群はMG群(p=0.005)、FS群(p=0.005)よりも有意に高かった。RIはMG群4.4±3.2°、FS群3.6±3.1°、CTN群2.8±2.5°であり、CTN群はMG群(p=0.01)よりも有意に誤差が小さかった。RAはMG群5.8±4.7°、FS群4.8±4.1°、CTN群2.8±1.9°で、CTN群はMG群(p=0.0001)、FS群(p=0.02)より有意に誤差が小さかった。RI、RAに対して絶対値誤差3°以上をoutlierとし各群間で比較した。RI についてMG群63.5%(40/63)、FS群43.1%(25/58)、CTN群36%(18/50)で、CTN群はMG群(p=0.03)より有意にoutlierが少なかった。RAについて、MG群66.7%(42/63)、FS群58.6%(34/58)、CTN群48%(24/50)でCTN群はMG群(p=0.04)よりも有意にoutlierが少なかった。カップの骨頭中心座標(内外:X軸、前後:Y軸、上下:Z軸)については、X軸、Y軸では3群とも有意差は認めなかった。しかしZ軸ではMG群3.3±3.2mm、FS群3.2±3.0mm、CTN群1.8±1.4mmで、CTN群がMG群(p=0.02)、FS群(p=0.007)に対して有意に誤差が少なかった。絶対値誤差より2mm以上をoutlierとし各群間で比較を行った。X軸、Y軸において有意差は認められなかった。一方Z軸に関してはCTN群がMG群(p=0.03)、FS群(p=0.04)よりも有意にoutlierが少なかった。今回の結果から、DAAでのTHAにおいて、CT-basedNavigation使用することでmechanical cup alignment guide使用や、fluoroscopyを使用するよりもカップ設置精度が向上し、有用であることが確認された。
Creators : 松木 佑太 Dissertation Number : 医博甲第1669号 Degree Names : 博士(医学) Date Granted : 2023-03-16 Degree Grantors : Yamaguchi University
背景:The Union for International Cancer Control(UICC)の tumour、node、metastasis(TNM)分類によって大腸がんの治癒あるいは再発の可能性を予測出来るため、治療方針の決定に役立っている。しかしこの分類法単独による予後の予測は不十分である。そのため予後予測因子として新たなバイオマーカーの同定が望まれている。過去に我々は、根治切除を行ったステージI、II、およびIIIの結腸直腸がん(CRC)患者において免疫組織化学によって同定されたCD4およびforkhead box P3(FOXP3)陽性T細胞密度の組み合わせの無再発生存期間(RFS)・全生存期間に対する有用性を報告した。本研究は、統計的パターン認識の手法である離散ベイズ識別則を応用することにより、T3/T4a ステージIIのCRC患者の再発を予測するマーカーの最適な組み合わせを抽出した。 方法:T3/T4aステージII患者の137症例の切除標本を用いて、12の臨床病理学的および免疫的因子を再発の予後予測因子の候補として解析を行った。 結果:比較的に予後良好とされている T3/T4aステージ II 症例で、CD4・FOXP3陽性T細胞両方の腫瘍浸潤度に最も強い影響があることが示唆された。CD4・FOXP3陽性T細胞両方の腫瘍浸潤度が低い症例群のRFSが明らかに不良であった。 結論:CD4とFOXP3陽性T細胞を組み合わせた腫瘍浸潤度がCRCの予後予測因子となり得ることが示唆され、従来のステージ分類では不十分な患者の層別化も可能になるという新規の知見が明らかになった。補助化学療法は、CD4・FOXP3陽性T細胞両方の腫瘍浸潤度が低い患者に対して考慮されるべきであることが示唆された。
Creators : 中上 裕有樹 Dissertation Number : 医博甲第1668号 Degree Names : 博士(医学) Date Granted : 2023-03-16 Degree Grantors : Yamaguchi University
背景・目的:大腸癌(CRC)は、世界的に癌関連死亡の第2位の原因となっており、転移を伴う大腸癌(mCRC)患者の予後不良は緊急の課題である。以前、我々はSOMAscanアッセイを用いて、予後を予測する10種類のバイオマーカー候補を得ることができた。本研究の目的は、得られた候補タンパクの一つであるC-C motif chemokine ligand 7(CCL7)について、mCRC患者における治療前の血清CCL7濃度の予後予測性能を明らかにすることであった。 材料と方法:mCRC患者の血清(n=110)および手術標本(n=85)について、それぞれCCL7のタンパク濃度をELISA法および免疫組織化学法で検討した。また、Cox回帰分析、受信者動作特性曲線(ROC)分析、Kaplan-Meier法を用いて、タンパクの濃度と予後との関係を検討した。結果:血清CCL7濃度が高い患者の全生存期間(OS)は、低い患者と比較し、有意に不良であった。間質中のCCL7発現レベルが高い患者は、低い患者に比べ、有意に予後不良であった。 Carcino embryonic antigen(CEA)および糖鎖抗原19-9(CA19-9)の濃度は、CCL7低値群に比べ、高CCL7群で有意に高値であった。単変量解析および多変量解析により、血清CCL7濃度はmCRCの有意な予後因子であることが明らかになった。また、血清CCL濃度とCEA濃度の組み合わせにおいて、血清CCL7濃度、CEAの両方が高値である患者は、両方が低値である群と比較し、有意に予後不良であった。 結論:治療前の血清CCL7濃度および血清CCL7濃度とCEAとの組み合わせは、mCRCの予後を予測する有用なバイオマーカーである。
Creators : 千々松 日香里 Dissertation Number : 医博甲第1667号 Degree Names : 博士(医学) Date Granted : 2023-03-16 Degree Grantors : Yamaguchi University
背景:肝癌は肝内転移を生じやすく、その予後は不良である。がん幹細胞様細胞(CSLCs)とは、幹細胞性、腫瘍形成能、治療抵抗性に加え、転移能亢進といった特徴を有している。近年では、がんの転移形成や制御において、宿主の免疫機構が重要な働きを担っていると考えられており、今回、肝癌細胞株から誘導したCSLCsの免疫逃避能について検討を行った。 方法:Sphere誘導培地を用いて、Sphere細胞の形態で肝癌細胞株からCSLCsを誘導した。免疫逃避に関わる遺伝子およびタンパク発現を、RNAシーケンス、フローサイトメトリー、ELISA法を用いて解析し、親株とSphere細胞とで比較した。親株とSphere細胞それぞれの、NK細胞に対する感受性について、クロム放出試験を用いて比較検討した。BALB/cヌードマウスを用いた異種移植実験にて、親株とSphereの腫瘍形成能を比較した。 結果:肝癌細胞株SK-HEP-1から誘導したSphere細胞(SK-sphere)では、親株と比較し、細胞膜上のPD-L1、PD-L2、CEACAM1の発現が亢進し、ULBP1、MICA/MICBの発現は低下していた。また、SK-sphereの培地中では、可溶型MICAの濃度が上昇していた。SK-sphereにおけるHLA class I発現低下は見られなかった。肝癌細胞株SK-HEP-1およびHLEから誘導したSphere細胞を用いて、NK細胞に対する感受性をそれぞれの親株と比較したところ、どちらのSphere細胞においてもNK細胞による細胞障害性がより低下していた。NK細胞を保持するヌードマウスにおいて、親株の移植と比較してSK-sphereを移植した際により大きな腫瘍を形成した。 結論:肝癌細胞株から誘導したCSLCsはNK細胞を介した免疫系からの逃避能が亢進している事が示唆された。
Creators : 木村 祐太 Dissertation Number : 医博甲第1666号 Degree Names : 博士(医学) Date Granted : 2023-03-16 Degree Grantors : Yamaguchi University
背景:UGT1A1*28および*6遺伝子多型は、イリノテカンに関連する毒性の危険因子として知られている。しかし、UGT1A1*28および*6に遺伝子変異を持たない患者においても、イリノテカンによる重篤な副作用が認められている。我々は、UGT1A以外のイリノテカン毒性の有用なバイオマーカーを同定するために、全エクソームにおける遺伝子多型を調査した。 方法:FOLFIRI療法、FOLFOX療法、FOLFOXIRI療法を投与された転移性大腸癌(mCRC)患者178例とmodified FOLFIRINOX療法、ゲムシタビン+ナブパクリタキセル療法を投与された膵臓癌患者87例を対象とした。ゲノムワイドスクリーニングは全エクソームシーケンス(WES)を用いて行い、バリデーション解析は加水分解プローブを用いたqPCRを用いて実施した。 結果:FOLFIRI療法症例のWES(n = 15)により、7つの一塩基多型(SNP)がイリノテカン関連毒性である好中球減少のバイオマーカー候補として同定された。7つのSNPのうち、R3H domain and coiled-coil containing 1(R3HCC1; c.919G>A, rs2272761)のSNPは、検証サンプル症例のグレード3以上の好中球減少と有意な関連性を示した。mCRC患者に対するFOLFOXIRI療法(n = 23)または膵臓癌に対するmodified FOLFIRINOX療法(n = 40)といったイリノテカン含有の3剤併用化学療法患者でも、R3HCC1多型と好中球減少との間に有意な線形傾向がみられた(それぞれP = 0.017 および0.046 )。一方で、イリノテカンを含まないレジメン(mCRC患者に対するFOLFOX療法(n = 66)、膵臓癌に対するゲムシタビン+ナブパクリタキセル療法(n = 47))患者では、有意な関連は認められなかった。 結論:R3HCC1多型は、mCRCと膵臓癌に対するイリノテカンを含む化学療法の毒性に関する有用なバイオマーカーとなる可能性がある。
Creators : 兼定 航 Dissertation Number : 医博甲第1665号 Degree Names : 博士(医学) Date Granted : 2023-03-16 Degree Grantors : Yamaguchi University
細胞シート移植治療の普及には利便性の高い細胞シートの保存方法の開発が不可欠である。細胞シートから分泌される成長因子によって創傷治癒は促進されると考えられてきたため、その保存には細胞生存率が重要視されてきた。そのため、積層線維芽細胞シートの乾燥保存に関する検討はこれまでにない。本研究では、乾燥保存した積層線維芽細胞シート(Dryシート)を開発し、糖尿病マウス全層皮膚欠損モデルでの創傷治癒促進効果を検証した。 マウスの尾から単離した線維芽細胞を用いて、積層線維芽細胞シート(Livingシート)を作製した。Livingシートを風乾させ、Dryシートとした。Livingシートに凍結解凍操作を繰り返してFreeze-thaw(FT)シートとした。各シートを培地に浸漬して溶出液とし、各溶出液中の成長因子を測定した。Vascular endothelial growth factor(VEGF)とhepatocyte growth factor(HGF)はDryシートとLivingシートで検出したのに対し、fibroblast growth factor-2(FGF-2)とhigh mobility group box 1(HMGB1)はDryシートのみで検出した。FTシートではこれらの成長因子をほとんど検出しなかった。細胞シートの溶出液を添加して線維芽細胞を培養し、溶出液の生理活性を線維芽細胞増殖試験で検討した。DryシートはLivingシートと比べ、細胞増殖と成長因子産生量を有意に促進し、FGF-2中和抗体で阻害すると、この細胞増殖反応は抑制された。糖尿病マウス全層皮膚欠損モデル(C57BL/6N)において、自家及び他家(C3H/He)の線維芽細胞から作製したDryシート貼付群は無治療群に比べ、創の閉鎖を有意に促進した。Dryシートは常温(23℃)よりも冷蔵(4℃)での保存安定性に優れ、少なくとも4週間の冷蔵保存ではDryシートのFGF-2の減少を認めなかった。 以上から、DryシートはFGF-2の放出という新たな作用機序で創傷治癒を促進することが明らかになった。他家細胞から作製されたDryシートは、創傷治癒を促す再生医療において新たな扱いやすい被覆材であることが示唆された。
Creators : 松野 祐太朗 Dissertation Number : 医博甲第1664号 Degree Names : 博士(医学) Date Granted : 2023-03-16 Degree Grantors : Yamaguchi University
本研究の目的は、皮膚潰瘍モデルマウスにおいて、凍結保存した他家線維芽細胞シートの治療効果を検討することである。他家細胞シートの凍結保存が可能であれば、様々な疾患への応用が可能であり、大幅なコストダウンによる再生医療の普及に貢献できると考えられる。本研究では、3Dフリーザーを用いて線維芽細胞シートの凍結を行った。凍結融解した線維芽細胞シートは、非凍結線維芽細胞シートと比較して、細胞生存率は約80であり、vascularendothelial growth factor VEGF )、hepatocyte growth factor HGF)、stromalderived factor 1α SDF1αの培養上清中の濃度が50%以上で、transforminggrowth factor β1 TGFβ1の分泌能は同等であった。皮膚潰瘍モデルマウスにおいて、非凍結線維芽細胞シート群と凍結融解した線維芽細胞シート群の間で、自家細胞、他家細胞のどちらも創傷治癒率に差はなかった。また、血管新生の程度も同等であった。治癒組織におけるCD3陽性細胞数は、自家線維芽細胞シート群と比較して他家線維芽細胞シート群で多く見られた。しかし、病理組織学的には、凍結融解した他家線維芽細胞シート群の線維化、新生血管密度、創傷治癒速度は、非凍結他家線維芽細胞シート群に比べて凍結融解した自家線維芽細胞シート群に類似していた。これらの結果から、凍結融解した他家線維芽細胞シートが難治性皮膚潰瘍に対する有望な治療オプションとなる可能性が示唆された。
Creators : 池 創一 Dissertation Number : 医博甲第1663号 Degree Names : 博士(医学) Date Granted : 2023-03-16 Degree Grantors : Yamaguchi University
ミエリン関連糖蛋白 (myelin-associated glycoprotein: MAG) は,神経組織の髄鞘に局在する膜貫通糖蛋白であり,MAGに対するIgM型自己抗体 (MAG抗体) を有する患者では脱髄性末梢神経障害をきたす.末梢神経には血液神経関門 (blood-nerve barrier: BNB) があるために,通常は免疫グロブリンなどの大きな分子が神経内に侵入することはできない.しかし,MAGニューロパチー患者から採取した腓腹神経内有髄神経線維の髄鞘にはMAG抗体が沈着しており,MAG抗体はBNBを通過していることが想定される.MAG抗体のBNB通過機序を明らかにすることを目的に,MAGニューロパチー患者血清,ヒトBNB構成内皮細胞株と周皮細胞株,MAGニューロパチー患者から採取した腓腹神経検体を用いて解析を行った.MAGニューロパチー患者血清を作用させた内皮細胞に対して,全RNAトランスクリプトーム解析と免疫染色を用いたハイコンテントイメージング解析を行い,NF-κBの活性化とTNF-αの発現増加を確認した.次に内皮細胞と周皮細胞を共培養したBNB in vitroモデルで透過性を解析した. MAGニューロパチー患者血清を作用させた結果,10 kDaデキストランやIgGの透過性を変化させることなく,IgMやMAG抗体の透過性を亢進させ,TNF-αの中和抗体を添加することでIgMやMAG抗体の透過性は抑制された.電子顕微鏡による観察ではMAGニューロパチー患者の腓腹神経内でBNBを構成する微小血管の密着結合は保たれており,内皮細胞内に多数の小胞が確認された.MAGニューロパチー患者では,MAG抗体はBNB構成内皮細胞の自己分泌TNF-αの増加を介して内皮細胞質内をトランスサイトーシスの機序により通過していることが示唆された.TNF-α阻害薬は既存の薬剤であり,本研究結果から,TNF-α阻害薬によるMAGニューロパチー患者への新たな治療戦略が期待される.
Creators : 佐藤 亮太 Dissertation Number : 医博甲第1662号 Degree Names : 博士(医学) Date Granted : 2023-03-16 Degree Grantors : Yamaguchi University
小胞体ストレスの増加は、動脈硬化において血管平滑筋培養細胞(VSMCs)の形質転換(分化→脱分化)と強く関連している。小胞体のCa2+貯蔵量減少は、VSMCs における小胞体ストレスの増加の主要な原因の一つである。リアノジン受容体(RyR)は筋小胞体膜上に存在する主要なCa2+放出チャネルである。正常細胞の安静状態ではカルモジュリン(CaM)はRyR と結合し、RyR を閉鎖した状態で安定化させている。CaM とRyR の結合が減弱すると、RyR から異常なCa2+漏出が起こり、Ca2+貯蔵量が減少し、小胞体ストレスが増加する原因となり得る。そこで我々は、マウスのVSMCs を用いてRyR に結合しているCa(CaM-RyR)が小胞体ストレスにより引き起こされるVSMCs の形質転換に重要な役割を果たしているか否か、また、CaM-RyR の結合親和性を高める作用を有するダントロレン(DAN)がVSMCs の形質転換に影響を与えるか否かを評価した。 小胞体ストレスによりCaM がRyR から解離し、核内へ移行することにより、MEF2 とKLF5 の核内での発現量が増加し、このMEF2-KLF5 のシグナル伝達経路が活性化することでVSMCs が形質転換(分化→脱分化)し、増殖能や遊走能を有するようになり動脈硬化巣の形成や不安定化につながるという新たな知見を得ることができた。さらにCaM-RyR の結合親和性を高めるDAN は、RyR チャネルを安定化させ、異常なCa2+漏出を抑制し、小胞体内のCa2+貯蔵量を保持することで小胞体ストレスの増加を抑制し、さらにCaM の核内への移行を制御することで、MEF2-KLF5 経路の活性化を抑制し、その結果としてVSMCs の形質転換を抑制することが示され、動脈硬化巣の進展化、不安定化に対する全く新しい治療戦略となり得る可能性があることが示唆された。
Creators : 内田 智之 Dissertation Number : 医博甲第1661号 Degree Names : 博士(医学) Date Granted : 2023-03-16 Degree Grantors : Yamaguchi University
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.
Creators : 木村 献 Dissertation Number : 医博乙第1106号 Degree Names : 博士(医学) Date Granted : 2023-03-08 Degree Grantors : Yamaguchi University
背景:がん幹細胞 (CSC) は、発がん、再発、転移、治療抵抗性に重要な役割を果たすと考えられている。我々は、化学療法抵抗性と転移能を有するがん幹細胞様スフィア細胞 (CSLC) の誘導に成功した。CSLC に対する標的治療の開発を可能にするため、CSLC のこの表現型の原因となる遺伝子を同定した。 方法:ヒト肝がん細胞株SK-HEP-1 を用い、独自のスフィア誘導培地を用いてCSLCを誘導し、HuH-7 細胞を非スフィア形成細胞として同条件で使用した。RNA シーケンシングを行った後、定量的 RT-PCR とウェスタンブロッティングで検証した。ノックダウン (KD) 実験はCRISPR-Cas9 によるゲノム編集により行い、レスキュー実験は発現プラスミドベクターを用いて行った。細胞の化学療法抵抗性と肝転移は、MTS アッセイと細胞の重度免疫不全マウスへの脾臓注入後の解析で評価した。培地中のエクソソームの定量は、EL ISA 法を用いて行った。 結果: RAB3B は、RNA シーケンシングによりCSLC と予後不良の肝細胞がん (HCC)の両方で発現が増加している遺伝子として同定された。RAB3B-KD 細胞は、スフィア形成、化学療法抵抗性、転移能などのCSLC 表現型の変化を示し、これらはRAB3Bの相補化によって回復された。CSLC ではエクソソーム分泌の増加が観察されたが、RAB3B-KD 細胞では観察されなかった。また、RAB3B の発現は、ABCG2、APOE、LEPR、LXN、TSPAN13 の発現と相関していた。 結論:RAB3B のアップレギュレーションは、CSLC の化学療法抵抗性と転移能に重要な役割を担っている可能性がある。
Creators : 恒富 亮一 Dissertation Number : 医博乙第1105号 Degree Names : 博士(医学) Date Granted : 2023-02-08 Degree Grantors : Yamaguchi University