Ontology-Based Reasoning for Educational Assistance in Noncommunicable Chronic Diseases

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대사 수술을 통한 포도당 항상성 호전의 기전

학위논문(박사)--서울대학교 대학원 :의과대학 의학과,2019. 8. 조영민.비만은 현대사회에서 가장 큰 의료 부담을 야기하는 질병의 하나로써 다양한 대사, 심혈관, 근골격 질환 그리고 종양과 연관되어 있다. 특히 제2형 당뇨병은 이러한 비만의 동반 질환 중에서 가장 대표적인 질병으로 환자들의 삶의 질 저하와 사망률의 증가로 이어진다. 현재까지 많은 연구와 노력에도 불구하고 비만과 당뇨 치료법들은 한계점은 가지고 있다. 비교적 최근에 도입된 대사 수술은 위장관계 수술을 통하여 체중을 감소시키고 나아가 당대사를 호전시키고자 하는 치료법이다. 현재까지 개발된 어떠한 약물치료에 비하여 대사 수술은 더 강력한 혈당 저하 및 체중감소 효과를 보이며, 이러한 효과는 10년이상 오래 유지됨이 밝혀졌다. 특히, 대사 수술은 당뇨 약제를 중단하여도 정상 혈당이 유지되는 당뇨 관해를 유도할 수도 있다고 알려졌다. 이러한 대사 수술의 기전을 연구함으로써 비만과 당뇨병을 치료할 수 있는 새로운 방향을 제시할 수 있을 것으로 기대된다. 이를 위하여, 본 연구에서 두 종류의 대사 수술 동물 모델을 연구하였다. 먼저 회장 전치술 렛트 모델을 통해서 대사 수술에서 원위 회장의 역할 및 수술 후 장의 적응 변화를 살펴보았다. 회장 전치술은 후위부 회장의 일부를 수술적으로 십이지장 다음으로 위치시켜 대사 수술에서 말단부 회장의 역할을 연구하고자 하는 수술법이다. 회장전치술을 고지방사료 섭취로 비만을 유도한 식이 유발 비만 렛트에서 시행하여 대사적인 효과를 살펴보았다. 회장전치술은 혈당을 감소시켰는데, 특히 식후 인슐린과 GLP-1 분비 증가를 통하여 이를 일으키는 것으로 생각되었다. 또한 이러한 변화는 췌장 베타세포의 증가와 동반되었다. 다음으로 전치된 회장에서의 유전자 발현 변화를 분석하였다. 회장 전치술 후에 1주, 4주가 지나고 회장 조직을 채취하고 마이크로어레이 분석을 시행하여 유전자 발현을 살펴보았다. 흥미롭게도, 1주와 4주의 유전자 발현사이에 큰 차이가 있어 회장 전치술 후 초기에 회장에서 매우 역동적인 적응 변화가 일어남을 알 수 있었다. 추가적인 유전자 경로 분석 및 네트워크 분석을 통하여 첫 1주에는 구조적인 적응이, 4주에는 대사적인 적응과 면역학적인 적응이 주된 반응임을 알 수 있었다. 다음으로, 당대사에 중요한 간, 지방, 근육 조직에서의 변화를 살펴보기 위하여 마우스에서 위소매절제술을 시행하여 연구하였다. 식이 유도 비만 마우스에서 위소매절제술을 시행한 뒤 간, 지방, 근육 조직을 채취하여 RNA 시퀀싱 분석을 통해 유전자 발현의 차이를 비교하였다. 또한 이를 sham 수술 대조군 뿐만 아니라 sham 수술 후 위소매절제술 수술과 동일한 식이를 섭취하도록 한 pair-fed 그룹과도 비교하여 위소매절제술의 효과에서 체중 감소 독립적인 부분을 확인하고자 하였다. 이러한 실험을 통하여 위소매절제술이 간, 지방, 근육에 모두 유전자 발현 변화를 유도하는데, 특히 이러한 차이는 단순한 식이 제한을 통해 체중 감소를 유도한 pair-fed 마우스에서 대조군과 비교한 차이보다 훨씬 크게 나타나서 위소매절제술의 간, 지방, 근육에 대한 효과 중 체중감소 독립적인 기전에 중요함을 알 수 있었다. 또한 면역 반응과 관련된 유전자들이 세가지 조직에서 모두 공통적으로 변화되어 있었다. 본 연구를 통해서 장에서는 수술 후 다이나믹한 적응 변화가 일어남을 알 수 있었고 말초에서 당을 대사하는 간, 지방, 근육 조직에서는 체중감소 독립적인 유전자 발현 변화가 크게 일어남을 알 수 있었다. 이러한 변화 중 면역 반응과 연관된 유전자 발현 변화가 모두 공통적으로 나타나서 대사 수술 후 면역 반응의 변화가 중요한 역할을 할 가능성을 시사하였다.Obesity increases the risk of metabolic, cardiovascular, musculoskeletal diseases and even some types of cancer. Among various complications of obesity, type 2 diabetes mellitus (T2DM) is the prototype of metabolic complications. Obesity is the primary contributor to the development of T2DM. Despite of tremendous efforts to bring better treatment for obesity and diabetes, there are still significant unmet needs. Metabolic surgery is a surgical treatment to reduce body weight and improve glucose metabolism. Unlike other pharmacologic treatment for obesity and diabetes, metabolic surgery demonstrated superior clinical efficacy and longer durability. Furthermore, metabolic surgery can induce remission of T2DM which is defined as achieving normoglycemia without any anti-diabetic medication. By unraveling the mechanism of metabolic surgery to improve metabolic homeostasis, we can develop new insights into glucose metabolism and better treatments. To elucidate the molecular mechanism of metabolic surgery, two rodent models of metabolic surgery were used. First, ileal transposition (IT) is an experimental surgery which translocate a segment of distal ileum into proximal jejunum. The metabolic effects of IT were investigated in diet-induced obese rats. IT improved glucose tolerance by augmenting postprandial insulin and GLP-1 secretion. IT also increased pancreatic β-cell mass which was thought to be associated with increased GLP-1 secretion. However, IT did not have significant effect on body weight and insulin sensitivity. On histologic examination, the transposed ileum showed hypertrophic change and increased enteroendocrine cell density positively stained for GLP-1 and GLP-1/GIP. Then, an unbiased transcriptomic analysis was applied on the transposed ileum to investigate the adaptive process of the intestine after IT. Using microarray analysis of the transposed ileum at week-1 and week-4 after surgery, I could demonstrate that the transposed ileum undergoes a dynamic adaptation process after IT. Functional enrichment analysis and network analysis further characterized the major components of each stage, which were structural adaptation at week 1 and metabolic and immune adaptations at week 4. Secondly, a mouse model of vertical sleeve gastrectomy (VSG) was constructed to investigate the effects of VSG in glucose metabolizing tissues including liver, fat and muscle. Vertical sleeve gastrectomy removes lateral 80% of the stomach and leaves only tube like remnant of the stomach. I examined gene expression profiles of liver, fat and muscle in VSG mice compared with sham and sham pair-fed (sham-PF) mice using RNA sequencing analysis at 8 weeks after surgery. VSG improved glucose tolerance significantly than sham, but only marginally than sham-PF. Unexpectedly, gene expression profiles of liver, fat, and muscle tissues were significantly different between VSG and sham-PF, which was more distinct than the comparison between sham and sham-PF, suggesting the weight-loss independent effects on gene expression of peripheral tissues are more robust than weight-loss dependent effects. In addition, immune response-related gene ontology and pathways were consistently un-regulated in the three organs. In further analysis, the immune response in adipose tissue was characterized as up-regulation of M2 phenotype macrophage and B lymphocytes. In summary, IT in rats and VSG in mice could demonstrate the metabolic improvements after metabolic surgery. The intestine undergoes dynamic adaptation process after surgery which can have implications in metabolic homeostasis with structural and functional changes. The glucose metabolizing peripheral tissues, liver, fat and muscle, showed both weight-loss dependent and independent changes in gene expression. The immune response was the common pathway enriched in the three organs after metabolic surgery.General Introduction 1 Chapter 1: Metabolic effects of ileal transposition and the adaptive process of the transposed distal ileum Background and objectives of chapter 1 27 Material and Methods 29 Results 39 Discussion of chapter 1 70 Chapter 2: Effects of vertical sleeve gastrectomy on the gene expression of liver, fat and muscle and their implications in glucose homeostasis Background and objectives of chapter 2 76 Material and Methods 78 Results 85 Discussion of chapter 2 124 Discussion 127 Acknowledgement 140 References 141 Abstract in Korean 159Docto

A novel and validated agile Ontology Engineering methodology for the development of ontology-based applications

The goal of this Thesis is to investigate the status of Ontology Engineering, underlining the main key issues still characterizing this discipline. Among these issues, the problem of reconciling macro-level methodologies with authoring techniques is pivotal in supporting novel ontology engineers. The latest approach characterizing ontology engineering methodologies leverages the agile paradigm to support collaborative ontology development and deliver efficient ontologies. However, so far, the investigations in the current support provided by these methodologies and the delivery of efficient ontologies have not been investigated. Thus, this work proposes a novel framework for the investigation of agile methodologies, with the objective of identifying the strong point of each agile methodology and their limitations. Leveraging on the findings of this analysis, the Thesis introduces a novel agile methodology – AgiSCOnt – aimed at tackling some of the key issues characterizing Ontology Engineering and weaknesses identified in existing agile approaches. The novel methodology is then put to the test as it is adopted for the development of two new domain ontologies in the field of health: the first is dedicated to patients struggling with dysphagia, while the second addresses patients affected by Chronic obstructive pulmonary disease.The goal of this Thesis is to investigate the status of Ontology Engineering, underlining the main key issues still characterizing this discipline. Among these issues, the problem of reconciling macro-level methodologies with authoring techniques is pivotal in supporting novel ontology engineers. The latest approach characterizing ontology engineering methodologies leverages the agile paradigm to support collaborative ontology development and deliver efficient ontologies. However, so far, the investigations in the current support provided by these methodologies and the delivery of efficient ontologies have not been investigated. Thus, this work proposes a novel framework for the investigation of agile methodologies, with the objective of identifying the strong point of each agile methodology and their limitations. Leveraging on the findings of this analysis, the Thesis introduces a novel agile methodology – AgiSCOnt – aimed at tackling some of the key issues characterizing Ontology Engineering and weaknesses identified in existing agile approaches. The novel methodology is then put to the test as it is adopted for the development of two new domain ontologies in the field of health: the first is dedicated to patients struggling with dysphagia, while the second addresses patients affected by Chronic obstructive pulmonary disease

Ontology-based personalized performance evaluation and dietary recommendation for weightlifting.

Studies in weightlifting have been characterized by unclear results and information paucity, mainly due to the lack of information sharing between athletes, coaches, biomechanists, physiologists and nutritionists. Becoming successful in weightlifting performance requires a unique physiological and biomechanics profile based on a distinctive combination of muscular strength, muscular power, flexibility, and lifting technique. An effective training which is carefully designed and monitored, is needed for accomplishment of consistent high performance. While it takes years of dedicated training, diet is also critical as optimal nutrition is essential for peak performance. Nutritional misinformation can do as much harm to ambitious athletes as good nutrition can help. In spite of several studies on nutrition guidelines for weightlifting training and competition as well as on design and implementation of weightlifting training programs, to the best of authors' knowledge, there is no attempt to semantically model the whole "training-diet-competition" cycle by integrating training, biomechanics, and nutrition domains.This study aims to conceive and design an ontology-enriched knowledge model to guide and support the implementation of "Recommender system of workout and nutrition forweightlifters". In doing so, it will propose: (i) understanding the weightlifting training system, from both qualitative and quantitative perspectives, following a modular ontology modeling, (ii) understanding the weightlifting diet following a modular ontology modeling, (iii) semantically integrating weightlifting and nutrition ontologies to mainly promote nutrition and weightlifting snatch exercises interoperability, (iv) extending modular ontology scope by mining rules while analyzing open data from the literature, and (v) devising reasoning capability toward an automated weightlifting "training-diet-competition" cycle supported by previously mined rulesTo support the above claims, two main artefacts were generated such as: (i) a weightliftingnutritional knowledge questionnaire to assess Thai weightlifting coaches' and athletes'knowledge regarding the weightlifting "training-diet-competition" cycle and (ii) a dual ontologyoriented weightlifting-nutrition knowledge model extended with mined rules and designed following a standard ontology development methodology.Studies in weightlifting have been characterized by unclear results and information paucity, mainly due to the lack of information sharing between athletes, coaches, biomechanists, physiologists and nutritionists. Becoming successful in weightlifting performance requires a unique physiological and biomechanics profile based on a distinctive combination of muscular strength, muscular power, flexibility, and lifting technique. An effective training which is carefully designed and monitored, is needed for accomplishment of consistent high performance. While it takes years of dedicated training, diet is also critical as optimal nutrition is essential for peak performance. Nutritional misinformation can do as much harm to ambitious athletes as good nutrition can help. In spite of several studies on nutrition guidelines for weightlifting training and competition as well as on design and implementation of weightlifting training programs, to the best of authors' knowledge, there is no attempt to semantically model the whole "training-diet-competition" cycle by integrating training, biomechanics, and nutrition domains.This study aims to conceive and design an ontology-enriched knowledge model to guide and support the implementation of "Recommender system of workout and nutrition forweightlifters". In doing so, it will propose: (i) understanding the weightlifting training system, from both qualitative and quantitative perspectives, following a modular ontology modeling, (ii) understanding the weightlifting diet following a modular ontology modeling, (iii) semantically integrating weightlifting and nutrition ontologies to mainly promote nutrition and weightlifting snatch exercises interoperability, (iv) extending modular ontology scope by mining rules while analyzing open data from the literature, and (v) devising reasoning capability toward an automated weightlifting "training-diet-competition" cycle supported by previously mined rulesTo support the above claims, two main artefacts were generated such as: (i) a weightliftingnutritional knowledge questionnaire to assess Thai weightlifting coaches' and athletes'knowledge regarding the weightlifting "training-diet-competition" cycle and (ii) a dual ontologyoriented weightlifting-nutrition knowledge model extended with mined rules and designed following a standard ontology development methodology

Technological Applications for the Automation of Food Questionnaires in Medical Studies: a state-of-art-review and future prospective

Applications for automating the most commonly used dietary surveys in nutritional research, Food Frequency Questionnaires (FFQs) and 24 h Dietary Recalls (24HDRs), are reviewed in this paper. A comprehensive search of electronic databases was carried out and findings were classified by a group of experts in nutrition and computer science into: (i) Computerized Questionnaires and Web-based Questionnaires; (ii) FFQs and 24HDRs and combinations of both; and (iii) interviewer-administered or self-administered questionnaires. A discussion on the classification made and the works reported is included. Finally, works that apply innovative technologies are outlined and the future trends for automating questionnaires in nutrition are identified