DRIVER Technology Watch Report

This report is part of the Discovery Workpackage (WP4) and is the third report out of four deliverables. The objective of this report is to give an overview of the latest technical developments in the world of digital repositories, digital libraries and beyond, in order to serve as theoretical and practical input for the technical DRIVER developments, especially those focused on enhanced publications. This report consists of two main parts, one part focuses on interoperability standards for enhanced publications, the other part consists of three subchapters, which give a landscape picture of current and surfacing technologies and communities crucial to DRIVER. These three subchapters contain the GRID, CRIS and LTP communities and technologies. Every chapter contains a theoretical explanation, followed by case studies and the outcomes and opportunities for DRIVER in this field

A Systems Approach to Dissecting the Role of the Mucosal Microbiome in Disease

The microbial community harbored by the mammalian gastrointestinal tract, collectively called the gut microbiota, plays a critical role in host health, metabolism, and immunity. Quantifiable changes in the gut microbiota have been implicated in a myriad of pathologies, including autoimmune, metabolic, and neurodegenerative diseases. Because of the gut microbiota’s plasticity, manipulating this community for therapeutic benefit presents as a novel strategy to combat modern diseases. Yet, only a fraction of the total microbial diversity that exists within the gut has been successfully cultured in a laboratory, leaving the clinical implications and functional attributes of many gut microbes undetermined. To address this issue, studies in this dissertation focused on bioinformatically investigating (i) the role of dietary and genetic factors on the gut microbiota in metabolic syndrome and (ii) the anatomic niche and immunomodulating antigens of the culture-resistant commensal, Segmented Filamentous Bacteria (SFB). Comprehensive characterization of the cecal microbial community in normal and metabolic syndrome-susceptible mice revealed that dietary factors overshadow the effects of host genetics and are determinist of the microbial patterns that emerge in metabolically healthy or diseased hosts. Moreover, we identified a microbial community proximal to the Peyer’s Patches that was phylogenetically distinct from the cecum. Through a multi-omics approach, we show that independent of mouse genetics, vendor, age, or gender, SFB are highly abundant in the Peyer’s Patches mucosa. Our in silico antigen prediction analyses identified thirty-five potential antigens within the reference proteome of SFB. Shotgun proteomics of the murine ileal mucosa confirmed the in situ presence of several potential antigens expressed by SFB, of which included multiple flagellar proteins. To experimentally valid bioinformatically-inferred antigen targets, we developed a collection of broad-host bacterial vectors to enable microbial products of interest to be precisely expressed in vitro, ex vivo, and in vivo. Collectively, our studies reveal important findings about the mechanisms by which (i) exogenous factors modulate the gut microbiota and (ii) an endogenous microbe modulates the host immune system and provides a novel molecular platform by which microbial products of interest can be causally investigated in polymicrobial communities

Searching for biomarkers of non-alcoholic fatty liver disease and metabolic syndrome

151 p.El desarrollo de esta tesis doctoral ha aportado luz sobre los mecanismos que subyacen a la enfermedad del hígado graso no alcohólico (NAFLD por sus siglas en inglés), ya que los resultados han revelado la existencia de al menos 2 subtipos diferentes de pacientes al comparar (mediante cromatografía de líquidos acoplada a espectrometría de masas) el perfil metabolómico sérico de estos con el perfil metabolómico de dos modelos animales de esta enfermedad: ratones MAT1A-KO y 0.1MCD.Por otra parte, experimentos in vitro, in cellulo e in vivo han revelado parte del mecanismo de acción del Aramchol®, una molécula compuesta por un ácido biliar y un ácido graso saturado. El tratamiento con esta molécula en ratones 0.1MCD ha mostrado una clara reducción en la acumulación de grasa en el hígado, así como una disminución de la fibrosis y de un aumento en la capacidad antioxidante, todo ello disminuyendo los síntomas de esta enfermedad. Así mismo, el estudio clínico en humanos muestra el efecto del Aramchol en el metabolismo hepático de la glucosa, resultados que hemos complementado y validado en esta tesis con el modelo 0.1MCD.Por último, hemos caracterizado una cohorte de personas pertenecientes a población general, para determinar mediante Resonancia Magnética Nuclear (RMN) una huella metabólica en orina que nos permita distinguir pacientes con síndrome metabólico de personas sana

Searching for biomarkers of non-alcoholic fatty liver disease and metabolic syndrome

151 p.El desarrollo de esta tesis doctoral ha aportado luz sobre los mecanismos que subyacen a la enfermedad del hígado graso no alcohólico (NAFLD por sus siglas en inglés), ya que los resultados han revelado la existencia de al menos 2 subtipos diferentes de pacientes al comparar (mediante cromatografía de líquidos acoplada a espectrometría de masas) el perfil metabolómico sérico de estos con el perfil metabolómico de dos modelos animales de esta enfermedad: ratones MAT1A-KO y 0.1MCD.Por otra parte, experimentos in vitro, in cellulo e in vivo han revelado parte del mecanismo de acción del Aramchol®, una molécula compuesta por un ácido biliar y un ácido graso saturado. El tratamiento con esta molécula en ratones 0.1MCD ha mostrado una clara reducción en la acumulación de grasa en el hígado, así como una disminución de la fibrosis y de un aumento en la capacidad antioxidante, todo ello disminuyendo los síntomas de esta enfermedad. Así mismo, el estudio clínico en humanos muestra el efecto del Aramchol en el metabolismo hepático de la glucosa, resultados que hemos complementado y validado en esta tesis con el modelo 0.1MCD.Por último, hemos caracterizado una cohorte de personas pertenecientes a población general, para determinar mediante Resonancia Magnética Nuclear (RMN) una huella metabólica en orina que nos permita distinguir pacientes con síndrome metabólico de personas sana

BlogForever D3.2: Interoperability Prospects

This report evaluates the interoperability prospects of the BlogForever platform. Therefore, existing interoperability models are reviewed, a Delphi study to identify crucial aspects for the interoperability of web archives and digital libraries is conducted, technical interoperability standards and protocols are reviewed regarding their relevance for BlogForever, a simple approach to consider interoperability in specific usage scenarios is proposed, and a tangible approach to develop a succession plan that would allow a reliable transfer of content from the current digital archive to other digital repositories is presented

Access to recorded interviews: A research agenda

Recorded interviews form a rich basis for scholarly inquiry. Examples include oral histories, community memory projects, and interviews conducted for broadcast media. Emerging technologies offer the potential to radically transform the way in which recorded interviews are made accessible, but this vision will demand substantial investments from a broad range of research communities. This article reviews the present state of practice for making recorded interviews available and the state-of-the-art for key component technologies. A large number of important research issues are identified, and from that set of issues, a coherent research agenda is proposed

장내 원소가 대사성 질환과 장내 마이크로비옴에 미치는 영향

학위논문 (박사)-- 서울대학교 대학원 : 보건대학원 보건학과, 2019. 2. 고광표.Metabolic syndrome (MetS) including obesity and diabetes is one of the major global public health concerns. Recent studies suggest a possible role of gut microbiota in MetS, demonstrating that microbial alteration could affect energy intake by changing the digestive capacity as well as induce low-grade inflammation by metabolic endotoxemia. Meanwhile, with the importance of gut microbiota on MetS being emphasized, there has also been considerable evidence that exposure to environmental chemicals could be associated with MetS. In particular, the elements including essential minerals and metals play an important part in host metabolic homeostasis. Most elements studies on MetS were conducted on the host side without considering the role of gut microbiota, and have only been done with a few elements such as As and Cd. Thus, in this thesis, we studied the relationships of fecal elements with gut microbiota and MetS. First, we elucidated the association of various fecal elements with human gut microbiome and MetS status. We analyzed 29 elements from human feces samples and performed the correlation study between fecal elements, MetS, and gut microbiota. Beryllium (Be), calcium (Ca), and thallium (Tl) had the significant odds ratios for MetS, and MetS-related biomarkers had a significant positive correlation with Be and Tl, whereas Ca showed a significant negative correlation with those. Be and Tl also had the high relationships with the reduction of microbial diversity. Besides, Be and Ca showed conflicting associations with the MetS-related gut microbiota, Akkermansia and Bifidobacterium. We additionally confirmed that the abundance of two elements had a link with gut microbial functions using metagenomics-based or metabolomics-based function predictions. Second, we evaluated whether a low dose of Be exposure could affect gut microbial changes and promote MetS. In mice fed a high fat diet (HFD), 30 ppb of Be exposure resulted in significant body weight gain as well as adiposity increase, whereas normal diet groups did not show obvious changes. The shifts in the gut microbial community were caused by the exposure to both 3 ppb and 30 ppb of Be in HFD groups, with the microbial diversity reduction and the significant decrease of Akkermansia. In vitro human feces culture experiments also showed the reduction of species evenness and Mets-related Bifidobacterium due to a low dose of Be. The changes in cecal short chain fatty acids (SCFAs) profiles (increase in acetate, but decrease in propionate and butyrate) in HFD groups were related to appetite increase with a significant decrease in the anorexigenic hormone. Furthermore, the expression of inflammation-related genes and plasma LPS levels significantly increased in HFD groups, showing the evidence of metabolic endotoxemia and low-grade inflammation. Third, we assessed and compared the effects of two different Ca supplements, Ca-carbonate and Ca-citrate, on the improvement of host metabolic homeostasis in HFD mice. High concentration of Ca-citrate supplementation showed significant decreases in body weight and MetS-related plasma biomarkers compared to Ca-carbonate groups. Although both Ca-carbonate and Ca-citrate supplementations led to similar changes in gut microbial composition, Ca-citrate groups showed more noticeable differences in the metabolic production of SCFAs, especially propionate, with the increase in anorexigenic GLP-1 gene expression. Also, Ca-citrate groups significantly reduced the expression of inflammatory cytokines, with the increases in the expression of the mucosal barrier function-related genes. In conclusion, this study indicated that fecal elements were highly associated with MetS, and some elements had strong relationships with gut microbiota. Exposure to Be could affect the changes in gut microbial composition and worsen MetS in HFD mice even at very low concentrations. Ca supplementations effectively helped attenuate MetS with the increase in MetS-suppressing microbiota, and Ca-citrate showed greater improvement in MetS compared to Ca-carbonate. These data suggest that fecal elements analysis will provide important information to understand the relationship between gut microbiota and diseases and further research will be required in the future.비만과 당뇨 등을 포함한 대사증후군은 전세계적으로 주요 공중 보건 이슈 중 하나이다. 최근 보고되고 있는 연구들은 장내 미생물이 에너지 섭취, 대사 내독성증 등에 영향을 주어 대사증후군을 유발할 수 있음을 보여준다. 한편, 환경 속 화학물질에 대한 노출이 대사증후군과 연관될 수 있다는 다양한 증거들이 함께 보고되고 있다. 특히, 무기질, 금속을 포함하는 장내 원소들은 생물체의 대사 과정에서 중요한 역할을 한다. 지금까지 대사증후군에 각 원소들이 미치는 영향에 대한 연구는 대부분 장내 미생물의 역할을 고려하지 않고 주로 호스트 관점에서 수행되었으며, 비소, 카드뮴과 같은 소수의 원소들에 연구가 집중되어왔다. 따라서, 본 연구에서는 다양한 장내 원소에 대하여 장내 미생물, 대사증후군과의 연관성을 규명하고 이들 사이의 인과관계를 밝히고자 하였다. 먼저, 우리는 장내 원소가 장내 미생물 군집 그리고 대사증후군과 연관성을 나타내는지 확인하였다. 인체 대변 시료로부터 29개의 장내 원소 함량을 측정하였고, 대사증후군, 장내 미생물과의 상관관계 분석을 수행하였다. 베릴륨(Be), 칼슘(Ca), 탈륨(Tl)은 유의적인 대사증후군 odds ratio를 나타냈고, 대사증후군과 관련된 각각의 세부 바이오마커와도 유의적인 상관관계를 보였다. 또한 Be, Tl은 미생물 다양성 감소와 높은 연관성을 가지고 있었다. 특히, Be와 Ca는 대사증후군 억제 효과가 있는 것으로 보고되고 있는 Akkermansia, Bifidobacterium 등의 장내 미생물 분포에서 서로 음과 양의 상반된 연관성을 보여주었다. 또한 두 장내 원소는 장내 환경에서 미생물 대사 기능에도 서로 다르게 영향을 주었다. 둘째, 저농도 Be 노출이 장내 미생물 변화를 유도하고 대사증후군을 악화시킬 수 있는지를 평가했다. 고지방 식이 생쥐의 경우, 30 ppb의 Be 노출이 유의적인 체중 및 지방 증가로 이어졌지만, 일반 식이 그룹은 분명한 변화를 나타내지 않았다. 고지방 식이와 함께 3 ppb와 30 ppb의 Be에 노출시켰을 때 미생물 다양성 감소, Akkermansia의 현저한 감소와 같은 장내 미생물 변화가 나타났다. 인체 대변 시료 배양 실험에서도 저농도 Be 처리 시 미생물 다양성 감소와 Bifidobacterium의 감소가 야기되었다. 이밖에도 고지방 식이 그룹에서 베릴륨 노출에 의해 야기된 유의적인 단쇄 지방산 변화는 거식성 감소 및 식욕 증가와 관련이 있었고, 염증 관련 유전자의 유의적인 발현 증가와 혈중 LPS의 상승은 대사 내독소증과 만성 염증이 대사증후군을 더욱 악화시켰을 가능성을 보여주었다. 셋째, Ca-carbonate와 Ca-citrate가 고지방 식이 생쥐의 대사 항상성 개선에 미치는 영향을 평가하고 비교하였다. 높은 농도의 Ca-citrate 보충제는 Ca-carbonate에 비해 현저한 체중 감소와 함께 대사증후군 관련 혈장 바이오마커의 유의적인 변화를 나타냈다. Ca-carbonate와 Ca-citrate 보충제는 장내 미생물 구성에는 서로 유사한 변화를 가져왔지만, Ca-citrate 그룹이 단쇄 지방산 중 특히 식욕억제 호르몬인 GLP-1 분비와 관련이 있는 propionate를 더 현저하게 증가시켰다. 또한 Ca-citrate 그룹은 점막 기능 관련 유전자 발현 증가와 함께 염증성 사이토카인 유전자의 발현과 혈중 LPS 농도를 유의적으로 감소시켰다. 결론적으로, 본 연구는 장내 원소가 대사증후군과 높은 관련성을 가지며, Be, Ca와 같은 일부 원소는 장내 미생물의 군집 형성 및 기능성에 강한 상관관계를 가지고 있음을 보여주었다. 실제로 Be에 대한 노출은 고지방 식이 생쥐에서 장내 미생물 구성 및 대사에 영향을 줌과 동시에 매우 낮은 농도에서도 대사증후군을 악화시킬 수 있었다. Ca 보충제는 대사증후군 억제 효능이 알려진 장내 미생물의 증가와 함께 대사증후군 지연에 도움을 주었고 Ca-citrate가 Ca-carbonate에 비해 더 좋은 효과를 나타내었다. 이러한 연구결과는 장내 미생물과 질병 사이의 관계를 이해하는데 장내 원소 분석이 중요한 정보를 제공해줄 수 있음을 보여준다. 향후 이와 관련된 더욱 다양한 후속 연구가 필요할 것이다.ABSTRACT i CONTENTS iv LIST OF TABLES vi LIST OF FIGURES vii LIST OF ABBREVIATIONS xi CHAPTER I. 1 BACKGROUNDS Gut Microbiome Research 2 Metabolic Syndrome and Gut Microbiome 3 Elements and Metabolic Syndrome 5 Objectives and Hypotheses 8 CHAPTER II. ９ ASSOCIATIONS OF FECAL ELEMENTS WITH METABOLIC SYNDROME, HUMAN GUT MICROBIOME, AND THEIR FUNCTION Introduction １０ Materials and Methods １２ Results ２０ Discussion ４１ CHAPTER III. ４６ LOW DOSE OF BERYLLIUM INFLUENCES GUT MICROBIOTA PROMOTING METABOLIC SYNDROME Introduction ４７ Materials and Methods ４９ Results ５５ Discussion ８２ CHAPTER IV. ８９ CALCIUM SUPPLEMENTS IMPROVE HOST METABOLIC HOMEOSTASIS IN HIGH FAT DIET MICE WITH CHANGES IN GUT MICROBIOTA Introduction ９０ Materials and Methods ９２ Results ９６ Discussion １１２ CHAPTER V. １１８ CONCLUSIONS REFERENCES １２２ APPENDICES １４２ 국문초록 １５２Docto