1,654 research outputs found
Interview with Jean Francois Revel, author
No full textJean Francois Revel, the author of Without Marx or Jesus, has been quoted as saying, "The United States is now a microcosm for all of the problems man faces." In this interview with Meredith Watts, he discusses a new kind of revolution which could produce successful change without violent upheavalGrayscaleSoun
ChemInform Abstract: Design and Synthesis of Functional Molecular Architecture
No full textThe central theme of the research conducted by the Diederich group is the creation of functional molecular architecture by design and advanced synthesis. Function is explored through interdisciplinary study, wherein national and international collaborations provide fertile grounds. Four areas of research are pursued: (i) In covalent fullerene chemistry, regio- and stereoselective templated synthesis protocols are developed to prepare three-dimensional building blocks for supramolecular construction and advanced materials such as electrochemical ion sensors. (ii) Advanced materials are also targeted by acetylenic scaffolding. Macrocyclic scaffolds of interest include perethynylated expanded radialenes featuring large π-conjugated all-carbon cores. Acyclic scaffolds such as monodisperse poly(triacetylene) (PTA)oligomers, with linear, π-conjugated allcarbon backbones expanding up to 18 nm length, are also actively investigated. Arylated tetraethynylethenes undergo photochemical cis→ trans and trans→ cis isomerization without competing thermal isomerization pathways – promising applications of these materials are foreseen in optical switching and memory storage devices. (iii) In supramolecular chemistry, dynamic receptors are developed with the potential to function as \u27molecular grippers\u27 on the single molecule level. Dendritic porphyrins are efficient models of hemoglobin and myoglobin and bind O2 strongly and reversibly. They are also ideal model systems to explore the influence of the protein shell on the redox potential ofthe FeIII/II couple in electron transfer proteins such as the cytochromes. (iv) Finally, the detailed understanding of molecular recognition principles generated in the studies with artificial receptors provides the basis for a modern medicinal chemistry program aimed at the structure-based de novo design of nonpeptidic enzyme inhibitors
Beauregard House
No full textGeneral view; The architect Francois Correjolles, whose creole French family emigrated from St. Domingue (Haiti), added new American Federal elements while preserving some of the traditional creole plan. The Beauregard-Keyes House, built in 1826 for wealthy auctioneer Joseph Le Carpentier, is a fine example of a raised, center-hall house. It is named for two of its former tenants, Confederate General Pierre Gustave Toutant (P.G.T.) Beauregard and author Frances Parkinson Keyes. General Beauregard lived in the home from 1866 to 1868 while he was president of the New Orleans, Jackson, and Great Northern Railroad. The home features twin curved staircases, leading to a Tuscan portico. The garden's design duplicates the original 1865 plans. (Common Routes: St. Domingue-Louisiana exhibition, 2006) Source: Historic New Orleans Collection [website]; http://www.hnoc.org/ (accessed 1/24/2008
반합성천연물 TMQ0153 (Tetrahydrobenzimidazole)이 일으키는 세포사멸과 만성 백혈병 치료법 연구
No full text학위논문(박사)--서울대학교 대학원 :약학대학 약학과,2020. 2. Marc Francois Diederich.Abstract in Korean (국문초록)
새로운 반합성 천연물 TMQ (Unaromatized Tetrahydrobenzimidazole)는 p-Benzoquinone 과 N-Arylamidines에서 합성된 물질이며, 만성 골수성 백혈병 (CML) 에서 다양한 세포 사멸 형태인 apoptosis, necroptosis 및 Autophagy를 동시에 유발하는 새로운 저분자 천연물질이다. 오랫동안 Programmed cell death에 있어서 apoptosis가 유일한 것으로 여겨져 왔으나 최근에는 necrosis과정에도 programmed necrosis 또는 necroptosis라 불리는 세포사멸이 존재한다는 것이 밝혀졌다. 최근 necroptosis에는 RIP1과 RIP3가 중요 조절인자임이 알려지고 있으나 현재까지 관련 연구의 많은 부분이 미미한 수준이고 많은 연구가 필요한 분야임을 확인할 수 있었다. 또한 기존에 알려지지않은 autophagy가 apoptosis와 necroptosis에 어떤 작용을 하는지에 대한 연구가 필요하며, 특이적이고 결정적인 조절인자의 차이점에 대하여 많은 연구가 필요한 실정이다. 선행연구를 통해 TMQ 시리즈 중 건강한 PBMC (A peripheral blood mononuclear cell) 세포에서는 독성을 일으키지 않으며 여러 종류의 암세포에서 특이적으로 세포독성을 일으키는 TMQ0153을 선별하였다.
따라서 TMQ0153을 통해 낮은 농도에서 유도된 canonical-programmed 세포사멸은 caspase에 의존적이지만 높은 농도에서 유도된 non-canonical-programmed 세포사멸은 caspase와 무관하며 미토콘드리아의 기능장애를 거쳐 ROS를 축적시켜 그 결과 세포스트레스와 다른 미토콘드리아의 손상을 일으킴을 seahorse XFp cell mito stress 및 FACS를 통해 입증하였고, 세포스트레스의 작용으로 necroptosis 세포사멸이 일어나기 전에 autophagy가 먼저 일어남을 공초점 형광 현미경과 관련 단백질 LC3과 p62의 western blotting을 통해 관찰하였다. 또한 autophagy의 핵심 단백질 Beclin-1의 knockdown을 통해 억제시킨뒤 TMQ0153을 투여하였을때 세포사멸이 더 증가하였으며 이는 암세포를 민감하게 (Sensitization)하는 것을 밝혀내었다. 전자 현미경 이미지를 분석함으로써 autophagy가 일어나는 시점에서 미토콘드리아의 팽창 및 autophagosome 의 형성을 추가 관찰하였고, 세포스트레스의 요소로 세포질의 Ca2+ 축적, 세포내 GSH (Glutathione)의 감소 및 Lysosomal membrane potential (LMP) 의 증가를 FACS와 형광 현미경을 통해 분석하였다. 세포스트레스의 증가 및 necroptosis와 관련있는 특이적 PARP-1 (C2-10), RIP1 단백질의 검출, 세포내 ATP의 급격한 감소가 necroptosis의 원인임을 알 수 있었고 이러한 효과는 necrostatin-1에 의해 저해됨을 증명하였다. 이어서 TMQ0153 에 의해 유도되는 necroptosis는 mitochondria membrane permeabilization (MMP) 를 증가시키고 N-Acetyl Cysteine (NAC)에 의해 세포사멸 및 미토콘드리아가 보존되는 것을 입증할 수 있었다.
최근 선행연구에 따르면 RIP3단백질은 necroptosis를 조절 하는 핵심 단백질로 알려져 있는데, 많은 암세포에서 현저히 감소되어 새로운 암세포 사멸 전략으로 활용하는데 한계가 있었다. 또한 암세포의 특징중 하나인 apoptosis에 대한 저항성은 암세포가 항암제에 저항할 수 있게 함으로써, 암세포 사멸 전략의 한계점을 가져왔다. 따라서 이를 극복할 Necroptosis를 일으키는 약물의 기전연구를 통해 약물의 저항성을 극복하는 방법을 제시할 수 있었다. 탈메틸화제 (5-aza-2'-deoxycytidine; 5aza)를 투여하여 암발생으로 감소된 RIP3 단백질을 복구한 뒤 TMQ0153을 투입한 결과, TMQ0153만 투여한 암세포보다 더 많은 necroptosis를 관찰할 수 있었음을 형광현미경을 통해 확인하였다. TMQ0153이 처리된 Necroptosis가 일어난 세포로부터 HMGB1의 방출과 세포 외 ATP의 증가, Ecto-Calreticulin와 ERp57 의 세포막 노출 및 증가를 관찰함으로써 이 천연물질의 면역세포사멸과 이에 따른 중계연구의 가능성을 제시할 수 있었다. 마지막으로 TMQ0153가 콜로니와 In vivo 제브라피쉬 xenograft 모델에서 종양형성의 발달을 저해하는 것을 추가적으로 관찰하였다. 따라서 본 연구를 통해 제시된 다양한 세포사멸의 현상을 조절하는 세포스트레스의 원인 분석 및 항암제의 분자 작용과 세포사멸 제어 기전을 규명하여 효과적인 암 치료제 개발에 활용하고자 한다.
주요어
세포스트레스, 미토콘드리아, 활성산소, 만성 골수성 백혈병, 프로그램된 세포사멸Overall Abstract
Tetrahydrobenzimidazole TMQ0153 induces autophagy followed by controlled necrosis via oxidative stress induction in chronic myeloid leukemia cell lines
Sungmi Song
College of Pharmacy
Department of Pharmacy Graduate School
Advisor: Prof. Marc Francois Diederich
Chronic myeloid leukemia (CML) is characterized by the Philadelphia (Ph) chromosome with a t(9;22)(q34;q11) reciprocal translocation in single hemopoietic stem cells (HSC) and resulting in expression of the BCR-ABL chimeric oncoprotein. This abnormal gene stimulates the production of reactive oxygen species (ROS). ROS levels increase with CML progression and induce BCR-ABL self-mutagenesis. Imatinib and other tyrosine kinase inhibitors (TKIs) such as dasatinib and nilotinib radically improved the diseases outcome, but TKI-resistance is still considered as a major problem. TKI resistance can be associated with even higher ROS production than in TKI-sensitive cells. So far, a role for redox changes in apoptosis has been established; however, several new modalities of regulated cell death have been recently described, The importance of ROS production as well as cellular stress are being actively investigated. Taken together, we investigate here the role of ROS and redox changes in the activation and execution of regulated necroptosis. We also discuss how cellular stress and redox modulation by TMQ0153 concentration-dependently leads to different cell death modalities including controlled necrosis in CML cell models.Chapter 1. Redox biology of regulated cell death in cancer: A focus on necroptosis 1
1.1. Abstract 2
1.2. Introduction 3
1.3. Regulated cell death and ROS 8
1.4. Redox cancer therapy 16
1.5. Future direction 21
Chapter 2. Tetrahydrobenzimidazole TMQ0153 triggers apoptosis, autophay and necroptosis crosstalk in chronic myeloid leukemia 22
2.1. Abstract 23
2.2. Introduction 24
2.3. Material and methods 26
2.4. Results 34
2.5. Discussion 79
References 84
Abstract in Korean (국문초록) 102Docto
Alien theory : the decline of materialism in the name of matter
No full textThe thesis tries to define and explain the rudiments of a 'nonphilosophical'
or 'non-decisional' theory of materialism on the basis of a
theoretical framework provided by the 'non-philosophy' of Francois
Laruelle. Neither anti-philosophical nor anti-materialist in character, non-materialism
tries to construct a rigorously transcendental theory of matter by
using certain instances of philosophical materialism as its source material.
The materialist decision to identify the real with matter is seen to retain a
structural isomorphy with the phenomenological decision to identify the real
with the phenomenon. Both decisions are shown to operate on the basis of a
methodological idealism; materialism on account of its confusion of matter
and concept; phenomenology by virtue of its confusion of phenomenon and
logos. By dissolving the respectively 'materiological' and
'phenomenological' amlphibolies which are the result of the failure to effect a
rigorously transcendental separation between matter and concept on the one
hand; and between phenomenon and logos on the other, non-materialist
theory proposes to mobilise the non-hybrid or non-decisional concepts of a
'matter-without-concept' and of a 'phenomenon-without-logos' in order to
effect a unified but non-unitary theory of phenomenology and materialism.
The result is a materialisation of thinking that operates according to matter's
foreclosure to decision. That is to say, a transcendental theory of the
phenomenon that licenses limitless phenomenological plasticity,
unconstrained by the apparatus of eidetic intuition or any horizon of
apophantic disclosure; yet one which is simultaneously a transcendental
theory of matter, uncontaminated by the bounds of empirical perception and
free of all phenomenological circumscription
Supramolecular [60]fullerene chemistry on surfaces
No full textThis critical review documents the exceptional range of research avenues in [60]fullerene-based monolayers showing unique and spectacular physicochemical properties which prompted such materials to have potential applications in several directions, ranging from sensors and photovoltaic cells to nanostructured devices for advanced electronic applications, that have been pursued during the past decade. It illustrates how progress in covalent [60]fullerene functionalisation led to the development of spectacular surface-immobilised architectures, including dyads and triads for photoinduced electron and energy transfer, self-assembled on a wide variety of surfaces. All of these molecular assemblies and supramolecular arrays feature distinct properties as a consequence of the presence of different molecular units and their spatial arrangement. Since the properties of [60]fullerene-containing films are profoundly controlled by the deposition conditions, substrate of adsorption, and influenced by impurities or disordered surface structures, the progress of such new [60]fullerene-based materials strongly relies on the development of new versatile and broad preparative methodologies. Therefore, the systematic exploration of the most common approaches to prepare and characterise [60]fullerene-containing monolayers embedded into two- or three-dimensional networks will be reviewed in great detail together with their main limitations. Recent investigations hinting at potential technological applications addressing many important fundamental issues, such as a better understanding of interfacial electron transfer, ion transport in thin films, photovoltaic devices and the dynamics associated with monolayer self-assembly, are also highlighted
The ethical and moral-based dimension of leadership in CSR-oriented strategies and sustainable entrepreneurship
No full textThis chapter addresses the theme of leadership and its influence on corporate social
responsibility (CSR) and sustainability-oriented strategies. Specifically, it aims to analyse,
through a deductive and literature-based approach, the relevance of the ethical and moral
leadership models with respect to the diffusion of CSR and sustainable entrepreneurship. Linking ethical and moral-based leadership to the CSR and sustainable entrepreneurship discourse allows us to point out the relevance of an authentic orientation in supporting
change and fostering sustainable entrepreneurship The theoretical construct of responsible and sustainable leadership derives from the
intersection of the moral-based leadership concepts with those of CSR and sustainable
entrepreneurship..Drawing from these premises, this chapter seeks to identify leadership models and
attributes consistent with (and necessary to develop) an authentic CSR-oriented strategy
and able to foster sustainable entrepreneurship.
Accordingly, in this chapter, we argue that leadership represents a key aspect that
warrants more research within both CSR and sustainable entrepreneurship studies. The
research questions that orients this study can be summarised as follows: Which leadership
models favour authentic CSR practices? Are moral, ethical-based and virtues-based models
of leadership effective in developing CSR and fostering sustainable entrepreneurship?
These questions guide the critical review of the different leadership approaches, bringing
attention to the models that are most coherent in regard to the actual socio-economic
context which requires managers and entrepreneurs to govern the internal and external
complexity and actively contribute to sustainability. The methodological approach is
mainly based on a literature review that surveys critical points in current literature that is
relevant to the topic.
The work is structured as follows. First, we offer an analysis of the leadership theoretical
framework in the context of the CSR debate. We begin with a brief methodological
note, followed by an analysis of the antecedents of CSR and sustainable entrepreneurship
in terms of values and virtues.
Second, a review of relevant literature on leadership approaches and models consistent
with the CSR and sustainable entrepreneurship discourse is presented, emphasising the relationship between transformational, moral and virtues-based leadership and
CSR-oriented strategies and sustainable entrepreneurship. Drawing from the analysis,
four main propositions are introduced. The final sections illustrate the propositions and
summarise the implications and limitations of the study
The medieval forms and meanings of Francois: The political and cultural vicissitudes of an ethnonym
No full textThe article looks at the evolution of the ethnonym Francois in the Middle Ages and its significance to Germanic peoples known as Franks in the context of their cross-cultural relations with Muslim, Byzantine and British people. The author analyzes chronicles of the First Crusade and examines the use of Francois as an exonym and an autonym, and its role in the development of the French identity
OT-55와 후성 유전 조절 물질 martinostat의 면역 세포 사멸을 통한 imatinib 민감성 및 저항성 만성 골수성 백혈병 (chronic myeloid leukemia)의 표적 항암 치료
No full text학위논문 (박사)-- 서울대학교 대학원 : 약학대학 약학과, 2018. 8. Marc Francois Diederich.면역 원성 세포 사멸 (Immunogenic cell death, ICD)은 면역 체계의 적응력있는 팔에 관여하는 일련의 사건으로 나타났습니다. 초기 자극에 따라 암 세포 사멸은 세포 표면의 변화와 손상 관련 분자 패턴의 방출과 관련된 일련의 사건을 특징으로하는 ICD로 정의 할 수 있습니다. 이 현상은 암에 대항하여 작용하는 면역계의 대 식세포 및 수지상 세포를 관여시킵니다.
본 연구에서는 만성 골수성 백혈병 (CML) 세포에서 bis (4- hydroxycoumarin) 유도체 인 OT-55와 histone deacetylase inhibitor martinostat가 소포체 ER 응력에 따라 ICD를 유발한다는 것을 발견했다. 우리는 T315I 돌연변이가있는 세포에서 ICD 유도의 첫 번째 시연을 제공합니다. OT-55는 종양 괴사 인자 α에 의해 유도 된 핵 인자 -κB의 활성화를 억제하고, 생체 내 제브라 피쉬 모델에서 CML 일차 폭발에 의해 종양 형성을 억제하기 위해 이마티닙과 함께 사용될 때 상승 효과를 나타냈다. 또한 OT-55는 T315I 돌연변이 세포에서 omacetaxine과 상승 작용하여 골수 세포 백혈병 1의 발현을 억제함으로써 세포 사멸을 유발한다. OT-55는 상승 된 알데하이드 탈수소 효소 활성 및 미토콘드리아 산화 대사를 약화시킴으로써 줄기 유사 특성을 갖는 CML 세포를 표적으로 삼았다.
vorinostat와 비교하여, 마티노 스탯은 아세틸 화 수준을 증가시키고, 세포 증식, 생존력 및 CML 세포의 콜로니 형성을 훨씬 낮은 농도로 증가시켰다. 이마티닙 감수성 및 내성 CML 세포 모두에서 이마 닙과 함께 시너지 효과가 나타났다.INTRODUCTION 1
1. Cancer-associated cell death 1
2. Immune surveillance against cancer 4
3. Immunogenic cell death 5
4. Chronic myeloid leukemia (CML) 10
5. Immune surveillance in CML 11
CHAPTER 1 13
1. Purpose of this study 14
2. Materials and methods 16
2.1. Chemistry 16
2.2. Cell culture and treatment 16
2.3. Human primary sample 17
2.4. Cell Proliferation and viability 17
2.5. Cell cycle distribution 18
2.6. Protein extraction and western blot 18
2.8. Colony formation assay 19
2.9. Transient transfection and luciferase reporter gene assay 20
2.10. Analysis of immunogenic cell death markers calreticulin and ectopic expression of ERp57 20
2.11. Detection of HMGB1 release 20
2.12. Phagocytosis of OT-55 treated cell by macrophage 21
2.13. Detection of cancer stem cells 21
2.14. Measurement of mitochondrial metabolic activity 22
2.15. In vivo toxicity assay 22
2.16. Zebrafish xenograft assay 22
2.17. Transmission electron microscopy (TEM) 23
2.18. Statistical analysis and bioinformatics 24
3. Results 25
3.1. OT-55 inhibits the proliferation and viability of imatinib-sensitive or -resistant CML cell lines. 25
3.2. OT-55 shows differential toxicity in healthy PBMCs and no acute and chronic toxicity in mice. 26
3.3. OT-55 inhibits CML cell cycle and colony formation, and induces apoptosis. 27
3.4. OT-55 induces ER stress response in CML. 29
3.5. OT-55 induces ectopic-calreticulin, ectopic ERp57 and HMGB1 release in CML. 30
3.6. OT-55 promotes phagocytosis of imatinib-sensitive and -resistant CML. 31
3.7. OT-55 shows synergistic cytotoxicity in combination with imatinib. 33
3.8. OT-55 and imatinib combination show mitochondrial damage and onset of apoptosis. 35
3.9. OT-55 and imatinib abrogate tumor formation in zebrafish xenograft assay. 36
3.10. OT-55 inhibits tumor necrosis factor α (TNFα)-induced NF-кB activation in K562 cells. 38
3.11. OT-55 shows synergistic cytotoxicity in combination with omacetaxine on KBM-5-T315I and K562R cells. 40
3.12. OT-55 inhibits ALDH positive cells and mitochondrial oxidative metabolism of ALDH high K562R cells. 42
3.13. OT-55 and omacetaxine abrogate tumor formation of K562 R cells in zebrafish xenograft assay. 44
4. Discussion 45
CHAPTER 2 50
1. Purpose of this study 51
2. Material and methods 52
2.1. Cell culture and treatment 52
2.2. Cell proliferation and viability 53
2.3. Cell cycle distribution 53
2.4. Protein extraction and western blot 54
2.5. Evaluation of apoptosis 54
2.6. Colony formation assay 55
2.7. Analysis of immunogenic cell death markers calreticulin and ectopic expression of ERp57 55
2.8. Detection of HMGB1 release 56
2.9. Statistical analysis 56
3. Results 57
3.1. Martinostat inhibits cell proliferation in la ow concentration range compared to vorinostat 57
3.2. Martinostat inhibits CML cell viability in low concentration range compared to vorinostat 58
3.3. Martinostat and vorinostat inhibit CML colony formation 59
3.4 . Martinostat inhibits CML cell cycle 60
3.5. Martinostat showed ectopic expression of calreticulin and ERp57 61
3.6. Martinostat in combination with imatinib shows caspase dependent apoptosis in CML. 62
3.7. Martinostat shows synergistic cytotoxicity in combination with imatinib in CML. 64
3.8. Martinostat re-sensitizes imatinib-resistant cells to imatinib treatment and shows synergistic cytotoxicity 65
3.9. Martinostat in combination with imatinib inhibits colony formation of imatinib-sensitive and resistant CML 66
4. Discussion 68
REFERENCES 71
ABSTRACT IN KOREAN 81Docto
Henri Matisse Drawing: An Eye-Hand Interaction Study Based on Archival Film.
No full textHenri Matisse (1869-1954) attached fundamental importance to his drawings, in particular to the famous Themes et Variations series. These were accomplished following a precise method, starting with arduous life studies and evolving into brilliant spontaneous drawings. A 1946 archival documentary film showing the artist drawing four portraits of his grandson Gerard was shot in such a way as to allow the present author to undertake a detailed eye-hand interaction analysis of the drawing process.
It was found that Matisse’s temporal working rhythm and use of motor memory resulted in a more direct approach than that used by most painters. Taken together with remarks the artist made throughout his lifetime, these results provide a cognitive interpretation of his drawing method
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