Refine
Year of publication
Document Type
- Article (16363)
- Part of Periodical (2735)
- Working Paper (2364)
- Preprint (2319)
- Doctoral Thesis (2082)
- Book (1738)
- Conference Proceeding (1234)
- Part of a Book (1071)
- Report (471)
- Review (166)
Language
- English (30711) (remove)
Has Fulltext
- yes (30711) (remove)
Keywords
- taxonomy (752)
- new species (451)
- morphology (180)
- Deutschland (142)
- Syntax (126)
- Englisch (120)
- distribution (118)
- biodiversity (104)
- inflammation (101)
- Deutsch (98)
Institute
- Medizin (5467)
- Physik (4299)
- Wirtschaftswissenschaften (1935)
- Frankfurt Institute for Advanced Studies (FIAS) (1882)
- Biowissenschaften (1574)
- Informatik (1522)
- Center for Financial Studies (CFS) (1504)
- Biochemie und Chemie (1097)
- Sustainable Architecture for Finance in Europe (SAFE) (1083)
- House of Finance (HoF) (715)
Professor Darah turned seventy on Wednesday November 22, 2017 and to celebrate his very productive career, his colleagues and many of those he has mentored thought it appropriate to mark his official exit from the university in a dignified way by commissioning for publication, in the now acceptable festschrift tradition, the highly compelling and outstanding collection of essays titled: Scholarship and Commitment: Essays in Honour of G.G. Darah. The book is a ground-breaking collection of essays; some are couched as tributes to the ebullient celebrant, there are others on more serious discourses in the areas of literary theories and criticism, language and linguistics, popular literature and politics, the African woman, identity and contemporary realities, oral literature, the news media and cultural studies. The essays, on their own, attest to the vivacity and liveliness as well as the encouraging state of health of publishing in the Nigerian academia, which in this collection alone, parades forty-two essays in different fields or discourses.
This is a story of Nigeria, told from the inside. After a successful career in the private sector, Nasir El-Rufai rose to the top ranks of Nigeria's political hierarchy, serving first as the privatization czar at the Bureau for Public Enterprises and then as Minister of the Federal Capital Territory of Abuja under former President Olesegun Obasanjo. In this tell-all memoir, El-Rufai reflects on a life in public service to Nigeria, the enormous challenges faced by the country, and what can be done while calling on a new generation of leaders to take the country back from the brink of destruction. The shocking revelations disclosed by El-Rufai about the formation of the current leadership and the actions of prominent statesmen make this memoir required reading for anyone seeking to understand the dynamics of power politics in Africa's most populous nation.
All over Africa, an explosion in cultural productions of various genres is in evidence. Whether in relation to music, song and dance, drama, poetry, film, documentaries, photography, cartoons, fine arts, novels and short stories, essays, and (auto)biography; the continent is experiencing a robust outpouring of creative power that is as remarkable for its originality as its all-round diversity. Beginning from the late 1970s and early 1980s, the African continent has experienced the longest and deepest economic crises than at any other time since the period after the Second World War. Interestingly however, while practically every indicator of economic development was declining in nominal and/ or real terms for most aspects of the continent, cultural productions were on the increase. Out of adversity, the creative genius of the African produced cultural forms that at once spoke to crises and sought to transcend them. The current climate of cultural pluralism that has been produced in no small part by globalization has not been accompanied by an adequate pluralism of ideas on what culture is, and/or should be; nor informed by an equal claim to the production of the cultural - packaged or not. Globalization has seen to movement and mixture, contact and linkage, interaction and exchange where cultural flows of capital, people, commodities, images and ideologies have meant that the globe has become a space, with new asymmetries, for an increasing intertwinement of the lives of people and, consequently, of a greater blurring of normative definitions as well as a place for re-definition, imagined and real. As this book - Contemporary African Cultural Productions - has done, researching into African culture and cultural productions that derive from it allows us, among other things, to enquire into definitions, explore historical dimensions, and interrogate the political dimensions to presentation and representation. The book therefore offers us an intervention that goes beyond the normative literary and cultural studies' main foci of race, difference and identity; notions which, while important in themselves might, without the necessary historicizing and interrogating, result in a discourse that rather re-inscribes the very patterns that necessitate writing against. This book is an invaluable compendium to scholars, researchers, teachers, students and others who specialize on different aspects of African culture and cultural productions, as well as cultural centers and general readers.
There is a general agreement that piracy; counterfeiting and passing off are unfair. However, there is often surreptitious - or even open - sympathy for, say, those who purchase counterfeit designer fashions or the latest technical gadgets. The pirate is even sometimes represented as a daring evil hero. In this book, Prof. Dora Nkem Akunyili, Director General of Nigeria's National Agency for Food and Drug Administration and Control, presents a unique study of a global phenomenon in which law-breaking and profiteering prevail at the cost of human health and life - and of the ways in which this can be fought by appropriate legislation, regulation and enforcement.
The Botsotso literary journal started in 1996 as a monthly 4 page insert in the New Nation, an independent anti-apartheid South African weekly and reached over 80,000 people at a time largely politisized black workers and youth with a selection of poems, short stories and short essays that reflected the deep changes taking place in the country at that time. Since the closure of the New Nation in 1999, the journal has evolved into a stand-alone compilation featuring the same mix of genres, and with the addition of photo essays and reviews. The Botsotso editorial policy remains committed to creating a mix of voices which highlight the diverse spectrum of South African identities and languages, particularly those that are dedicated to radical expression and examinations of South Africa's complex society.
The Botsotso literary journal started in 1996 as a monthly 4 page insert in the New Nation, an independent anti-apartheid South African weekly and reached over 80,000 people at a time ? largely politisized black workers and youth ? with a selection of poems, short stories and short essays that reflected the deep changes taking place in the country at that time. Since the closure of the New Nation in 1999, the journal has evolved into a stand-alone compilation featuring the same mix of genres, and with the addition of photo essays and reviews. The Botsotso editorial policy remains committed to creating a mix of voices which highlight the diverse spectrum of South African identities and languages, particularly those that are dedicated to radical expression and examinations of South Africa's complex society.
Most Nigerians, when they talk about Nigeria, will always refer to her with bubbling jingoism as 'giant of Africa' or 'our great nation, Nigeria' but fail to ask 'giant of what?' Goodness or Evil? Productivity or Consumption? Success or Failure? Meritocracy or Mediocrity? Hollowness or Substance? Capturing the 'mood of the nation' this book offers diagnosis on the country which are broad-based, instructive and well presented. Part I outlines the developmental stages of Nigeria while Part II gives an in depth diagnosis of the major problems besetting Nigeria, following Part III gives examples of nations and leadership traits Nigeria could emulate.
An important feature of Ghanaian tertiary education is the foundational African Studies Programme which was initiated in the early 1960s. Unfortunately hardly any readers exist which bring together a body of knowledge on the themes, issues and debates which inform and animate research and teaching in African Studies particularly on the African continent. This becomes even more important when we consider the need for knowledge on Africa that is not Eurocentric or sensationalised, but driven from internal understandings of life and prospects in Africa. Dominant representations and perceptions of Africa usually depict a continent in crisis. Rather than buying into external representations of Africa, with its 'lacks' and aspirations for Western modernities, we insist that African scholars in particular should be in the forefront of promoting understanding of the pluri-lingual, overlapping, and dense reality of life and developments on the continent, to produce relevant and usable knowledge. Continuing and renewed interest in Africa's resources, including the land mass, economy, minerals, visual arts and performance cultures, as well as bio-medical knowledge and products, by old and new geopolitical players, obliges African scholars to transcend disciplinary boundaries and to work with each other to advance knowledge and uses of those resources in the interests of Africa's people.
Theatre and drama are very much part of our every day lives. These four plays: Belonging by Mirirai Moyo, When I Meet my Mother by Kathleen McCreery, In the Continuum by Danai Gurira and Nikkole Salter, and Power Failure by Jide Afoylan reveal the dynamism and variety of theatre. They also reveal that from Zimbabwe to Brazil, Nigeria to the USA, societies despite their diversity share many common problems and challenges. Annotated for schools with questions and notes by Rory Kilalea, teachers and students will find this a richly accessible text.
The poems, stories and essays of Mphutlane wa Bofelo operate within a framework of thinking that is an amalgam of philosophies: that of black consciousness, humanistic Islam and socialism. His voice is both lyrical and satirical, expressing anger and tenderness even as his barbs are sharp and his kisses tender. His beats are complex polyrhythms that roll on in incantatory style or achieve mystical brevity. Bofelo entered the world of sociopolitical and cultural activism in the early 1980s through the black consciousness movement in Zamdela Township in Sasolburg. He lives in Durban, where he has built up an audience as a performer of poetry, a speaker and a facilitator. He has self-published two poetry collections and is represented in journals, newspapers and on web sites.
Understanding Confusion in Africa : The Politics of Multiculturalism and Nation-building in Cameroon
(2013)
Cameroon is often considered to be Africais legendary pathfinder. This book argues essentially that Cameroon cannot competently champion African unity and progress until it can correctly pursue its own multicultural nation-building. Cameroon's success continental-wise would depend on its theory and practice of multiculturalism, as particularly reflected in (1) the rejoicing in its historical diversity and the harmonious co-existence of its Systems of Education which must, of necessity, be linked to (2) effective federalization or decentralization of uniquely cultural matters. Critically examining history and education as components of culture, and therefore, of multiculturalism, the book makes some bold recommendations while demonstrating how nation-building is meaningless without the peopleis authentic history. It argues that Cameroon national culture cannot be a national culture without embodying the distinct culture of the English-speaking minority. Anything else is nothing but deliberate confusion of assimilation for multiculturalism, a confusion that is heavily tied to the countryis phoney independence. Hinging on education (and its associates of bilingualism and bijuralism), the book demonstrates that Cameroonis over-sung cultural dualism is a charade, epitomized by the 1998 Education Law. Rather than reaffirm Cameroonis biculturalism as it superficially avows, Cameroonis purported cultural dualism is really out to efface any semblance of cultural or educational dualism that may still be resisting assimilation. The continuous and persistent employment of terms such as biculturalism, bilingualism and bijuralism in legal texts in Cameroon is only to confuse the international community, especially from seeing exactly the kind of eethnic cleansingi which is taking place in the country.
The Cowrie Necklace is a graphic account of the struggle for meaning in life. The poems are a carefully woven sizzling and cracking attempt to mirror society. The poet runs a long and wide gamut of poetic themes which include the intricacies of joy and sadness, God and the devil, nature and nurture, good and evil, love, deceit and treachery. The narrative style is reminiscent of Wole Soyinka, Francesco Nditsouna and D.H. Lawrence. The Cowrie Necklace is a "must read".
Nhakanomics: Harvesting Knowledge and Value for Re-generation Through Social Innovation is a radical departure from the commonly held belief that neo-liberal economics from the US and the West is universal, and is the only solution to underdevelopment and poverty throughout the world. Instead, the book teases out and theorises the intellectually rutted terrain of development studies, and neo-liberal economics from a decolonial Pan-Africanist perspective. Following a path of social innovation, with perspectives drawn from social anthropology, economics, and business and management studies Nhakanomics is a unique socio-economic approach applicable in the Global South and in Southern Africa in particular. The study argues that the process and substance of nhakanomics with its pre-emphasis on the relational South provides a robust and holistic approach to social innovation and social transformation grounded in relational networks and meshworks. The central idea is a call to re-GENE-rate society, through local Grounding and Origination, and tapping into local-global Emergent Foundations via a newly global Emancipatory Navigation, while ultimately culminating in global-local transformative Effects in four recursive cycles of re-GENE-rating C(K)umusha, Culture, Communication, and Capital after re-Constituting Africa-the 5Cs. With a novel and radical approach the book is an interrogation of neo-liberal economics in the Global South. As such, this book is remarkably handy to students and practitioners in the fields of economics, development studies, political science, science and technology studies, business management, sociology, transformation studies, and development related non-Governmental Organisations working with grassroots communities.
In line with the federal structure of the Nigerian State, tax administration in the country is multi-tiered. The Federal Inland Revenue Service is responsible for assessing, collecting and accounting for tax and other revenues accruing to the Federal Government. The States Boards of Internal Revenue and the Local Government Revenue Committees perform similar functions at the State and Local Government levels respectively. This book attempts to chronicle the changes that have been taking place within the Federal Inland Revenue Service since 2004 and how these activities have contributed to the reforms in the Nigerian tax system. In terms of value, the book facilitates an understanding of the role played by the Service; its staff and stakeholders in repositioning the Nigerian tax system. It is an essential reference material for everyone that seeks an understanding of the processes that underscore the ongoing changes in the Nigerian tax system.
This book provides useful pointers to help journalists navigate the dilemmas they face in the professional practice. It provides an enlightening overview of the views of Mauritian journalists on their own industry and an in-depth look at the South African model for self-regulation. As part of the ethical approach, the book also reviews the main issues related to gender-sensitive reporting, in view of the significant role the media have to play in gender education. In an age of information overload, over-exposure to a hyper-mediated culture and the rise of user-generated content, journalists increasingly strive to remain relevant. The temptation to use lower standards, resort to sensationalism and even paycheck journalism is strong. Such examples of unethical practice can only further undermine the credibility of a profession which purports to act as a watchdog, a Fourth Estate. Claims that ethics is a private affair no longer hold good. Journalism is a public good and the need to a clear social contract is stronger than ever in a world where transparency and accountability are on the agenda. Mechanisms for ensuring ethical practice are essential and should be hailed as beacons for a stronger journalism.
The independence of Mozambique in 1975 and its decolonisation process attracted worldwide attention as a successful example of ìnational unityî. Yet, the armed conflict that broke out between the government and the guerrilla force in 1977 lasted for sixteen years and resulted in over a million deaths and several million refugees, placing this concept of ìnational unityî into doubt. For nearly twenty years, Sayaka Funada-Classen interviewed people in rural communities in Mozambique. By examining their testimonies, historical documents, previous studies, international and regional politics, and the changes that various interventions under colonialism brought to the traditional social structure, this book demonstrates that the seeds of ìdivisionî had already been planted while the liberation movement was seeking ìunityî in the struggle years. Presenting a comprehensive history of contemporary Mozambique, this book is indispensable for Mozambican scholars. It promises to serve as a landmark study not only for historians and the scholars of African studies but also for those who give serious consideration to the problems of conflict and peace in the world.
Tanzania has been independent in 2011 for 50 years. While most neighbouring states have gone through violent conflicts, Tanzania has managed to implement extensive reforms without armed political conflicts, Hence, Tanzania is an interesting case for Peace and Development research. This dissertation analyses the political development in Tanzania since the introduction of the multiparty system in 1992, with a focus on the challenges for the democratisation process in connection with the 2000 and 2005 elections. The question of to what extent Tanzania had moved towards a consolidation of democracy, is analysed by looking at nine different institutions of importance for democratisation grouped in four spheres: the state, the political, civil and economic society. Focus is on the development of the political society, and the role of the opposition in particular. The analysis is based on secondary and primary material collected between September 2000 to April 2010. The main conclusion is that even if the institutions of liberal democracy have gradually developed, in practice single-party rule has continued, manifested in the 2005 election when the CCM won 92% of seats. Despite impressive economic growth, poverty remains deep and has not been substantially reduced. On a theoretical level this brings the old debate between liberal and substantive democracy back to the fore. Neither the economic nor the political reforms have brought about a transformation of the political and economic system resulting in the poor majority gaining substantially more political influence and improved economic conditions. Hence, it is argued that the interface between the economic, political and administrative reforms has not been sufficiently considered in the liberal democratic tradition. Liberal democracy is necessary for a democratic development, but not sufficient for democracy to be consolidated. For that a substantive democratic development is necessary.
Conviviality in Bellville: An Ethnography of Space, Place, Mobility and Being in Urban South Africa
(2014)
This book provides insight into the experiences of mobility and migration in contemporary South Africa, contributing to a field of literature about multiculturalism and urban public space in globalizing cities. It takes into consideration the greater international political and local socio-economic factors that drive migration, relationships and conviviality, and how they are intertwined in the everyday narrative of 'insiders' and 'outsiders'. The Bellville central business district demonstrates the realities of interconnected local and global hierarchies of citizenship and belonging and how they emerge in a world of accelerated mobility. The book further demonstrates how the emergence of conviviality in everyday public life represents a critical field for contemplating contemporary notions of human rights, citizenship and belonging.
As part of its on-going public dialogue program on progress in Ethiopia's development and public policy the Forum for Social Studies is undertaking a project of research and public dialogue on a number of selected topics on the theme of 'Prospects and Challenges for Inclusive and Participatory Development in Ethiopia'. The aim is to enable researchers and professionals to present evidence-based papers to stimulate debate and reflection. This first book in the program looks at the impact of development or lack of it, on specific social groups, namely women, young people and vulnerable groups that should be entitled to decent social care.
Elections provide a tremendous opportunity for national transformation and the pursuit of democratic practice. They can be a moment of national renewal. However, in most of Africa elections are often characterized by violent conflict as politicians seek to capture or maintain power through ethnic mobilization, propaganda and misrepresentation. Considering opportunities offered by information technology especially mobile phones and the discovery of extensive natural resources, Africa has an opportunity to significantly change the lives of ordinary citizens. But this transformation requires that youth are fully 'present' in the political, economic, social and cultural arenas. They will need to marshal their energies and stay focused on the things that are important for the continent of Africa. In the case of Kenya, youth should not wait to be invited to take up political leadership. Instead, they will need to invite themselves to the table and take advantage of the opportunity provided in Constitution and demand accountability and transparency in the conduct of national affairs. This book is part of ongoing work at Twaweza Communications in the pursuit of democracy, peace and justice. Themes covered include youth and leadership; elections and peace; youth as peace makers; family and global values among other topics.
From an exploration of the cooperative movement's various international iterations to a perspicacious survey of the history of cooperatives in Tanzania, Dr. Lyimo highlights the issues facing farmers and business people and illustrates the way in which cooperative effort- enterprises that put people, and not capital, at the center of their business- can not only improve members' economic power in bargaining for better marketing conditions and prices, but also to increase employment opportunities, thereby improving the standard of living for a large number of people.
It is the aim of this book while clarifying doubts and misconceptions, to provide a thorough reappraisal of the intellectual and rich cultural heritage of Islam with regards to the principles and practice of medicine and its representation to the world in the language of today. In nine chapters a range of topics are discussed including: The Promotion of Medical Education and Health Services; Personal and Environmental Hygiene; Circumcision; Manners of Eating; Social and Mental Heath; Curative Medicine; The Provision of Adequate and Potable Water; Magic, Witchcraft, Enchantments and Charms; Euthanasia; Suicide; The Rehabilitation of the Sick and the Needy; The Source of Human Creation; Sex Differentiation and Determination; Healing through Miracles; Magic and Soothsaying; HIV Infection and AIDS; Abortion; Females in Medical Practice; and The Challenges of Modem Medicine to Muslims.
Migration in the Service of African Development : Essays in honour of Professor Aderanti Adepoju
(2011)
Fifteen chapters are included here in this compendium in honour of the Nigerian migration scholar Professor Aderanti Adepoju. Though the authors come from diverse disciplinary backgrounds: geography, demography, sociology and law they all work within the fields of internal and international migration in Africa. Chapters on Uganda, Kenya, Botswana, Nigeria and Mali are devoted to aspects of internal migration, while those on African emigration to Mexico and migration between Burkina Faso and Côte d'Ivoire address various aspects of international migration. Migration issues in relation to women, students and climate change are also discussed.
The Millennium Development Goals address poverty, hunger, disease, illiteracy, environmental degradation, and discrimination against women, by the year 2015. In this volume scholars and policymakers in the fields of population and health reflect on the attainments of some of these goals, on the basis of empirical evidence in the Ghanaian context. The eight paper, with an introduction by the editors, synthesises papers presented at a seminar held in Ghana on ?Population, Health and Development in Relation to the Millennium Development Goals?, organised by the Population Association of Ghana.
Critical Issues in Nigerian Property Law, a collection of writings in honour of Professor Jelili Adebisi Omotola, SAN, a former Vice Chancellor of the University of Lagos, who died on the 29th of March 2006, has ten chapters that closely examine not only the current state of Property Law in Nigeria, but also recent developments and other challenges that have surfaced since the infamous Land Use Act of 1999. The book is clearly a useful contribution to a growing body of knowledge on property law and practice in Nigeria.
In 2009, Anglophone Cameroon literature celebrated its fifty years of existence. Now at the mature age of fifty plus this literature has a great deal to write home about even if it still has a lot to do in its pursuit of excellence. Part of its maturity resides in the fact that although the scale of literary creativity and literary criticism is skewed in favour of the former, Anglophone Cameroon literary criticism is gradually waking up from slumber in an attempt to catch up with the rapidly expanding creativity. The essays in this book comment practically on some aspects of all the genres of written literature that the Anglophone Cameroon creative writers have produced so far: the novel, drama, poetry, the short story, the essay and children's literature. The essays, on the whole, are a testimony of the transition and reality from the apparent drought of Anglophone Cameroon literary paucity to the actual fruitful period of Anglophone Cameroon abundance of literary creativity. The Anglophone Cameroonians have appropriated an imperial language, English, to serve their postcolonial Cameroonian vision. Their various literary texts are vehicles of representations that are essentially cultural and ideological constructs. The works examined are initially anchored on Cameroonian experiences to take on social significance. As they are grounded on moving human experiences, these works necessarily make references to the immediate Cameroonian environment of their authors before taking on universal human significance. The book abundantly evidences and crowns Shadrach Ambanasom's achievements and reputation as a skilled pedagogue on the art of practical literary criticism.
African land rights systems
(2014)
This book, from ethical, interdisciplinary, and African perspectives, unveils the root causes of the increasing land disputes. Its significance lies upon the effort of presenting a broad overview founded upon a critical analysis of the existing land-related disputes. It is a perspective that attempts to evaluate the renewed interest in evolving theories of land rights by raising questions that can help us to understand better differences underlying land ownership systems, conflict between customary and statutory land rights systems, and the politics of land reform. Other dimensions explored in the book include the market influence on land-grabbing and challenges accompanying trends of migration, resettlement, and integration. The methodology applied in the study provides a perspective that raises questions intended to identify areas of contention, dispute, and conflict. The study, which could also be categorized as a critical assessment of the African land rights systems, is intended to be a resource for scholars, activists, and organizations working to resolve land-related disputes.
Prevalent poverty and related problems in the East African region call for substantial action from various stakeholders, including social workers. This book, based on comprehensive empirical research, portrays an emerging yet powerful profession that has a significant role to play in the endeavour towards social development, social justice, human rights and gender equality. The book is the first of its kind to provide first-hand theoretical and empirical evidence about social work in East Africa.
The most popularised concept in the economics of innovation literature has been the national system of innovation (NSI). It was in the late 1980s that the concept that Frederik List coined as the National Political Economy of Production took off again with different thinkers writing about the peculiarities and distinctions of the Japanese, American, British, German, East Asian Tigers and other varieties of system construction. Freeman defines National System of Innovation as the network of institutions in the public and private sectors whose activities and interactions initiate, import, modify and diff use new technologies. Richard Nelson defines it as a set of institutions whose interactions determine the innovative performance of national firms. Lundvall defines the system of innovation as the elements and relationships which interact in the production, diffusion and use of new and economically useful knowledge and are either located within or rooted inside the borders of a nation state. The normative assumption is that those nations that succeeded in building economic strength relied on the science, engineering, technology and innovation capability that made them to achieve an innovation advantage to put them ahead in the world, acquiring national or regional economic leadership as the case may be depending on what level of analyses is selected to look at particular failure, success or progress they made.. In this volume we have a glimpse of how in different African economies from Ghana, Uganda, Kenya, South Africa and Nigeria specific cases have been taken to explore how systems of innovation is evolving.
The "Suma de tratos y contratos" (1569-1571) by Tomás de Mercado is the first legal treatise on trade that explicitly takes into account the specificities of Spanish trade with the Indias. Tomás de Mercado was faced with very profound changes in trade: long distances, large convoy sizes, the need for large amounts of funding, high risk, variations in prices and the value of money...
From a theological-legal point of view, these upheavals posed new and complex questions.
Mercado, advisor to the merchants of Seville and an excellent knowledge of New Spain, analyses the sudden transformation of economic and juridical practice with finesse and realism. The 'Suma' is thus an extraordinary real-time testimony to the profound transformations taking place in 16th century commerce.
Moreover, faced with fundamental questions of moral order and juridical legitimacy, Mercado proposes legal solutions of high equilibrium in which theological imperatives are masterfully reconciled with the needs of transatlantic commercial practice.
The blood-brain barrier (BBB) protects the brain microenvironment from external damage. It is formed by endothelial cells (ECs) lining the brain vessels, expressing tight junctions and having reduced transcytosis, resulting in a very low paracellular and transcellular passage of substances, respectively (low permeability). The specific BBB phenotype is maintained by Wnt molecules secreted by astrocytes (ACs) that bind to receptors in ECs, and start a molecular cascade that leads to β-catenin translocating to the nucleus and activating the transcription of BBB genes.
An increasing number of studies report BBB dysfunction in Alzheimer’s disease (AD), although the topic is currently under debate. AD is a neurodegenerative condition characterized by brain depositions of Aβ aggregates and Tau neurofibrillary tangles. The aetiology of AD is unknown, although round 5% of all AD cases have a genetic origin. Mutations in APP or PSEN1/2 can lead to Aβ over-production and accumulation, causing familiar AD. There is no cure for AD, as all clinical trials failed during the past years. Consequently, I studied the role of the BBB in AD, aiming to investigate if a BBB dysfunction occurs in AD, and to identify by transcriptomic analysis novel gene regulations happening at the BBB in AD. The final objective was to evaluate the potential of identified BBB genes as therapeutical target.
I used transgenic mice expressing the human APP mutations Swiss, Dutch and Iowa under the control of the neuronal promoter Thy1 (Thy1-APPSwDI) as AD model. In this AD mouse model, I could detect Aβ deposits and memory loss by immunofluorescence (IF) and behavioural tests. Importantly, I identified an increase of BBB permeability to 3-4 kDa dextrans in 6 months, 9-12 months, and 18 months or older AD mice compared to age-matched control wild types (WT), indicating BBB dysfunction in AD mice.
In order to study the BBB transcriptional changes in AD, I sequenced the RNA from 6 and 18 months old AD and WT mouse brain microvessels (MBMVs), as well as of FACS-sorted ECs, mural cells (MuCs), ACs, and microglia (MG) in collaboration with GenXPro, a company specialized in 3’ RNA sequencing. Currently, no transcriptomic datasets of ECs and MuCs are publicly available, suggesting that this is the first study sequencing those cell types in the context of AD.
The analysis of sequencing data from MBMVs and ECs revealed a Wnt/β-catenin repression, and an increase of inflammatory genes like Ccl3 in ECs, that could explain the BBB dysfunction observed in AD mice. Furthermore, the sequencing data from MuCs identified a set of 11 genes strongly regulated in both 6 and 18 month AD groups. Three of those 11 genes are known to be involved in inflammatory processes, demonstrating that inflammation affects and plays an important role in MuCs and ECs during AD.
Thanks to published sequencing data, some up-regulated MG genes in AD are well known and recognized, such as Trem2 and Apoe. Those genes were found in the FACS-sorted MG data as well, validating the AD model and with it, the other novel sequenced datasets. Importantly, one of the most strongly AD-regulated genes in MBMV and MG samples was Dkk2, a member of the Dickkopf family of secreted proteins known to be involved in Wnt signalling modulation. Importantly, a dual luciferase reporter assay proved that Dkk2 is a Wnt inhibitor. A preliminary immunohistochemistry examination of DKK2 in human brain autopsy tissue from an AD patient and age-matched control revealed a stronger DKK2 immunoreactivity in the AD brain.
In order to answer the question whether a rescue of BBB function would ameliorate AD symptoms, I made use of a tamoxifen-inducible transgenic mouse line to activate the Wnt/β-catenin pathway specifically in ECs, leading to a gain of function (GOF) condition (Cdh5-CreERT2+/–/Ctnnb1(Ex3)fl/fl). This mouse line was then crossed with the AD line, creating AD/GOF and AD/control groups.
AD/GOF mice performed better in a Y-Maze memory test than AD/controls when the Wnt/β-catenin pathway was induced before AD onset, indicating a protective effect. Moreover, the finding implies that shielding BBB functioning in AD further protects the brain from AD toxic effects, suggesting an important role of brain vasculature in AD and its potential as therapeutic target.
Synaptic plasticity is the activity dependent alteration of the composition, form and strength of synapses and believed to be the underlying mechanism of learning and memory formation. While initial changes in synaptic transmission are caused by second messenger signaling pathways and rapid modifications in the cytoskeleton, to achieve stable and persistent changes at individual synapses, the expression of new mRNAs and proteins is required. The central dogma postulated that the cell body is the only source of newly synthesized proteins. For neurons, with their unique morphology, this meant that proteins would need be transported long distances, often hundreds of microns, to reach their destined locations in dendrites and at spines. To overcome this limitation, neurons have developed a strategy to regulate protein synthesis locally by distributing thousands of mRNAs into neuronal processes and use them for local protein synthesis. Ample research has demonstrated the importance of local protein synthesis to many forms of long-term synaptic plasticity. One potential regulator of mRNA localization and local translation in neurons are non-coding RNAs. Intensive work over the past decades has highlighted the importance of non-coding RNAs in many aspects of brain function. The aim of this thesis is to obtain a better understanding of the role of non-coding RNAs in synaptic function and plasticity in the murine hippocampus. For this, we focused our studies on two classes of non-coding RNAs.
In the first part of my thesis, I describe our efforts on characterizing circular RNAs, a novel and peculiar family of non-coding RNAs, in the murine hippocampus by combining high throughput RNA-Sequencing with fluorescence in situ hybridization. Furthermore, we investigated the mechanisms of circular RNA biogenesis in hippocampal neurons by temporarily inhibiting spliceosome activity and analyzing the differentially regulated circular RNAs.
Die Forschung beschrieben in dieser Dissertation ist ein Teil der "European Research and Innovation Programme - PEARRL", und wurde von Horizon 2020 Marie Sklodowska-Curie actions der Europäischen Union, unter Förderungsnummer 674909 unterstützt.
In den letzten Jahren, wurde Senkung der Intensität der pharmazeutischen Forschung und Entwicklung beobachtet, da die Weiterentwicklung der Wirkstoffmolekülen hinzu einer "handlichen" Formulierung viele Schwierigkeiten aufweist. Meiste der neuen Wirkstoffkandidaten, die sich in Entwicklung befinden, haben suboptimale Eigenschaften in Bezug zur Löslichkeit und Auflösung und zeigen schlechte Bioverfügbarkeit, wenn eingenommen. Deswegen verlangen meiste neue Wirkstoffkandidate einen besonderen Ansatz in Bezug auf Formulierung, um akzeptable orale Bioverfügbarkeit zu erreichen. Diese neue Formulierungen werden meistens als “bio-enabling” Formulierungen bezeichnet und werden in Heilmittelentwicklung immer häufiger verwendet.
Hauptziel dieser Dissertation ist zu erforschen ob, durch Verbinden von biorelevanten in vitro Werkzeugen mit in silico Modeling und Simulationen, die in vitro Löslichkeit und Auflösung von bio-enabling Formulierungen mechanistisch erkläert und besser verstanden werden kann und somit eine erfolgreiche Simulation von in vivo Leistung erreicht werden kann.
Als Erstes wurden die physiologische Parameter, die die pharmakokinetik oraler Formulierungen beeinflüssen, identifiziert, indem die Auswirkung der Wirkstoffe, die zur Behandlung Magen-Darm-Krankheiten genutzt werden, sowie deren Pharmakokinetik, beurteilt wurde. Unter anderem wurde pH als einer der entscheinenden phyisiologischen Parameter erkannt, da es die Pharmakokinetik peroral verabreichter Stoffe signifikant beeinflüssen kann.
Als zweiter Schritt, mit besonderer Beachtung auf die Verwendung der biorelevanten in vitro Werkzeugen für die Erforschung der in vivo Auflösungsprozesse von bio-enabling Formulierungen, Fokus auf die biorelevante Medien und in vitro Apparaturen, die mögliche Prezipitationskinetik einschätzen können, wurde gesetzt. Biorelevante Medien sind wässrige Flüssigkeiten, die die Zusammensetzung der gastrointestinaler Flüssigkeiten nachmachen und für die Auflösungsuntersuchungen genutzt werden. Bis heute beinhalten die Aspirationsstudien die wichtigsten Hinweise und Informationen für den Design biorelevanter Medien. Es wurde beobachtet, dass die berichteten Werte mancher phyisiologisher Parameter erhebliche Unterschiede zwischen den Aspirationsstudien zeigen. Deswegen wurde untersucht, ob die Ergebnisse durch die Auswahl an Methodologie, die für die Entnahme und die Auswertung der Proben genutzt worden sind, beeinflusst werden können, wobei besondere Aufmerksamkeit den pH und der Pufferkapazität geschenkt wurde. Es wurde gezeigt, dass Unterschiede im Prozess der Probenhandhabung, z.B. Zentrifugieren und Lagerung einen deutlichen Einfluss auf die gemessenen Werte haben kann. Ausserdem, wurden in dieser Arbeit die in vitro Setups, die bisher in der Literatur zur Beurteilung der Übersättigung u.o. Ausfällung von Arzneimitteln im oberen Magen-Darm-Trakt vorgeschlagen wurden, überprüft und ihre Nützlichkeit und aktuelle Anwendung bewertet.
Nach Behebung der oben genannten Probleme, wurden zwei Fallbeispielformulierungen ausgewählt, um die Haupthypothese zu untersuchen. Die erste Formulierung ist auf den Markt unter dem Namen EMEND® und enthält den Wirkstoff in Nanoform. Die zweite Formulierung wird als INTELENCE® vermarktet und ist eine amorphe feste Dispersion des Wirkstoffs Etravirin. Durch die Wahl zwei unterschiedlicher Formulierungsansätzen konnten unterschiedliche Fallszenarien untersucht werden, wodurch umfassendere Vorschläge für die Bewältigung der Herausforderungen bei in vitro Experimenten und in silico Modelling mit bio-enabling Formulierungen möglich waren.
Bezogen auf den in dieser Dissertation beschriebenen Ansatz, ein mechanistisches Verständnis des in vivo Absorptionsprozesses, sowie eine erfolgreiche Simulation der nach der Verabreichung resultierenden Plasmaprofile einer bio-enabling-Formulierung der Nanoskala- und einer amorphen festen Dispersion wurde erreicht. Darüber hinaus wurden mögliche Wege vorgeschlagen, um einige Herausforderungen im Hinblick auf die Entwicklung von PBPK-Modellen für biofähige Formulierungen anzugehen. Diese Arbeit zeigt die mögliche Anwendung und Bedeutung der Absorptionsmodellierung für die rationale Formulierungsentwicklung und für die Stärkung des Wissens über Bio-Heilmittel in Bezug auf bio-enabling Formulierungen. Mithilfe dieses Ansatzes können die wesentlichen Parameter identifiziert werden, die das pharmakokinetische Verhalten schwerlöslicher Wirkstoffe beeinflussen, die als bio-enabling Formulierungen formuliert sind, und ermöglichen wiederum eine robuste Vorhersage der klinischen Ergebnisse.
Fokus meiner Doktorarbeit ist die Anwendung und Entwicklung NMR-spektroskopischer Methoden zur Charakterisierung zeitabhängiger Strukturänderungen von Biomolekülen – von lokalen dynamischen Veränderungen bis zur vollständigen Rückfaltung von Proteinen – und fasst die Ergebnisse meiner drei wichtigsten PhD-Projekte zusammen.
In meinem ersten Projekt habe ich die Leistung eines Temperatursprung-Probenkopfs – mit dem Proben mit hoher Salzkonzentration schnell erwärmt werden können – mithilfe einer Hochfrequenzspule technisch optimiert. Die optimierten Radiofrequenz-Bestrahlungsparameter, Lösungsmittel-bedingungen und der reduzierte Arbeitszyklus führten zu einem Temperatursprung von 20 °C in 400 ms. Ich habe eine Cystein-freie Mutante von Barstar hergestellt, die nach Zugabe von Harnstoff bei 0 °C kalt denaturiert werden kann, während sie ihren gefalteten Zustand bei 30 °C hält. Dadurch wurde auch ermöglicht, dass der Rückfaltungsprozess hunderte Male ohne Abbau oder Aggregation wiederholt werden kann. Die Kombination von reversibler Rückfaltung und rascher Temperaturänderung des kalt denaturierten Barstars ermöglichte die Entwicklung eines neuen kinetischen Experiments, bei dem der Rückfaltungsprozess von Barstar mit einem zweidimensionalen Echtzeit-NMR in hoher Zeitauflösung untersucht wird. Die vollständige Rückgratresonanzzuweisung wurde sowohl für den gefalteten als auch für den kalt denaturierten Zustand von Barstar durchgeführt und ergab, dass in der denaturierten Form beide Prolin-Reste einen gemischten Konformationszustand aufweisen. Dabei befindet sich die Tyr47-Pro48-Amidbindung im ungefalteten Zustand hauptsächlich in trans-, während im gefalteten Zustand in der seltenen cis-Konformation. Das neue hochauflösende kinetische Experiment zeigte, dass die Rückfaltung von Barstar durch die trans-cis-Isomerisierung der Tyr47-Pro48-Amidbindung verlangsamt wird, was sowohl die Sekundärstruktur als auch die Bildung der Tertiärstruktur beeinflusst. Basierend auf diesen Ergebnissen konnte ich einen plausiblen Faltungsmechanismus für den langsamen Faltungsweg von kalt denaturiertem Barstar skizzieren. Durch Änderung der Zeitparameter des Heizungszyklus wurde erreicht, dass die Tyr47-Pro48-Amidbindung im ungefalteten Zustand in der cis-Konformation bleibt und daher der schnelle Faltungsweg dominant wird. Das Starten des Magnetisierungstransfers vor der Temperaturänderung ermöglichte die Aufzeichnung eines Spektrums, das den entfalteten Zustand mit dem gefalteten Zustand korreliert. Dieses Spektrum ermöglichte quantitative Analysen des schnellen Faltungsweges und lieferte sogar indirekte Hinweise auf einen Zwischenzustand. Diese Methode aus Kombination von schnellem Temperatursprung und Kaltdenaturierung zeigt ein hohes Potenzial, Proteinfaltung auf atomarer Ebene experimentell zu untersuchen und ein tieferes Verständnis verschiedener Faltungswege zu erlangen.
In meinem zweiten Projekt – das Teil einer interdisziplinären Forschung war – konzentrierte ich mich auf die NMR-spektroskopische Charakterisierung von Nukleinsäuren, die mit einer photolabilen Schutzgruppe modifiziert wurden. Zuerst wurde mithilfe homonuklearer Korrelationsexperimente eine vollständige Protonresonanzzuweisung erreicht. Danach wurde die relative Konfiguration der photolabilen Schutzgruppen bestimmt basierend auf einer dreidimensionalen Modellstruktur und spezifischer NOE-Korrelationen. Des Weiteren wurde ein Strukturmodell unter Verwendung von NOE-Einschränkungen berechnet. Dieses Strukturmodell zeigte eine eingeschränkte Rotation um die CN-Bindung zwischen dem Käfig und der Nukleobase. Das Modell zeigte auch, dass der Käfig in der Hauptrille positioniert ist und nicht in das Lösungsmittel herausklappt. Im Vergleich zu einem zuvor charakterisierten NPE-Käfig führte die erhöhte Größe zu einer weiteren Senkung des Schmelzpunkts, zeigte jedoch einen geringeren Schmelzpunktunterschied zwischen der S- und der R-Konfiguration des Käfigs, wobei die S-Konfiguration zu einer größeren Reduktion des Schmelzpunktes führt. Dieser Trend wurde weiter untersucht und durch ein Screening unterstützt. Durch selektive Wasserinversions-Rückgewinnungsexperimente konnte ich auch zeigen, dass der Käfig die lokale Stabilität nur bis zu einer Entfernung von zwei benachbarten Basenpaaren von der Modifikationsstelle verringert. Die NOE-Daten dienten auch als guter Bezugspunkt, um die Qualität molekulardynamischer Simulationen zu testen, mit denen zusätzliche Käfigdesigns untersucht wurden. Die Kombination aus Synthese, NMR-Spektroskopie und MD-Simulationen ermöglichte bis jetzt die detaillierteste Untersuchung des Effekts vom Einbau eines einzelnen Käfigs zur Destabilisierung der DNA-Sekundärstruktur. Dabei wurden Einschränkungen des möglichen Designs aufgedeckt, aber auch die Entwicklung einer neuen, effizienteren Struktur ermöglicht.
Mein drittes Projekt konzentrierte sich auf die Charakterisierung eines RNA-Modellsystems. NMR-spektroskopische Daten von kleinen RNA-Modellsystemen – wie NOE, skalare Kopplungen, kreuzkorrelierte Relaxationsraten und RDC – sind eine unschätzbare Referenz für MD-Simulationen, obwohl die Menge der verfügbaren Literaturdaten – bis jetzt – sehr begrenzt ist. ...
Congenital diaphragmatic hernia (CDH) is a major congenital malformation with high mortality. Outcome data on larger unselected patient groups in Germany are unavailable as there is no registry for CDH. Therefore, routine data from the largest German health insurance fund were analyzed for the years 2009–2013. Main outcome measures were incidence, survival and length of hospital stay. Follow-up was 12 months. 285 patients were included. The incidence of CDH was 2.73 per 10,000 live births. Overall mortality was 30.2%. A total of 72.1% of the fatalities occurred before surgery. Highest mortality (64%) was noted in patients who were admitted to specialized care later as the first day of life. Patients receiving surgical repair had a better prognosis (mortality: 10.8%). A total of 67 patients (23.5%) were treated with ECMO with a mortality of 41.8%. The median cumulative hospital stay among one-year survivors was 40 days and differed between ECMO- and non-ECMO-treated patients (91 vs. 32.5 days, p < 0.001). This is the largest German cohort study of CDH patients with a one-year follow-up. The ECMO subgroup showed a higher mortality. Another important finding is that delayed treatment in specialized care increases mortality. Prospective clinical registries are needed to elucidate the treatment outcomes in detail.