9,399 research outputs found

    Studies on genetic and epigenetic regulation of gene expression dynamics

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    The information required to build an organism is contained in its genome and the first biochemical process that activates the genetic information stored in DNA is transcription. Cell type specific gene expression shapes cellular functional diversity and dysregulation of transcription is a central tenet of human disease. Therefore, understanding transcriptional regulation is central to understanding biology in health and disease. Transcription is a dynamic process, occurring in discrete bursts of activity that can be characterized by two kinetic parameters; burst frequency describing how often genes burst and burst size describing how many transcripts are generated in each burst. Genes are under strict regulatory control by distinct sequences in the genome as well as epigenetic modifications. To properly study how genetic and epigenetic factors affect transcription, it needs to be treated as the dynamic cellular process it is. In this thesis, I present the development of methods that allow identification of newly induced gene expression over short timescales, as well as inference of kinetic parameters describing how frequently genes burst and how many transcripts each burst give rise to. The work is presented through four papers: In paper I, I describe the development of a novel method for profiling newly transcribed RNA molecules. We use this method to show that therapeutic compounds affecting different epigenetic enzymes elicit distinct, compound specific responses mediated by different sets of transcription factors already after one hour of treatment that can only be detected when measuring newly transcribed RNA. The goal of paper II is to determine how genetic variation shapes transcriptional bursting. To this end, we infer transcriptome-wide burst kinetics parameters from genetically distinct donors and find variation that selectively affects burst sizes and frequencies. Paper III describes a method for inferring transcriptional kinetics transcriptome-wide using single-cell RNA-sequencing. We use this method to describe how the regulation of transcriptional bursting is encoded in the genome. Our findings show that gene specific burst sizes are dependent on core promoter architecture and that enhancers affect burst frequencies. Furthermore, cell type specific differential gene expression is regulated by cell type specific burst frequencies. Lastly, Paper IV shows how transcription shapes cell types. We collect data on cellular morphologies, electrophysiological characteristics, and measure gene expression in the same neurons collected from the mouse motor cortex. Our findings show that cells belonging to the same, distinct transcriptomic families have distinct and non-overlapping morpho-electric characteristics. Within families, there is continuous and correlated variation in all modalities, challenging the notion of cell types as discrete entities

    General government fiscal plan for 2024–2027

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    The purpose of the General Government Fiscal Plan is to support decision-making related to general government finances as well as compliance with the Medium-Term Objective set for the structural budgetary position of general government finances. The plan contains sections related to central government finances, wellbeing services county finances, local government finances, statutory earnings-related pension funds and other social security funds. The Government prepares the General Government Fiscal Plan for the parliamentary term and revises it annually for the following four years by the end of April. The General Government Fiscal Plan also includes Finland’s Stability Programme, and it meets the EU’s requirement for a medium-term fiscal plan. The General Government Fiscal Plan for 2024–2027 does not propose any new policy definitions. It is based on current legislation and takes into account the impact of the decisions previously made by Prime Minister Marin’s Government on the expenditure and revenue levels in the coming years. This General Government Fiscal Plan does not set any budgetary position targets. The first General Government Fiscal Plan of the Government to be appointed after the parliamentary election in spring 2023 will be drawn up in autumn 2023, and this will include a Stability Programme. The General Government Fiscal Plan also includes the central government spending limits decision, but it does not specify a parliamentary term expenditure ceiling

    Command and Persuade

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    Why, when we have been largely socialized into good behavior, are there more laws that govern our behavior than ever before? Levels of violent crime have been in a steady decline for centuries—for millennia, even. Over the past five hundred years, homicide rates have decreased a hundred-fold. We live in a time that is more orderly and peaceful than ever before in human history. Why, then, does fear of crime dominate modern politics? Why, when we have been largely socialized into good behavior, are there more laws that govern our behavior than ever before? In Command and Persuade, Peter Baldwin examines the evolution of the state's role in crime and punishment over three thousand years. Baldwin explains that the involvement of the state in law enforcement and crime prevention is relatively recent. In ancient Greece, those struck by lightning were assumed to have been punished by Zeus. In the Hebrew Bible, God was judge, jury, and prosecutor when Cain killed Abel. As the state's power as lawgiver grew, more laws governed behavior than ever before; the sum total of prohibited behavior has grown continuously. At the same time, as family, community, and church exerted their influences, we have become better behaved and more law-abiding. Even as the state stands as the socializer of last resort, it also defines through law the terrain on which we are schooled into acceptable behavior. This title is also available in an Open Access edition

    Paternalism to Partnership

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    A biographical sketch of each head of Indian affairs between 1786 and 2021, including each commissioner’s political philosophy

    The Beginnings of National Politics

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    Originally published in 1982. Despite a necessary preoccupation with the Revolutionary struggle, America's Continental Congress succeeded in establishing itself as a governing body with national—and international—authority. How the Congress acquired and maintained this power and how the delegates sought to resolve the complex theoretical problems that arose in forming a federal government are the issues confronted in Jack N. Rakove's searching reappraisal of Revolution-era politics. Avoiding the tendency to interpret the decisions of the Congress in terms of competing factions or conflicting ideologies, Rakove opts for a more pragmatic view. He reconstructs the political climate of the Revolutionary period, mapping out both the immediate problems confronting the Congress and the available alternatives as perceived by the delegates. He recreates a landscape littered with unfamiliar issues, intractable problems, unattractive choices, and partial solutions, all of which influenced congressional decisions on matters as prosaic as military logistics or as abstract as the definition of federalism

    Arms and the People

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    This collection examines the relationship between mass movements and the military. Some argue that it is impossible to achieve and protect a revolution without the support of the army, but how can the support of the army be won? Arms and the People explores the impact of social extremes on the solidarity within the state’s military, and on the changing loyalties of these soldiers. The authors examine a series of historical moments in which a crisis in the military has reflected deep instability in the wider world, including Russia in 1917, Egypt during the Arab Spring, the Paris Commune, as well as long-standing instability in Venezuela and Indonesia, amongst many others. Including a range of international authors who have either studied or been directly involved in such social upheavals, Arms and the People is a pioneering contribution to the study of revolutionary change

    Queer spies in British Cold War culture: literature, film, theatre and television

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    This PhD thesis investigates how male homosexuality has been represented in British spy fiction from the 1950s to the 2010s in multiple media: literature, film, television and theatre. Due mainly to the betrayal of the Cambridge Spy ring around the middle of the century, British culture has associated spies with homosexuality, while the wider Anglophone world was in the grip of a homophobic atmosphere created by McCarthy's Red Scare. My thesis explores how this history is reflected in the spy genre from the Cold War to the present, in which male homosexuality and secret agency intersect as “queer”, in so far as they were both considered to be discreet and criminal, existing outside of the heteronormative order. By following multiple texts across media and time, I discuss how some writers, television and film directors and actors update queer identity in spy fiction, creating a shifting image of queer spies through decades. I refer to the findings of adaptation studies and queer studies, along with numerous studies on spy fiction. I conclude that the interrelation of different media has contributed to the re-drawing of queer identity in spy fiction. These developments have enabled the spies' queer identity to transcend its pejorative history in British culture, towards its more flexible and pliant sense which is designated by the term's modern usage. I also discuss that spies’ homosexuality has been represented as a fleeting ghost in most of the texts examined, hovering on the margins of pages and screen. Although homosexuality is not “the love that dare not speak its name” anymore, clandestine queer spies have been preserved as spectral others in the genre for many years. Spy fiction is a cultural repository retaining the memory of violence inflicted against those who have been called “queer” in twentieth century Britain, and the spectral nature of queer spies narrates this history reaching back to the Oscar Wilde trial in 1895, from which point British queer identity as we know now developed. This thesis benefits the study of spy fiction by filling a gap in the investigation of homosexual representation. It also contributes to the field of gender studies of literature, film, television, and theatre by illustrating queer history in a genre which has not received a great deal of focus on its representation of homosexuality. Spy fiction occupies a central position in British popular culture, and by exploring this genre in terms of homosexuality, this research will identify the role which same-sex desire has historically played in the British cultural imagination

    The Adirondack Chronology

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    The Adirondack Chronology is intended to be a useful resource for researchers and others interested in the Adirondacks and Adirondack history.https://digitalworks.union.edu/arlpublications/1000/thumbnail.jp

    Behold the Beasts Beside You: The Adaptation and Alteration of Animals in LXX-Job

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    “Behold the beasts beside you; they eat grass like cattle” (LXX-Job 40:15). The first translator for the book of Job into Greek was faced with a difficult text, replete with archaisms, corruptions, and convoluted Hebrew. He produced a distinctive – and often misunderstood – translation. Though its central characteristic is one of omission, its general approach to the text has proven hard to categorize. This study continues this trend by following one feature of Job that a casual reader cannot overlook: the book of Job’s zoological panoply. The LXX-translator handles these creatures in a variety of ways, often contextually-sensitive and quite creative. Furthermore, he brings in external material, from other LXX books and Greek literature, to translate other passages. Most surprisingly, he displays a remarkably “inclusive” approach to canonicity and “exclusive” ideas about animals and wisdom. At the end, the individual character of the translator is much more visible in the translation than what it would appear at first. “Beholding the beasts” in LXX-Job tells us as much about the translator as the translation itself

    The Pastoral Connection - Examining Parallels Between Pastoral and Political Rhetoric During the Revolutionary War

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    This paper examines the parallels between rhetoric in sermons preserved from the Revolutionary War period and rhetoric in political speeches and writings from the same period. The aim is to establish the extent of the parallels in rhetoric and to demonstrate that the rhetorical stances from the pulpit preceded the same rhetorical stances in political, secular work through establishing the date each document was published or presented. Studying these sources alongside reliable secondary sources on both the political and religious rhetorical themes will demonstrate, when put together to form a more complete picture of the period, that the political rhetoric was an echo of what was already being preached in the pulpits and published in sermons well before the war itself commenced. While sermon rhetoric was hardly the only influence on the rhetoric of politics at the time, this study will show that the rhetorical shift of the time—from supporting Britain to a war against Britain on the grounds of broken contracts, abuse of authority, and religious persecution—began in the pulpit and was then caught, in its final stages, by the political orators and writers of the day to set a nation on fire for freedom
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