9,399 research outputs found
Studies on genetic and epigenetic regulation of gene expression dynamics
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 2024â2027
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 Finlandâs Stability Programme, and it meets the EUâs requirement for a medium-term fiscal plan. The General Government Fiscal Plan for 2024â2027 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 Marinâs 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
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 centuriesâfor 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
A biographical sketch of each head of Indian affairs between 1786 and 2021, including each commissioner’s political philosophy
The Beginnings of National Politics
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 nationalâand internationalâauthority. 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
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 stateâs 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
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 âqueerâ,
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 spiesâ 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
âthe love that dare not speak its nameâ 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
âqueerâ 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
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
âBehold the beasts beside you; they eat grass like cattleâ (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 â and often misunderstood â 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 Jobâs 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 âinclusiveâ approach to canonicity and âexclusiveâ 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. âBeholding the beastsâ 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
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 timeâfrom supporting Britain to a war against Britain on the grounds of broken contracts, abuse of authority, and religious persecutionâbegan 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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