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

Crisis management: towards a model for the hotel industry : an examination of crisis preparedness and stakeholder relationships in crisis situations.

Crises are inevitable. There is no way to prevent all crises from happening. In fact, in today's business environment crises are an integral part of organizational life. Crisis situations are by nature novel, unstructured, frameworks. Crises are sudden, acute, and demand a timely response. Most man-made crises are in principle preventable. Crisis management is a new field of research that addresses the problems of dealing with crises, and the stress that accompanies crises. Crisis management involves efforts to prevent crises from occurring; to prepare for a better protection against the impact of a crisis agent; to make for an effective response to an actual crisis; and to provide plans and resources for recovery and rehabilitation in the aftermath of a crisis. It is no longer enough to consider "if" a crisis will happen but rather "when" a crisis will occur, "which type", and "how". There is no doubt that the travel and tourism industry is especially susceptible and vulnerable to crises. It is argued that the hotel industry, given its operational characteristics, management practices (which is strongly influenced by long established traditions), and its operating environment, is even more prone to crises. However, very little has been done to understand crisis (that is, how a crisis evolves, crisis typology, anatomy, and management of crisis). This study describes and discusses all major relevant elements and issues to the emerging field of crisis management. Within the domain of crisis management theory, the study describes and elaborates on critical issues such as crisis typology, anatomy of crisis, crisis planning and training, crisis decision making, crisis communication, and crisis management. It is argued in this study that organizational culture is the most fundamental element in crisis preparedness. That is, organizational culture, not organization structure, size, financial history, etc., is the main determinant of crisis preparedness. The research also argue that stakeholders are fundamental in crisis prevention, crisis management and crisis recovery. 2 This study, in a first instance, examines the crisis preparedness of 33 of the 50 top hotel organizations operating in the UK (HCIMA, 1995). Crisis preparedness is examined in the light of organizational culture. For that, top executives in those organizations were interviewed and responded to two questionnaires. A crisis preparedness framework (or continuum) was derived from the application of factor analysis on the questionnaire data. The results suggest that the hotel industry is not prepared for crises. Given that a crisis is a multi-stakeholder phenomenon (it inevitably involves other agents) this study also explores, building upon the results obtained from the crisis preparedness continuum, the notion of stakeholders relationships in crisis situations. More specifically, the research proposition states that organizations that are crisis "prepared" are more consistent on their opinions about stakeholders' role and behaviour in crisis situations than those organizations that are not prepared for crises. The study confirmed both the research question and proposition. The study also presents an operational definition of crisis management and proposes a model for crisis management

Changing the way the world thinks about computer security.

Small changes in an established system can result in larger changes in the overall system (e.g. network effects, émergence, criticality, broken Windows theory). However, in an immature discipline, such as computer security, such changes can be difficult to envision and even more difficult to amplement, as the immature discipline is likely to lack the scientific framework that would allow for the introduction of even minute changes. (Cairns, P. and Thimbleby, H, 2003) describe three of the signs of an immature discipline as postulated by (Kuhn, 1970): a. squabbles over what are legitimate tools for research b. disagreement over which phenomenon are legitimate to study, and c. inability to scope the domain of study. The research presented in this document demonstrates how the computer security field, at the time this research began, was the embodiment of thèse characteristics. It presents a cohesive analysis of the intentional introduction of a séries of small changes chosen to aid in maturation of the discipline. Summarily, it builds upon existing theory, exploring the combined effect of coordinated and strategie changes in an immature system and establishing a scientific framework by which the impact of the changes can be quantified. By critically examining the nature of the computer security system overall, this work establishes the need for both increased scientific rigor, and a multidisciplinary approach to the global computer security problem. In order for these changes to take place, many common assumptions related to computer security had to be questioned. However, as the discipline was immature, and controlled by relatively few entities, questioning the status quo was not without difficulties. However, in order for the discipline to mature, more feedback into the overall computer security (and in particular, the computer malware/virus) system was needed, requiring a shift from a mostly closed system to one that was forced to undergo greater scrutiny from various other communities. The input from these communities resulted in long-term changes and increased maturation of the system. Figure 1 illustrates the specific areas in which the research presented herein addressed these needs, provides an overview of the research context, and outlines the specific impact of the research, specifically the development of new and significant scientific paradigms within the discipline

Large-Scale Linear Programming

During the week of June 2-6, 1980, the System and Decision Sciences Area of the International Institute for Applied Systems Analysis organized a workshop on large-scale linear programming in collaboration with the Systems Optimization Laboratory (SOL) of Stanford University, and co-sponsored by the Mathematical Programming Society (MPS). The participants in the meeting were invited from amongst those who actively contribute to research in large-scale linear programming methodology (including development of algorithms and software). The first volume of the Proceedings contains five chapters. The first is an historical review by George B. Dantzig of his own and related research in time-staged linear programming problems. Chapter 2 contains five papers which address various techniques for exploiting sparsity and degeneracy in the now standard LU decomposition of the basis used with the simplex algorithm for standard (unstructured) problems. The six papers of Chapter 3 concern aspects of variants of the simplex method which take into account through basis factorization the specific block-angular structure of constraint matrices generated by dynamic and/or stochastic linear programs. In Chapter 4, five papers address extensions of the original Dantzig-Wolfe procedure for utilizing the structure of planning problems by decomposing the original LP into LP subproblems coordinated by a relatively simple LP master problem of a certain type. Chapter 5 contains four papers which constitute a mini-symposium on the now famous Shor-Khachian ellipsoidal method applied to both real and integer linear programs. The first chapter of Volume 2 contains three papers on non-simplex methods for linear programming. The remaining chapters of Volume 2 concern topics of present interest in the field. A bibliography a large-scale linear programming research completes Volume 2

Accountants\u27 index. Twenty-fourth supplement, January-December 1975

https://egrove.olemiss.edu/aicpa_accind/1026/thumbnail.jp

Changing the way the world thinks about computer security

Small changes in an established system can result in larger changes in the overall system (e.g. network effects, émergence, criticality, broken Windows theory). However, in an immature discipline, such as computer security, such changes can be difficult to envision and even more difficult to amplement, as the immature discipline is likely to lack the scientific framework that would allow for the introduction of even minute changes. (Cairns, P. and Thimbleby, H, 2003) describe three of the signs of an immature discipline as postulated by (Kuhn, 1970): a. squabbles over what are legitimate tools for research b. disagreement over which phenomenon are legitimate to study, and c. inability to scope the domain of study. The research presented in this document demonstrates how the computer security field, at the time this research began, was the embodiment of thèse characteristics. It presents a cohesive analysis of the intentional introduction of a séries of small changes chosen to aid in maturation of the discipline. Summarily, it builds upon existing theory, exploring the combined effect of coordinated and strategie changes in an immature system and establishing a scientific framework by which the impact of the changes can be quantified. By critically examining the nature of the computer security system overall, this work establishes the need for both increased scientific rigor, and a multidisciplinary approach to the global computer security problem. In order for these changes to take place, many common assumptions related to computer security had to be questioned. However, as the discipline was immature, and controlled by relatively few entities, questioning the status quo was not without difficulties. However, in order for the discipline to mature, more feedback into the overall computer security (and in particular, the computer malware/virus) system was needed, requiring a shift from a mostly closed system to one that was forced to undergo greater scrutiny from various other communities. The input from these communities resulted in long-term changes and increased maturation of the system. Figure 1 illustrates the specific areas in which the research presented herein addressed these needs, provides an overview of the research context, and outlines the specific impact of the research, specifically the development of new and significant scientific paradigms within the discipline.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Negoitation in Modernity : The BAZNAS (National Zakat Collection Agency) and the Philosophy of Zakat (Alms) Socialization in Indonesia

To pay Zakat (alms) is an obligation for a Muslim. However, this religious obligation cannot encourage Muslims in Indonesia to pay Zakat. In fact, in several cities, some Zakat organizations are established to collect the zakat. Some of them is the BAZNAS which is spread in most cities in Indonesia. In fact, this organization is a semi-government because there are some collaborations between the BAZNAS and local government in most regions. This collaboration indicates also that it tries to get benefit from the modern and established government structure. This article aims to know the BAZNAS negoitation with modernity, specifically it wants to deal with the BAZNAS zakat socialization. Using a case study, this article finds that the zakat organization like the BAZNAS Kepulauan Meranti Indonesia deals with a complicated negoitation with modernity through its zakat socialization. In fact, there is a religious understanding among Muslims there that to pay zakat is an obligation but it cannot deal with their religious awareness to pay zakat. This article identifies that disseminating the zakat payment obligation is a never ending project. The BAZNAS improves Muslim understanding about Zakat through socialization. Some socialization activities done are using modern instruments but some are not. Keywords : Zakat, BAZNAS (National Zakat Collection Agency), Socialization