Quantitative Approaches to the Genomics of Clonal Evolution

Many problems in the biological sciences reduce to questions of genetic evolution. Entire classes of medical pathology, such as malignant neoplasia or infectious disease, can be viewed in the light of Darwinian competition of genomes. With the benefit of today's maturing sequencing technologies we can observe and quantify genetic evolution with nucleotide resolution. This provides a molecular view of genetic material that has adapted, or is in the process of adapting, to its local selection pressures. A series of problems will be discussed in this thesis, all involving the mathematical modeling of genomic data derived from clonally evolving populations. We use a variety of computational approaches to characterize over-represented features in the data, with the underlying hypothesis that we may be detecting fitness-conferring features of the biology. In Part I we consider the cross-sectional sampling of human tumors via RNA-sequencing, and devise computational pipelines for detecting oncogenic gene fusions and oncovirus infections. Genomic translocation and oncovirus infection can each be a highly penetrant alteration in a tumor's evolutionary history, with famous examples of both populating the cancer biology literature. In order to exert a transforming influence over the host cell, gene fusions and viral genetic programs need to be expressed and thus can be detected via whole transcriptome sequencing of a malignant cell population. We describe our approaches to predicting oncogenic gene fusions (Chapter 2) and quantifying host-viral interactions (Chapter 3) in large panels of human tumor tissue. The alterations that we characterize prompt the larger question of how the genetics of tumors and viruses might vary in time, leading us to the study of serially sampled populations. In Part II we consider longitudinal sampling of a clonally evolving population. Phylogenetic trees are the standard representation of a clonal process, an evolutionary picture as old as Darwin's voyages on the Beagle. Chapter 4 first reviews phylogenetic inference and then introduces a certain phylogenetic tree space that forms the starting point of our work on the topic. Specifically, Chapter 4 describes the construction of our projective tree space along with an explicit implementation for visualizing point clouds of rescaled trees. The Chapter finishes by defining a method for stable dimensionality reduction of large phylogenies, which is useful for analyzing long genomic time series. In Chapter 5 we consider medically relevant instances of clonal evolution and the longitudinal genetic data sets to which they give rise. We analyze data from (i) the sequencing of cancers along their therapeutic course, (ii) the passaging of a xenografted tumor through a mouse model, and (iii) the seasonal surveillance of H3N2 influenza's hemagglutinin segment. A novel approach to predicting influenza vaccine effectiveness is demonstrated using statistics of point clouds in tree spaces. Our investigations into clonal processes may be extended beyond naturally occurring genomes. In Part III we focus on the directed clonal evolution of populations of synthetic RNAs in vitro. Analogous to the selection pressures exerted upon malignant cells or viral particles, these synthetic RNA genomes can be evolved against a desired fitness objective. We investigate fitness objectives related to reprogramming ribosomal translation. Chapter 6 identifies high fitness RNA pseudoknot geometries capable of inducing ribosomal frameshift, while Chapter 7 takes an unbiased approach to evolving sequence and structural elements that promote stop codon readthrough

3-D Registration on Carotid Artery imaging data: MRI for different timesteps

A common problem which is faced by the researchers when dealing with arterial carotid imaging data is the registration of the geometrical structures between different imaging modalities or different timesteps. The use of the "Patient Position" DICOM field is not adequate to achieve accurate results due to the fact that the carotid artery is a relatively small structure and even imperceptible changes in patient position and/or direction make it difficult. While there is a wide range of simple/advanced registration techniques in the literature, there is a considerable number of studies which address the geometrical structure of the carotid artery without using any registration technique. On the other hand the existence of various registration techniques prohibits an objective comparison of the results using different registration techniques. In this paper we present a method for estimating the statistical significance that the choice of the registration technique has on the carotid geometry. One-Way Analysis of Variance(ANOVA) showed that the p-values were <0.0001 for the distances of the lumen from the centerline for both right and left carotids of the patient case that was studied.Comment: 4 pages, 4 figures, 1 table, preprint submitted to IEEE-EMBC 201

The potential for craft brewing tourism development in the United States: A stakeholder view

The craft brewing industry is experiencing growth worldwide; however, research on this industry has been scant in various domains, including research exploring the relationships between craft breweries and tourism. This study contributes to extant academic literature, investigating the perceived potential and challenges of craft brewing tourism (CBT) among 221 micro/small United States craft brewing operators. The study adopts stakeholder theory (ST) as the theoretical framework. Overall, participants perceived the potential of craft beer tourism (CBT) in their region/state. Pubs/bars selling locally crafted beer, packaged tours, beer-food pairings, tours and trails were predominantly identified forms of CBT development, while limited logistics and lack of time were main perceived challenges. Various statistically significant differences were identified, particularly based on level of production and age of the brewery. However, overall, most tests yielded similar levels of agreement. Alignments were revealed between the findings and ST’s theses, namely, descriptive, instrumental, normative, and managerial

A resource based approach in the context of the emerging craft brewing industry

Purpose: The purpose of this exploratory study is to examine the perceived resources, strengths, weaknesses, opportunities and threats from the perspective of micro and small brewery owners, managers and brewing masters operating in three countries. To this end, the study adopts the resource based view (RBV) of the firm, complemented by a SWOT analysis. Design/methodology/approach: The research provides a mixed methods approach. Data were collected from craft breweries in Italy, Spain and the United Kingdom (UK). 165 valid responses were obtained from an online questionnaire, and an additional 24 face-to-face and telephone interviews with craft brewing operators in these three countries were conducted to further enrich the data. Independent samples t-test and Scheffé post hoc were used to analyse part of the quantitative data, while content analysis and word association were used for the qualitative component. Findings: Product quality and uniqueness of product emerged as important perceived resources and strengths, suggesting an alignment with some of the resource related attributes postulated by the RBV, such as valuable, rare, and (un)substitutable. Other elements, such as natural and sustainable resources, including water quality and the current and future involvement in growing or sourcing raw products locally emerged as key resources, and are suggested as additional attributes. These strategic and tangible resources are however challenged by perceived weaknesses, particularly lack of financial, infrastructure and commercialisation resources, as well as threats from competition. Originality/value: The exploratory study focuses on craft brewing from the perspective of micro/small operators. This industry has received very limited attention from the literature. The use of the RBV, with the potential to increase understanding of an emerging industry, and develop the theory further in this domain, adds to the originality and value of this research

Micro enterprises, self-efficacy and knowledge acquisition: evidence from Greece and Spain

Purpose: The purpose of this exploratory study is to investigate the significance of self-efficacy and knowledge acquisition among micro businesses operating in challenging economic environments. The study uses social cognitive theory (SCT) and the knowledge-based theory of the firm (KBTF), and it proposes a refinement of these theoretical frameworks in the context of the study. Design/methodology/approach: A case method was chosen, and face-to-face interviews with 14 owners of firms in island and rural regions of Greece and Spain were conducted. Findings: Content analysis identified the importance of self-efficacy, primarily illustrated by entrepreneurs’ determination and self-motivation, propensity to take risks and ability to anticipate consequences of their actions. Acquisition and accumulation of explicit knowledge, particularly through generational or mentoring processes, and subsequent wealth of tacit knowledge, also emerged as very significant in preparing and guiding entrepreneurs. Various links between the adopted theories and findings emerged, particularly regarding forethought, vicarious learning (SCT) and specialisation in knowledge acquisition (KBTF). Originality/value: The proposed theoretical refinement based on the SCT and KBTF paradigms allows for a more rigorous, in-depth reflection on the links between cognitive elements present in the participating micro entrepreneurs and knowledge-based attributes on their ability to increase organisational resilience. The study also contributes toward the micro business literature and addresses a knowledge gap, particularly, in that contemporary research has not explored entrepreneurial motivations among small firm entrepreneurs. Finally, the practical implications emerging from the findings provide a platform for various stakeholders (associations, government agencies) to appreciate and support entrepreneurs’ needs, notably, of acquiring, increasing and sharing knowledge. © 2018, Emerald Publishing Limited

Resilience and coping behaviour among micro and small sized enterprises in times of economic crisis: A mixed-methods exploration of Greek and Cypriot firms

The focus of this study was to explore organisational resilience in the context of micro, small, and medium sized enterprises (SMEs). Following the 2008 Global Financial Crisis (GFC), the deteriorating business conditions worldwide posed serious challenges to many firms. SMEs were particularly affected by the volatile environment due to acknowledged operational limitations (e.g., scarce resources) restricting their capacity to effectively respond to the new business reality. The impact was extremely high for businesses in the Southern European periphery, including Greece and Cyprus. Despite the growing academic interest in the concept of resilience over the past years, it remains unclear how SMEs can develop resilience and cope with different type of shocks (e.g., 2008 GFC, COVID-19). Due to the significant role SMEs have for the Greek and Cypriot economies (e.g., employment), among other countries, and various ongoing challenges (e.g., access to finance) that leave them exposed to impending turbulences, it is urgent to further explore the antecedents of resilience and determine how SMEs can promote resilience capabilities to adapt to volatile operational conditions. Based on a mixed-methods approach (parallel mixed design), empirical data were collected via semi-structured interviews (n=135) and questionnaires (n=406) from micro and small businesses (MSEs) in Greece and Cyprus; the lack of responses from medium sized enterprises represents one of the limitations of the study. In line with a parallel mixed data analysis, a distinct thematic analysis of qualitative data resulted in several themes that reflect the post-2008 business environment in Greece and Cyprus, and the factors that influence the resilience capacity of MSEs. Additional descriptive and inferential statistical tests provided evidence regarding the performance of Greek and Cypriot MSEs after the 2008 GFC and identified the critical success factors associated with a firm’s coping capacity, among other results. Following the integration of qualitative and quantitative findings (narrative, joint display approaches), the resulting meta-inferences highlight several characteristics that influence the different resilience phases, namely anticipation (e.g., environmental scanning), coping (e.g., financial resourcefulness), and adaptation (e.g., innovative activities). The findings provide additional empirical support about the antecedents of resilience, specifically in the context of micro and small firms from Greece and Cyprus, and respond to acknowledged knowledge gaps, thereby contribute to the existing body of literature focusing on organisational resilience

Corporate social responsibility in a burgeoning industry: a stakeholder analysis

Purpose: The purpose of this paper is to investigate the extent and significance of involvement of craft brewery operators in their community through the lens of the stakeholder theory (ST). In addition, differences between forms of involvement and demographic characteristics of operators and breweries are examined. Design/methodology/approach: As many as 218 operators of predominantly micro-craft breweries across the USA participated in an online questionnaire designed to gather their perceptions. Findings: While paying taxes was participants’ main perceived form of contribution, providing an artisan-made product, the significance of the craft brewery as a community “hub”, and that of increasing the number of leisure alternatives also emerged. A further 52.8 per cent of participants indicated contributing US$100,000 or more to the community annually. Statistically significant differences were revealed, for instance, based on craft breweries’ production volume, and the level of financial contribution. Various associations between operators’ perceived contributions and the ST theses were established in regard to cooperative interests (descriptive), stakeholder management (instrumental), and moral principles (normative). Originality/value: First, by examining corporate social responsibility (CSR) in the craft brewing industry and among predominantly smaller firms, the study addresses two under-researched areas. Second, a refinement of the ST in the context of the craft brewing industry is proposed, highlighting the links between ST-based theses and the findings. Third, the study contributes to three different types of literature: micro and small business, craft brewing entrepreneurship, and CSR. © 2018, Emerald Publishing Limited

Strengths, innovation, and opportunities in a burgeoning industry: an exploratory study

Purpose: The purpose of this paper is to examine key areas related to the craft brewing industry from the perspective of operators of micro and small craft breweries, and propose a framework based on the resourced-based theory of the firm and the theory of innovation. The areas investigated include participants’ perceived strengths of their craft brewery, involvement in innovative practices, opportunities for the craft brewing firm, and potential differences related to these areas based on the demographic characteristics of participants and their breweries. Design/methodology/approach: Given its growing significance and economic contribution, the US craft brewery industry was chosen for this study. An online questionnaire was designed to gather data from craft brewery operators across the nation. Findings: Product and service quality, knowledge, reputation, and expertise were revealed as key strengths, while creating new recipes and using social media tools were the most considered ways of innovating. Furthermore, opportunities were perceived through craft beer tourism, increased consumption, and quality improvements. Statistically significant differences emerged, particularly based on production levels, staff numbers, and involvement/no involvement in exports. Various associations between the findings and the adopted theoretical frameworks were revealed. Originality/value: In terms of originality, the proposed refinement based on the adopted theoretical frameworks and findings facilitates understanding of the significance of resources and innovation, particularly for firms operating in a growing industry. Regarding value, the findings have important implications for the industry, for instance, in the marketing of craft brewing, as well as in the development of new craft brewing products. © 2018, Emerald Publishing Limited