The Role of Splicing Factors and Small Nuclear RNAS in Spliceosomal Formation

Protein coding genes are comprised of protein-coding exons and non-protein-coding introns. The process of splicing involves removal of the introns and joining of the exons to form a mature messenger RNA, which subsequently undergoes translation into polypeptide. The spliceosome is a large, RNA/protein assembly of five small nuclear RNAs as well as over 300 proteins, which catalyzes intron removal and exon ligation. The selection of specific exons for inclusion in the mature messenger RNA is spatio-temporally regulated and results in production of an enormous diversity of polypeptides from a single gene locus. This phenomenon, known as alternative splicing, is regulated, in part, by protein splicing factors, which target the spliceosome to exon/intron boundaries. The first part of my dissertation (Chapters II and III) focuses on the discovery and characterization of the 45 kilodalton FK506 binding protein (FKBP45), which I discovered in the silk moth, Bombyx mori, as a U1 small nuclear RNA binding protein. This protein family binds the immunosuppressants FK506 and rapamycin and contains peptidyl-prolyl cis-trans isomerase activity, which converts polypeptides from cis to trans about a proline residue. This is the first time that an FKBP has been identified in the spliceosome. The second section of my dissertation (Chapters IV, V, VI and VII) is an investigation of the potential role of small nuclear RNA sequence variants in the control of splicing. I identified 46 copies of small nuclear RNAs in the 6X whole genome shotgun of the Bombyx mori p50T strain. These variants may play a role in differential binding of specific proteins that mediate alternative splicing. Along these lines, further investigation of U2 snRNA sequence variants in Bombyx mori demonstrated that some U2 snRNAs preferentially assemble into high molecular weight spliceosomal complexes over others. Expression of snRNA variants may represent another mechanism by which the cell is able to fine tune the splicing process.

Community library programs that work: Building youth and family literacy

A collection of versatile best practices for promoting literacy development by utilizing local community connections in school and public libraries. This book provides a fresh approach to learning as well as guidelines for creating dynamic and relevant library programs for children, teens, and families. Organized thematically, each chapter includes relevant topical research and three to eight community-focused approaches. Programs range from small, single-library initiatives in rural communities to multi-site, cross-border initiatives. This resource includes collaborative and locally inspired programs, many of which can be scaled to the budget of any library, school, or community organization.

Genome-wide association study reveals greater polygenic loading for schizophrenia in cases with a family history of illness

Genome-wide association studies (GWAS) of schizophrenia have yielded more than 100 common susceptibility variants, and strongly support a substantial polygenic contribution of a large number of small allelic effects. It has been hypothesized that familial schizophrenia is largely a consequence of inherited rather than environmental factors. We investigated the extent to which familiality of schizophrenia is associated with enrichment for common risk variants detectable in a large GWAS. We analyzed single nucleotide polymorphism (SNP) data for cases reporting a family history of psychotic illness (N = 978), cases reporting no such family history (N = 4,503), and unscreened controls (N = 8,285) from the Psychiatric Genomics Consortium (PGC1) study of schizophrenia. We used a multinomial logistic regression approach with model-fitting to detect allelic effects specific to either family history subgroup. We also considered a polygenic model, in which we tested whether family history positive subjects carried more schizophrenia risk alleles than family history negative subjects, on average. Several individual SNPs attained suggestive but not genome-wide significant association with either family history subgroup. Comparison of genome-wide polygenic risk scores based on GWAS summary statistics indicated a significant enrichment for SNP effects among family history positive compared to family history negative cases (Nagelkerke's R(2 ) = 0.0021; P = 0.00331; P-value threshold <0.4). Estimates of variability in disease liability attributable to the aggregate effect of genome-wide SNPs were significantly greater for family history positive compared to family history negative cases (0.32 and 0.22, respectively; P = 0.031). We found suggestive evidence of allelic effects detectable in large GWAS of schizophrenia that might be specific to particular family history subgroups. However, consideration of a polygenic risk score indicated a significant enrichment among family history positive cases for common allelic effects. Familial illness might, therefore, represent a more heritable form of schizophrenia, as suggested by previous epidemiological studies.

Product and Process Innovation: Antecedents and Performance outcomes in small IT firms in India

Innovation is a strategic necessity for the survival of today’s organizations. The wide recognition of innovation as a competitive necessity, particularly in dynamic market environments, makes it an evergreen domain for research. This dissertation deals with innovation in small Information Technology (IT) firms in India. The IT industry in India has been a phenomenal success story of the last three decades, and is today facing a crucial phase in its history characterized by the need for fundamental changes in strategies, driven by innovation. This study, while motivated by the dynamics of changing times, importantly addresses the research gap on small firm innovation in Indian IT.This study addresses three main objectives: (a) drivers of innovation in small IT firms in India (b) impact of innovation on firm performance (c) variation in the extent of innovation adoption in small firms. Product and process innovation were identified as the two most contextually relevant types of innovation for small IT firms. The antecedents of innovation were identified as Intellectual Capital, Creative Capability, Top Management Support, Organization Learning Capability, Customer Involvement, External Networking and Employee Involvement.Survey method was adopted for data collection and the study unit was the firm. Surveys were conducted in 2014 across five South Indian cities. Small firm was defined as one with 10-499 employees. Responses from 205 firms were chosen for analysis. Rigorous statistical analysis was done to generate meaningful insights. The set of drivers of product innovation (Intellectual Capital, Creative Capability, Top Management Support, Customer Involvement, External Networking, and Employee Involvement)were different from that of process innovation (Creative Capability, Organization Learning Capability, External Networking, and Employee Involvement). Both product and process innovation had strong impact on firm performance. It was found that firms that adopted a combination of product innovation and process innovation had the highest levels of firm performance. Product innovation and process innovation fully mediated the relationship between all the seven antecedents and firm performance The results of this study have several important theoretical and practical implications. To the best of the researcher’s knowledge, this is the first time that an empirical study of firm level innovation of this kind has been undertaken in India. A measurement model for product and process innovation was developed, and the drivers of innovation were established statistically. Customer Involvement, External Networking and Employee Involvement are elements of Open Innovation, and all three had strong association with product innovation, and the latter twohad strong association with process innovation. The results showed that proclivity for Open Innovation is healthy in the Indian context. Practical implications have been outlined along how firms can organize themselves for innovation, the human talent for innovation, the right culture for innovation and for open innovation. While some specific examples of possible future studies have been recommended, the researcher believes that the study provides numerous opportunities to further this line of enquiry.

Influence of Forecasting, Planning and Controlling on the performance of Small and Medium Enterprises

Production Planning and Control (PPC) systems have grown and changed because of the developments in planning tools and models as well as the use of computers and information systems in this area. Though so much is available in research journals, practice of PPC is lagging behind and does not use much from published research. The practices of PPC in SMEs lag behind because of many reasons, which need to be explored. This research work deals with the effect of identified variables such as forecasting, planning and control methods adopted, demographics of the key person, standardization practices followed, effect of training, learning and IT usage on firm performance. A model and framework has been developed based on literature. Empirical testing of the model has been done after collecting data using a questionnaire schedule administered among the selected respondents from Small and Medium Enterprises (SMEs) in India. Final data included 382 responses. Hypotheses linking SME performance with the use of forecasting, planning and controlling were formed and tested. Exploratory factor analysis was used for data reduction and for identifying the factor structure. High and low performing firms were classified using a Logistic Regression model. A confirmatory factor analysis was used to study the structural relationship between firm performance and dependent variables.

EULAR Recommendations for Women's Health and the Management of Family Planning, Assisted Reproduction, Pregnancy and Menopause in Patients with Systemic Lupus Erythematosus and/or Antiphospholipid Syndrome

OBJECTIVES: Develop recommendations for women's health issues and family planning in systemic lupus erythematosus (SLE) and/or antiphospholipid syndrome (APS). METHODS: Systematic review of evidence followed by modified Delphi method to compile questions, elicit expert opinions and reach consensus. RESULTS: Family planning should be discussed as early as possible after diagnosis. Most women can have successful pregnancies and measures can be taken to reduce the risks of adverse maternal or fetal outcomes. Risk stratification includes disease activity, autoantibody profile, previous vascular and pregnancy morbidity, hypertension and the use of drugs (emphasis on benefits from hydroxychloroquine and antiplatelets/anticoagulants). Hormonal contraception and menopause replacement therapy can be used in patients with stable/inactive disease and low risk of thrombosis. Fertility preservation with gonadotropin-releasing hormone analogues should be considered prior to the use of alkylating agents. Assisted reproduction techniques can be safely used in patients with stable/inactive disease; patients with positive antiphospholipid antibodies/APS should receive anticoagulation and/or low-dose aspirin. Assessment of disease activity, renal function and serological markers is important for diagnosing disease flares and monitoring for obstetrical adverse outcomes. Fetal monitoring includes Doppler ultrasonography and fetal biometry, particularly in the third trimester, to screen for placental insufficiency and small for gestational age fetuses. Screening for gynaecological malignancies is similar to the general population, with increased vigilance for cervical premalignant lesions if exposed to immunosuppressive drugs. Human papillomavirus immunisation can be used in women with stable/inactive disease. CONCLUSIONS: Recommendations for women's health issues in SLE and/or APS were developed using an evidence-based approach followed by expert consensus.

How do Small Players Deduce Beliefs about Uncertainty? A Look at Texas Shale Oil Investments

Thesis (Ph.D.)--University of Washington, 2016-08

Strategic Management of Resources for International Business Operations in Small Consulting Firms - People, Processes and Tools in Managing International operations

Research on strategic management of resources for small consulting firms which are international or planning to operate internationally is scarce or not existing at all. It is however important to start generating the theories that will support managers in their decision making and planning. This thesis investigates how do small management consulting firms manage their internal and external resources while operating in international markets. Throughout the study, aspects related to internal and external resources management as well as management strategies in these firms have been examined in relations to firm’s internationalisation activities. A qualitative analysis was carried out whereby four small consulting firms in Export Management Consulting, Integration Services Consulting-, Software Development Consulting- and Business Solutions Consulting companies were interviewed. In order to generate the holistic understanding of the study, the thesis writer selected Value Enhanced Collaborative Working (VECW) model as an analysis framework. The model focuses on people, processes and tools as key elements that small consulting firms consider when thinking about managing their international operations. The findings of the thesis reveal that, internal and external resources in the interviewed consulting firms are viewed similarly, but managed differently depending on the nature and size of the firm. Firm’s management strategies concentrate on the adequate utilisation of the employees' motivation and experiences, effective stakeholders' management, various administrative evaluation processes and tools, the ability to realise useful networks, constant improvement through employee trainings, employees and customers’ feedbacks as well as enhanced freedom in order to support employees’ creativity. Further research to examine functional administrative tools and tools that small consulting firms could use to assess their resource capabilities when planning to become international would benefit the smaller businesses in terms of resources management and certainty in planning.

Identification and Characterization of New Small Molecule Inhibitors of Picornavirus Replication

The Picornaviridae family consists of positive-strand RNA viruses that are the causative agents of a variety of diseases in humans and animals. Few drugs targeting picornaviruses are available, making the discovery of new antivirals a high priority. Here, we identified and characterized three compounds from a library of kinase inhibitors that block replication of poliovirus, coxsackievirus B3, and encephalomyocarditis virus. The antiviral effect of these compounds is not likely related to their known cellular targets because other inhibitors targeting the same pathways did not inhibit viral replication. Using an in vitro translation-replication system, we showed that these drugs inhibit different stages of the poliovirus life cycle. A4(1) inhibited the formation of a functional replication complex, while E5(1) and E7(2) affected replication after the replication complex had formed. A4(1) demonstrated partial protection from paralysis in a murine model of poliomyelitis. Poliovirus resistant to E7(2) had a single mutation in the 3A protein. This mutation was previously found to confer resistance to enviroxime-like compounds, which target either PI4KIIIβ (major enviroxime-like compounds) or OSBP (minor enviroxime-like compounds), cellular factors involved in lipid metabolism and shown to be important for replication of diverse positive-strand RNA viruses. We classified E7(2) as a minor enviroxime-like compound, because the localization of OSBP changed in the presence of this inhibitor. Interestingly, both E7(2) and major enviroxime-like compound GW5074 interfered with the viral polyprotein processing. Multiple attempts to isolate resistant mutants in the presence of A4(1) or E5(1) were unsuccessful, showing that effective broad-spectrum antivirals could be developed on the basis of these compounds. Studies with these compounds shed light on pathways shared by diverse picornaviruses that could be potential targets for the development of broad-spectrum antiviral drugs.

Small strain elastic behaviour of unsaturated soil investigated by bender/extender element testing

The aim of this project was to investigate very small strain elastic behaviour of soils under unsaturated conditions, using bender/extender element (BEE) testing. The behaviour of soils at very small strains has been widely studied under saturated conditions, whereas much less work has been performed on very small strain behaviour under unsaturated conditions. A suction-controlled double wall triaxial apparatus for unsaturated soil testing was modified to incorporate three pairs of BEEs transmitting both shear and compression waves with vertical and horizontal directions of wave transmission and wave polarisation. Various different techniques for measuring wave travel time were investigated in both the time domain and the frequency domain and it was concluded that, at least for the current experimental testing programme, peak-to-first-peak in the time domain was the most reliable technique for determining wave travel time. An experimental test programme was performed on samples of compacted speswhite kaolin clay. Two different forms of compaction were employed (i.e. isotropic and anisotropic). Compacted kaolin soil samples were subjected to constant suction loading and unloading stages at three different values of suction, covering both unsaturated conditions (s= 50kPa and s= 300kPa) and saturated conditions (s=0). Loading and unloading stages were performed at three different values of stress ratio (η=0, η=1 and η=-1 ). In some tests a wetting-drying cycle was performed before or within the loading stage, with the wetting-drying cycles including both wetting-induced swelling and wetting-induced collapse compression. BEE tests were performed at regular intervals throughout all test stages, to measure shear wave velocity Vs and compression wave velocity Vp and hence to determine values of shear modulus G and constrained modulus M. The experimental test programme was designed to investigate how very small strain shear modulus G and constrained modulus M varied with unsaturated state variables, including how anisotropy of these parameters developed either with stress state (stress-induced anisotropy) or with previous straining (strain-induced anisotropy). A new expression has been proposed for the very small strain shear modulus G of an isotropic soil under saturated and unsaturated conditions. This expression relates the variation of G to only mean Bishop’s stress p* and specific volume v, and it converges to a well-established expression for saturated soils as degree of saturation approaches 1. The proposed expression for G is able to predict the variation of G under saturated and unsaturated conditions at least as well as existing expressions from the literature and it is considerably simpler (employing fewer state variables and fewer soil constants). In addition, unlike existing expressions from the literature, the values of soil constants in the proposed new expression can be determined from a saturated test. It appeared that, in the current project at least, any strain-induced anisotropy of very small strain elastic behaviour was relatively modest, with the possible exception of loading in triaxial extension. It was therefore difficult to draw any firm conclusion about evolution of strain-induced anisotropy and whether it depended upon the same aspects of soil fabric as evolution of anisotropy of large strain plastic behaviour. Stress-induced anisotropy of very small strain elastic behaviour was apparent in the experimental test programme. An attempt was made to extend the proposed expression for G to include the effect of stress-induced anisotropy. Interpretation of the experimental results indicated that the value of shear modulus was affected by the values of all three principal Bishop’s stresses (in the direction of wave transmission, the direction of wave polarisation and the third mutually perpendicular direction). However, prediction of stress-induced anisotropy was only partially successful, and it was concluded that the effect of Lode angle was also significant.

Green supply chain management practices and firm performance: evidence from Finland

In order to address the increasing stakeholder requirements for environmentally sustainable products and processes, firms often need the participation of their supply chain partners. Green supply chain management has emerged as a set of managerial practices that integrate environmental issues into supply chain management. If implemented successfully, green supply chain management can be a way to achieve competitive advantage while enhancing the environmental sustainability of the firm. The overall purpose of this dissertation is to contribute to the discussion on green supply chain management practices from the perspective of their drivers and performance implications. The theoretical background arises from the literature on competitive strategy, firm performance and green supply chain management. The research questions are addressed by analysing firm-level data from manufacturing, trading and logistics firms operating in Finland. The empirical data comes from two consecutive Finland State of Logistics surveys in 2012 and 2014, combined with financial reporting data from external databases. The data is analysed with multiple statistical methods. First, the thesis contributes to the discussion of the drivers of GSCM practices. To enhance the understanding of the relationship between competitive strategy and GSCM practices, a conceptual tool to describe generic competitive strategy approaches was developed. The findings suggest that firms pursuing marketing differentiation are more likely to be able to compete by having only small environmental effects and by adopting a more advanced form of external green supply chain management, such as a combination of strong environmental collaboration and the increased environmental monitoring of suppliers. Furthermore, customer requirements for environmental sustainability are found to be an important driver in the implementation of internal GSCM practices. Firms can respond to this customer pressure by passing environmental requirements on to their suppliers, either through environmental collaboration or environmental monitoring. Second, this thesis adds value to the existing literature on the effects of green supply chain management practices on firm performance. The thesis provides support for the idea that there is a positive relationship between GSCM practices and firm performance and enhances the understanding of how different types of GSCM practices are related to 1) financial, 2) operational and 3) environmental performance in manufacturing and logistics. The empirical results suggest that while internal GSCM practices have the strongest effect on environmentalperformance, environmental collaboration with customers seems to be the most effective way to improve financial performance. In terms of operational performance, the findings were more mixed, suggesting that the operational performance of firms is more likely to be affected by firm characteristics than by the choices they make regarding their environmental collaboration. This thesis is also one of the first attempts to empirically analyse the relationship between GSCM practices and performance among logistics service providers. The findings also have managerial relevance. Management, especially in manufacturing and logistics industries, may benefit by gaining knowledge about which types of GSCM practice could provide the largest benefits in terms of different performance dimensions. This thesis also has implications for policy-makers and regulators regarding how to promote environmentally friendly activities among 1) manufacturing; 2) trading; and 3) logistics firms.

Three essays on corporate taxation : financial reporting, value, and firm creation

Doutoramento em Gestão

Social-cognitive Antecedents of Ambidextrous Orientation in Family-owned Startups: The Role of Family Ties, Achievement Motivation, and Internal Locus of Control

Regulatory Focus Theory predicts that the motivation to self-regulate goal-directed thought and behavior depends on two distinct regulation strategies: a promotion focus based on attaining gains and a prevention focus based on avoiding losses. This study took a social-cognitive approach predicting that regulatory focus has an impact on how family startups (several family related founders) explore “new ideas”, exploit “old certainties” and achieve the balance of both (ambidexterity), compared to lone founder startups (only one founder present). It was proposed that the social context of family ties among founders leads them to a prevention focus concerned with avoiding the loss of the socio-emotional benefits of those ties. In order to avoid such a loss, family founders were expected to increase their risk perceptions and thus, explore less than lone founders, who lack such socio-emotional ties. It was also proposed that two commonly used psychological traits in entrepreneurship research --achievement motivation and internal locus of control, predispose entrepreneurs to a promotion focus. Founders with a promotion focus, in turn, were hypothesized to lead startups to more risk-seeking behaviors and to more explorative orientation. The previous argument was used as a springboard to derive hypotheses about ambidexterity (the ability to exploit and explore simultaneously) and survival hazards. Using Regulatory Focus Theory, exploitative orientation, conceptualized as the motivational strength to continue on previous paths of action, was hypothesized to be not significantly different from that of lone founder startups. Taking previous arguments together, lone founder startups were hypothesized to be more ambidextrous than family startups. Finally, ambidexterity and internal locus of control were hypothesized to reduce survival hazards in family startups. The findings suggested that family startups explore less than lone founder startups even after controlling for group effects. Interesting but contradictory findings revealed that internal locus of control have both a positive direct effect and a positive interaction that increases the explorative and ambidextrous orientation gap of family startups over lone founder startups. As expected, ambidexterity and internal locus of control reduced survival hazards on family startups. Implications for practitioners were derived based on a sample of 470 nascent entrepreneurs.

Ownership Structure, Board Composition and Entrepreneurship : Evidence from Family Firms and Venture-Capital Backed Firms

The purpose of this article is to investigate how ownership structure, especially family and/or venture-capital involvement, as well as entrepreneurial activities, defined as strategic change and renewal, help explain the involvement of independent members on boards of directors. The CEOs of 2,455 small and medium-sized, private enterprises from practically all industries were contacted in a telephone survey, resulting in an exceptionally high response rate. The findings reveal that family firms are more reluctant to involve independent directors on their boards than non-family firms that presence of venture capitalists increases the frequency of independent board members and that ownership has an impact on board roles. The results do not support the hypothesised relationship that independent directors enhance entrepreneurial activities. One implication of our study is that the often-argued-for strategic contribution of outsiders to the boards in family firms may be overemphasised. Another implication is that family firms that choose to acquire additional capital should be aware that this could result in a change in the board composition and the loss of control of the business. However, new and external owners’ inclusion on the board seems to be negotiable since there are also venture capitalists that do not insist on board representation.

Behavioural theory and the family business

Fifty years have passed since Cyert and March’s 1963 A Behavioral Theory of the Firm. During this time, BTOF has been adopted across different research domains to investigate how organizations set goals, how they determine aspirations and how they finally react to performance aspiration discrepancies. Cyert and March’s framework has also recently emerged as one of the dominant paradigms to understand the ways in which family business organizations make decisions. In this chapter, I review the theoretical development and empirical results of BTOF and its application in the family business field of study in order to identify theoretical and empirical gaps and propose suggestions for future research. The conclusions suggest that BTOF is both a theoretically and empirically valid perspective in family business research, particularly when combined with other theoretical frameworks. The principal recommendation is to apply behavioral theory to enhance scholarly understanding of  how family organisations define their aspiration levels and respond to organizational problems.