Data integration from two microarray platforms identifies bi-allelic genetic inactivation of RIC8A in a breast cancer cell line

Background: Using array comparative genomic hybridization (aCGH), a large number of deleted genomic regions have been identified in human cancers. However, subsequent efforts to identify target genes selected for inactivation in these regions have often been challenging. Methods: We integrated here genome-wide copy number data with gene expression data and non-sense mediated mRNA decay rates in breast cancer cell lines to prioritize gene candidates that are likely to be tumour suppressor genes inactivated by bi-allelic genetic events. The candidates were sequenced to identify potential mutations. Results: This integrated genomic approach led to the identification of RIC8A at 11p15 as a putative candidate target gene for the genomic deletion in the ZR-75-1 breast cancer cell line. We identified a truncating mutation in this cell line, leading to loss of expression and rapid decay of the transcript. We screened 127 breast cancers for RIC8A mutations, but did not find any pathogenic mutations. No promoter hypermethylation in these tumours was detected either. However, analysis of gene expression data from breast tumours identified a small group of aggressive tumours that displayed low levels of RIC8A transcripts. qRT-PCR analysis of 38 breast tumours showed a strong association between low RIC8A expression and the presence of TP53 mutations (P = 0.006). Conclusion: We demonstrate a data integration strategy leading to the identification of RIC8A as a gene undergoing a classical double-hit genetic inactivation in a breast cancer cell line, as well as in vivo evidence of loss of RIC8A expression in a subgroup of aggressive TP53 mutant breast cancers.

Part I: Enzyme replacement versus neurotrophic factor viral vector-mediated gene therapy of Parkinson’s disease, Part II: The effects of orally dosed tolcapone and entacapone on dopamine metabolism in the dorsal striatum and nucleus accumbens in rats

Part I: Parkinson’s disease is a slowly progressive neurodegenerative disorder in which particularly the dopaminergic neurons of the substantia nigra pars compacta degenerate and die. Current conventional treatment is based on restraining symptoms but it has no effect on the progression of the disease. Gene therapy research has focused on the possibility of restoring the lost brain function by at least two means: substitution of critical enzymes needed for the synthesis of dopamine and slowing down the progression of the disease by supporting the functions of the remaining nigral dopaminergic neurons by neurotrophic factors. The striatal levels of enzymes such as tyrosine hydroxylase, dopadecarboxylase and GTP-CH1 are decreased as the disease progresses. By replacing one or all of the enzymes, dopamine levels in the striatum may be restored to normal and behavioral impairments caused by the disease may be ameliorated especially in the later stages of the disease. The neurotrophic factors glial cell derived neurotrophic factor (GDNF) and neurturin have shown to protect and restore functions of dopaminergic cell somas and terminals as well as improve behavior in animal lesion models. This therapy may be best suited at the early stages of the disease when there are more dopaminergic neurons for neurotrophic factors to reach. Viral vector-mediated gene transfer provides a tool to deliver proteins with complex structures into specific brain locations and provides long-term protein over-expression. Part II: The aim of our study was to investigate the effects of two orally dosed COMT inhibitors entacapone (10 and 30 mg/kg) and tolcapone (10 and 30 mg/kg) with a subsequent administration of a peripheral dopadecarboxylase inhibitor carbidopa (30 mg/kg) and L- dopa (30 mg/kg) on dopamine and its metabolite levels in the dorsal striatum and nucleus accumbens of freely moving rats using dual-probe in vivo microdialysis. Earlier similarly designed studies have only been conducted in the dorsal striatum. We also confirmed the result of earlier ex vivo studies regarding the effects of intraperitoneally dosed tolcapone (30 mg/kg) and entacapone (30 mg/kg) on striatal and hepatic COMT activity. The results obtained from the dorsal striatum were generally in line with earlier studies, where tolcapone tended to increase dopamine and DOPAC levels and decrease HVA levels. Entacapone tended to keep striatal dopamine and HVA levels elevated longer than in controls and also tended to elevate the levels of DOPAC. Surprisingly in the nucleus accumbens, dopamine levels after either dose of entacapone or tolcapone were not elevated. Accumbal DOPAC levels, especially in the tolcapone 30 mg/kg group, were elevated nearly to the same extent as measured in the dorsal striatum. Entacapone 10 mg/kg elevated accumbal HVA levels more than the dose of 30 mg/kg and the effect was more pronounced in the nucleus accumbens than in the dorsal striatum. This suggests that entacapone 30 mg/kg has minor central effects. Also our ex vivo study results obtained from the dorsal striatum suggest that entacapone 30 mg/kg has minor and transient central effects, even though central HVA levels were not suppressed below those of the control group in either brain area in the microdialysis study. Both entacapone and tolcapone suppressed hepatic COMT activity more than striatal COMT activity. Tolcapone was more effective than entacapone in the dorsal striatum. The differences between dopamine and its metabolite levels in the dorsal striatum and nucleus accumbens may be due to different properties of the two brain areas.

On the discursive construction of success/failure in narratives of post-merger integration

This article concentrates on the discursive constmction of success and failure in narratives of post-merger integration. Drawing on extensive interview material from eight Finnish-Swedish mergers and acquisitions, the empirical analysis leads to distinguishing four types of discourse — 'rationalistic', 'cultural', 'role-bound' and 'individualistic' — that narrators employ in recounting their experiences. In particular, the empirical material illustrates how the discursive frameworks enable specific (di.scursive) strategies and moves for (re)framing the success/failure, justification/legitimization of one's own actions, and (re)constniction of responsibility when dealing with socio-psychological pressures associated with success/failtire. The analysis also suggests that, as a result of making use of these discursive strategies and moves, success stories are likely to lead to overly optimistic or, in the case of failure stories, overly pessimistic views on the management's ability to control these change processes. Tliese findings imply that we should take the discursive elements that both constrain our descriptions and explanations seriously, and provide opportunities for more or less intentional (re)interpretations of postmerger integration or other organizational change processes.

Cultural differences and capability transfer in cross-border acquisitions: the mediating roles of capability complementarity, absorptive capacity, and social integration

This paper presents an integrative model of the impact of cultural differences on capability transfer in cross-border acquisitions. We propose that cultural differences affect the post-acquisition capability transfer through their impact on social integration, potential absorptive capacity, and capability complementarity. Two dynamic variables – the use of social integration mechanisms, and the degree of operational integration of the acquired unit – are proposed to moderate the effects of cultural differences on social integration and potential absorptive capacity. The implications for acquisition research and practice are discussed.

Integration or disintegration? Human resource implications of a common corporate language decision in a crossborder merger

The primary purpose of introducing a common corporate language in crossborder mergers is to integrate two previously separate organizations and facilitate communication. However, the present case study of a cross-border merger between two Nordic banks shows that the common corporate language decision may have disintegrating effects, particularly at organizational levels below top management. We identify such effects on performance appraisal, language training and management development, career paths, promotion and key personnel. Our findings show that top management needs to work through the consequences of the language decision upon those who are expected to make such a decision work.

Characterization of viral proteins ofOryctes baculovirus and comparison between two geographical isolates

BacilliformOryctes baculovirus particles have been visualized in electron micrographs of midgut sections from virus infectedOryctes rhinoceros beetles. Morphologically the Indian isolate (Oryctes baculovirus, KI) resembled the previously reportedOryctes baculovirus, isolate PV505. The constituent proteins of baculovirus KI have been analysed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and by Western blots using polyclonal antibodies raised against the complete viral particles, as probes. A total of forty eight viral proteins have been identified. Fourteen viral proteins were located on the viral envelope. Among the proteins constituting the nucleocapsid, three were located internally within the capsid. A 23.5 kDa protein was tightly associated with viral DNA in the nucleocapsid core. Two envelope and seven capsid proteins stained positive for glycosylation. Comparison between the viral proteins of KI and PV505 revealed differences in SDS-PAGE profiles and glycosylation patterns. Immunoblotting of KI and PV505 proteins with anti KI antiserum demonstrated antigenic differences between the two viral isolates.

The Impact of Cultural Factors on Post-Acquisition Integration: Domestic and Foreign Acquisitions of Finnish Companies in 1993-2004

Acquisitions are a central component of corporate strategy. They contribute to competitive advantage by offering possibilities for both cost reductions and for revenue enhancements. However, many acquisition benefits cannot be realized without a successful integration of the acquiring and the acquired firms. Previous research shows that national and organizational culture can play a major role in determining the integration outcomes. Therefore, the overall aim of the thesis is to map out and illustrate the impact mechanisms of cultural factors in post-acquisition integration in order to explain the cultural aspects of acquisitions. This study has three main contributions. First, the study shows that international and domestic acquisitions differ concerning both strategic and cultural fit. Second, the findings highlight the importance of acculturation and cultural integration in determining post-acquisition outcomes. Finally, the study uncovers several impact mechanisms that shed light to the contradictory results related to cultural differences in previous research.

The Impact of Readily Detected- and Underlying Attributes on Social Integration in Cross-Cultural Settings

The benefits and drawbacks of homogeneity and heterogeneity have been debated at length. Whereas some researchers assert that heterogeneity is beneficial for groups that are engaged in complex problem solving, the other researchers emphasize the potential costs associated with diversity. The inconsistency is a result of the incomplete measurement of diversity and focus one or two types of diversity. Most research concentrates on the readily detected/visible characteristics, making the assumption that such characteristics are related to underlying attributes (e.g., attitudes and values). In many cases, the demographic characteristics do not covary perfectly with the psychological attributes. Thus both types of attributes need to be utilized to fully understand the impact of diversity. The present research with four essays takes into account both types of attributes and tests their impact on social integration in cross-cultural settings. The results indicate that: (1) readily detectable- and underlying attributes are not related; (2) diversity has overall a negative impact on social integration; (3) socio-cultural context potentially influences the salience of diversity; and (4) diversity and social integration influences the formation of social cognition in form of transactive memory directories. The limits of research and managerial implications are discussed.

Multiple Perspectives on Networks: Conceptual Development, Application and Integration in an Entrepreneurial Context

Multiple Perspectives on Networks: Conceptual Development, Application and Integration in an Entrepreneurial Context. The purpose of this thesis is to enhance cross-fertilization between three different approaches to network research. The business network approach may contribute in terms of how relationships are created, developed and how tie content changes within ties, not only between them. The social network approach adds to the discussion by offering concepts of structural change on a network level. The network approach in entrepreneurship contributes by emphasizing network content, governance and structure as a way of understanding and capturing networks. This is discussed in the conceptual articles, Articles 2 and 3. The ultimate purpose of this thesis is to develop a theoretical and empirical understanding of network development processes. This is fulfilled by presenting a theoretical framework, which offers multiple views on process as a developmental outcome. The framework implies that change ought to be captured both within and among relationships over time in the firm as well as in the network. Consequently, changes in structure and interaction taking place simultaneously need to be included when doing research on network development. The connection between micro and macro levels is also stressed. Therefore, the entrepreneur or firm level needs to be implemented together with the network level. The surrounding environment impacts firm and network development and vice versa and hence needs to be integrated. Further, it is necessary to view network development not only as a way forward but to include both progression and regression as inevitable parts of the process. Finally, both stability and change should be taken into account as part of network development. Empirical results in Article 1 show support for a positive impact of networks on SME internationalization. Article 4 compares networks of novice, serial and portfolio entrepreneurs but the empirical results show little support for differences in the networks by type of entrepreneur. The results demonstrate that network interaction and structure is not directly impacted by type of entrepreneur involved. It indicates instead that network structure and interaction is more impacted by the development phase of the firm. This in turn is in line with the theoretical implications, stating that the development of the network and the firm impacts each other, as they co-evolve.

Integrating strong and weak discontinuities without integration subcells and example applications in an XFEM/GFEM framework

Partition of unity methods, such as the extended finite element method, allows discontinuities to be simulated independently of the mesh (Int. J. Numer. Meth. Engng. 1999; 45:601-620). This eliminates the need for the mesh to be aligned with the discontinuity or cumbersome re-meshing, as the discontinuity evolves. However, to compute the stiffness matrix of the elements intersected by the discontinuity, a subdivision of the elements into quadrature subcells aligned with the discontinuity is commonly adopted. In this paper, we use a simple integration technique, proposed for polygonal domains (Int. J. Nuttier Meth. Engng 2009; 80(1):103-134. DOI: 10.1002/nme.2589) to suppress the need for element subdivision. Numerical results presented for a few benchmark problems in the context of linear elastic fracture mechanics and a multi-material problem show that the proposed method yields accurate results. Owing to its simplicity, the proposed integration technique can be easily integrated in any existing code. Copyright (C) 2010 John Wiley & Sons, Ltd.

Examining effectiveness of an immigrant labor market integration intervention. The role of acculturation, discrimination, self-efficacy, outcome expectances, action and coping planning.

The designing of effective intervention tools to improve immigrants’ labor market integration remains an important topic in contemporary Western societies. This study examines whether and how a new intervention tool, Working Life Certificate (WLC), helps unemployed immigrants to find employment and strengthen their belief of their vocational skills. The study is based on quantitative longitudinal survey data from 174 unemployed immigrants of various origins who participated in the pilot phase of WLC examinations in 2009. Surveys were administered in three waves: before the test, right after it, and three months later. Although it is often argued that the unemployment among immigrants is due either to their lack of skills and cultural differences or to discrimination in recruitment, scholars within social psychology of behavior change argue that the best way of helping people to achieve their goals (e.g. finding employment) is to build up their sense of self-efficacy, alter their outcome expectances in a more positive direction or to help them to construct more detailed action and coping plans. This study aims to shed light on the role of these concepts in immigrants’ labor market integration. The results support the theories of behavior change moderately. Having positive expectances regarding the outcomes of various job search behaviors was found to predict employment in the future. Together with action and coping planning it also predicted increase in job search behavior. The intervention, WLC, was able to affect participants’ self-efficacy, but contrary to expectations, self-efficacy was found not to be related to either job search behavior or future labor market status. Also, perceived discrimination did not explain problems in finding employment, but hints of subtle or structural discrimination were found. Adoption of Finnish work culture together with strong family culture was found to predict future employment. Hence, in this thesis I argue that awarding people diplomas should be preferred in immigrant integration training as it strengthens people’s sense of self-efficacy. Instead of teaching new information, more attention should be directed at changing people’s outcome expectances in a more positive direction and helping them to construct detailed plans on how to achieve their goals.

Integration-free algorithms for fixed end-point regulator problems

A new formulation is suggested for the fixed end-point regulator problem, which, in conjunction with the recently developed integration-free algorithms, provides an efficient means of obtaining numerical solutions to such problems.

Post-acquisition Integration as Sensemaking: Glimpses of Ambiguity, Confusion, Hypocrisy, and Politicization

Though many studies have examined post-acquisition integration challenges, they have mainly focused on rationalistic explanations for the difficulties encountered in post-acquisition integration. There remains little knowledge of how the ‘irrational’ features of post-acquisition decision-making may impede organizational integration. This study attempts to bridge that gap by examining post-acquisition decision-making from a sensemaking perspective. The paper presents an in-depth analysis of a merger between a large Finnish furniture manufacturer and three smaller Swedish furniture companies. By focusing on the sensemaking processes surrounding integration issues, we uncover four interrelated tendencies that illuminate why the frequent problem of slow progress during post-acquisition integration occurs: inherent ambiguity concerning integration issues; cultural confusion in social interaction and communication; organizational hypocrisy in integration decision-making; and the politicization of integration issues.