Small dense lipoproteins, apolipoprotein B, and risk of coronary events in HIV-infected patients on antiretroviral therapy: the Swiss HIV Cohort Study.

OBJECTIVES: HIV infection and exposure to certain antiretroviral drugs is associated with dyslipidemia and increased risk for coronary events. Whether this risk is mediated by highly atherogenic lipoproteins is unclear. We investigated the association of highly atherogenic small dense low-density lipoproteins (LDLs) and apolipoprotein B and coronary events in HIV-infected individuals receiving antiretroviral therapy. METHODS: We conducted a case-control study nested into the Swiss HIV Cohort Study to investigate the association of small dense LDL and apolipoprotein B and coronary events in 98 antiretroviral drug-treated patients with a first coronary event (19 fatal and 79 nonfatal coronary events with 53 definite and 15 possible myocardial infarctions, 11 angioplasties or bypasses) and 393 treated controls matched for age, gender, and smoking status. Lipids were measured by ultracentrifugation. RESULTS: In models including cholesterol, triglycerides, high-density lipoprotein cholesterol, blood pressure, central obesity, diabetes, and family history, there was an independent association between small dense LDL and coronary events [odds ratio (OR) for 1 mg/dL increase: 1.06, 95% confidence interval (CI): 1.00 to 1.11] and apolipoprotein B (OR for 10 mg/dL increase: 1.16, 95% CI: 1.02 to 1.32). When adding HIV and antiretroviral therapy-related variables, ORs were 1.04 (95% CI: 0.99 to 1.10) for small dense LDL and 1.13 (95% CI: 0.99 to 1.30) for apolipoprotein B. In both models, blood pressure and HIV viral load was independently associated with the odds for coronary events. CONCLUSIONS: HIV-infected patients receiving antiretroviral therapy with elevate small dense LDL and apolipoprotein B are at increased risk for coronary events as are patients without sustained HIV suppression.

Genetic association tests: a method for the joint analysis of family and case-control data.

With the trend in molecular epidemiology towards both genome-wide association studies and complex modelling, the need for large sample sizes to detect small effects and to allow for the estimation of many parameters within a model continues to increase. Unfortunately, most methods of association analysis have been restricted to either a family-based or a case-control design, resulting in the lack of synthesis of data from multiple studies. Transmission disequilibrium-type methods for detecting linkage disequilibrium from family data were developed as an effective way of preventing the detection of association due to population stratification. Because these methods condition on parental genotype, however, they have precluded the joint analysis of family and case-control data, although methods for case-control data may not protect against population stratification and do not allow for familial correlations. We present here an extension of a family-based association analysis method for continuous traits that will simultaneously test for, and if necessary control for, population stratification. We further extend this method to analyse binary traits (and therefore family and case-control data together) and accurately to estimate genetic effects in the population, even when using an ascertained family sample. Finally, we present the power of this binary extension for both family-only and joint family and case-control data, and demonstrate the accuracy of the association parameter and variance components in an ascertained family sample.

CHARACTERIZATION OF NrsZ, A NOVEL SMALL REGULATORY NON-CODING RNA INVOLVED IN THE ADAPTATION OF PSEUDOMONAS AERUGINOSA PAO1

The opportunistic ubiquitous pathogen Pseudomonas aeruginosa strain PAOl is a versatile Gram-negative bacterium that has the extraordinary capacity to colonize a wide diversity of ecological niches and to cause severe and persistent infections in humans. To ensure an optimal coordination of the genes involved in nutrient utilization, this bacterium uses the NtrB/C and/or the CbrA/B two-component systems, to sense nutrients availability and to regulate in consequence the expression of genes involved in their uptake and catabolism. NtrB/C is specialized in nitrogen utilization, while the CbrA/B system is involved in both carbon and nitrogen utilization and both systems activate their target genes expression in concert with the alternative sigma factor RpoN. Moreover, the NtrB/C and CbrA/B two- component systems regulate the secondary metabolism of the bacterium, such as the production of virulence factors. In addition to the fine-tuning transcriptional regulation, P. aeruginosa can rapidly modulate its metabolism using small non-coding regulatory RNAs (sRNAs), which regulate gene expression at the post-transcriptional level by diverse and sophisticated mechanisms and contribute to the fast physiological adaptability of this bacterium. In our search for novel RpoN-dependent sRNAs modulating the nutritional adaptation of P. aeruginosa PAOl, we discovered NrsZ (Nitrogen regulated sRNA), a novel RpoN-dependent sRNA that is induced under nitrogen starvation by the NtrB/C two-component system. NrsZ has a unique architecture, formed of three similar stem-loop structures (SL I, II and II) separated by variant spacer sequences. Moreover, this sRNA is processed in short individual stem-loop molecules, by internal cleavage involving the endoribonuclease RNAse E. Concerning NrsZ functions in P. aeruginosa PAOl, this sRNA was shown to trigger the swarming motility and the rhamnolipid biosurfactants production. This regulation is due to the NrsZ-mediated activation of rhlA expression, a gene encoding for an enzyme essential for swarming motility and rhamnolipids production. Interestingly, the SL I structure of NrsZ ensures its regulatory function on rhlA expression, suggesting that the similar SLs are the functional units of this modular sRNA. However, the regulatory mechanism of action of NrsZ on rhlA expression activation remains unclear and is currently being investigated. Additionally, the NrsZ regulatory network was investigated by a transcriptome analysis, suggesting that numerous genes involved in both primary and secondary metabolism are regulated by this sRNA. To emphasize the importance of NrsZ, we investigated its conservation in other Pseudomonas species and demonstrated that NrsZ is conserved and expressed under nitrogen limitation in Pseudomonas protegens Pf-5, Pseudomonas putida KT2442, Pseudomonas entomophila L48 and Pseudomonas syringae pv. tomato DC3000, strains having different ecological features, suggesting an important role of NrsZ in the adaptation of Pseudomonads to nitrogen starvation. Interestingly the architecture of the different NrsZ homologs is similarly composed by SL structures and variant spacer sequences. However, the number of SL repetitions is not identical, and one to six SLs were predicted on the different NrsZ homologs. Moreover, NrsZ is processed in short molecules in all the strains, similarly to what was previously observed in P. aeruginosa PAOl, and the heterologous expression of the NrsZ homologs restored rhlA expression, swarming motility and rhamnolipids production in the P. aeruginosa NrsZ mutant. In many aspects, NrsZ is an atypical sRNA in the bacterial panorama. To our knowledge, NrsZ is the first described sRNA induced by the NtrB/C. Moreover, its unique modular architecture and its processing in similar short SL molecules suggest that NrsZ belongs to a novel family of bacterial sRNAs. -- L'agent pathogène opportuniste et ubiquitaire Pseudomonas aeruginosa souche PAOl est une bactérie Gram négative versatile ayant l'extraordinaire capacité de coloniser différentes niches écologiques et de causer des infections sévères et persistantes chez l'être humain. Afin d'assurer une coordination optimale des gènes impliqués dans l'utilisation de différents nutriments, cette bactérie se sert de systèmes à deux composants tel que NtrB/C et CbrA/B afin de détecter la disponibilité des ressources nutritives, puis de réguler en conséquence l'expression des gènes impliqués dans leur importation et leur catabolisme. Le système NtrB/C régule l'utilisation des sources d'azote alors que le système CbrA/B est impliqué à la fois dans l'utilisation des sources de carbone et d'azote. Ces deux systèmes activent l'expression de leurs gènes-cibles de concert avec le facteur sigma alternatif RpoN. En outre, NtrB/C et CbrA/B régulent aussi le métabolisme secondaire, contrôlant notamment la production d'importants facteurs de virulence. En plus de toutes ces régulations génétiques fines ayant lieu au niveau transcriptionnel, P. aeruginosa est aussi capable de moduler son métabolisme en se servant de petits ARNs régulateurs non-codants (ARNncs), qui régulent l'expression génétique à un niveau post- transcriptionnel par divers mécanismes sophistiqués et contribuent à rendre particulièrement rapide l'adaptation physiologique de cette bactérie. Au cours de nos recherches sur de nouveaux ARNncs dépendant du facteur sigma RpoN et impliqués dans l'adaptation nutritionnelle de P. aeruginosa PAOl, nous avons découvert NrsZ (Nitrogen regulated sRNA), un ARNnc induit par la cascade NtrB/C-RpoN en condition de carence en azote. NrsZ a une architecture unique, composée de trois structures en tige- boucle (TB I, II et III) hautement similaires et séparées par des « espaceurs » ayant des séquences variables. De plus, cet ARNnc est clivé en petits fragments correspondant au trois molécules en tige-boucle, par un processus de clivage interne impliquant l'endoribonucléase RNase E. Concernant les fonctions de NrsZ chez P. aeruginosa PAOl, cet ARNnc est capable d'induire la motilité de type « swarming » et la production de biosurfactants, nommés rhamnolipides. Cette régulation est due à l'activation par NrsZ de l'expression de rhlA, un gène essentiel pour la motilité de type swarming et pour la production de rhamnolipides. Étonnamment, la structure TB I est capable d'assurer à elle seule la fonction régulatrice de NrsZ sur l'expression de rhlA, suggérant que ces molécules TBs sont les unités fonctionnelles de cet ARNnc modulaire. Cependant, le mécanisme moléculaire par lequel NrsZ active l'expression de rhlA demeure à ce jour incertain et est actuellement à l'étude. En plus, le réseau de régulations médiées par NrsZ a été étudié par une analyse de transcriptome qui a indiqué que de nombreux gènes impliqués dans le métabolisme primaire ou secondaire seraient régulés par NrsZ. Pour accentuer l'importance de NrsZ, nous avons étudié sa conservation dans d'autres espèces de Pseudomonas. Ainsi, nous avons démontré que NrsZ est conservé et exprimé en situation de carence d'azote par les souches Pseudomonas protegens Pf-5, Pseudomonas putida KT2442, Pseudomonas entomophila L48, Pseudomonas syringae pv. tomato DC3000, quatre espèces ayant des caractéristiques écologiques très différentes, suggérant que NrsZ joue un rôle important dans l'adaptation du genre Pseudomonas envers la carence en azote. Chez toutes les souches étudiées, les différents homologues de NrsZ présentent une architecture similaire faite de TBs conservées et d'espaceurs. Cependant, le nombre de TBs n'est pas identique et peut varier de une à six copies selon la souche. Les différentes versions de NrsZ sont clivées en petites molécules dans ces quatre souches, comme il a été observé chez P. aeruginosa PAOl. De plus, l'expression hétérologue des différentes variantes de NrsZ est capable de restaurer l'expression de rhlA, la motilité swarming et la production de rhamnolipides dans une souche de P. aeruginosa dont nrsZ a été inactivé. Par bien des aspects, NrsZ est un ARNnc atypique dans le monde bactérien. À notre connaissance, NrsZ est le premier ARNnc décrit comme étant régulé par le système NtrB/C. De plus, son unique architecture modulaire et son clivage en petites molécules similaires suggèrent que NrsZ appartient à une nouvelle famille d'ARNncs bactériens.

Three essays on internationalization and firm entrepreneurial behavior

PAPER 1: A THEORY ON THE EFFECTS OF INTERNATIONALIZATION ON FIRM ENTREPRENEURIAL BEHAVIOR AND GROWTH Abstract This article addresses the relationship. Past findings reveal that the direct effects of internationalization on performance are mixed and inconclusive. Our framework integrates firm entrepreneurial behavior as a mediating force of the troublesome Drawing on the tension between the entrepreneurship literature and the organizational inertia theory, we argue that internationalization is key to minimizing the stifling effects of inertia and in engendering entrepreneurial behavior towards growth. We suggest that firms that internationalize at a young age and enjoy an intense degree of internationalization tend to become more entrepreneurial than do late and weakly internationalized firms. As a consequence, early and intense internationalizers experience superior growth. Aware of the inherent endogeneity of our propositions, we also discuss how consistent estimates can be obtained when testing the model empirically. PAPER 2: DOES INTERNATIONALIZATION MATTER FOR GROWTH? THE CASE OF SWISS SOFTWARE FIRMS. Abstract This paper seeks to address the issue of whether early and intense internationalization leads to superior firm growth. We revisit the hypotheses of previous studies within the emerging research domain of international entrepreneurship. Empirical analyses on the performance implications of internationalization have so far been limited and inconsistent. Our paper intends to make two contributions to the international entrepreneurship literature. First, we bring additional empirical evidence as to the inconclusive firm performance endogeneity in our causal model, using a sample of 103 Swiss international small and medium-sized enterprises (SMEs). On one hand, we find that the degree of internationalization significantly increases perceived firm growth (i.e., relative firm performance in a market); however, age at internationalization was unrelated to perceived firm growth. On the other hand, we reproduced the causal path of a highly cited study that showed how age at internationalization was significantly and negatively associated with objective firm growth (i.e., sales). Interestingly, our results support the study similar setting (OLS regression with comparable control variables); however, the effect for age at internationalization reverses when we correct for endogeneity. PAPER 3: EFFECT OF INTERNATIONALIZATION ON FIRM ENTREPRENEURIAL ORIENTATION AND PERFORMANCE: THE CASE OF SWISS SOFTWARE FIRMS. Abstract How does internationalization influence a firm orientation (EO) and is this related to firm growth? This paper inquires into the performance theorizing, we test a process model in which EO plays a mediating role in accounting for the relationship between internationalization and growth. We position this paper on the tension zone between the entrepreneurship literature and the organizational inertia theory. We lay out the argument that internationalization is source of opportunities that drives a firm and thus mitigates inertial pressure. Using a sample of Swiss software small and medium-sized enterprises (SMEs), we found that degree of internationalization (but not age of internationalization) increases EO, which subsequently increased firm growth.

Genome-wide search reveals a novel GacA-regulated small RNA in Pseudomonas species.

BACKGROUND: Small RNAs (sRNAs) are widespread among bacteria and have diverse regulatory roles. Most of these sRNAs have been discovered by a combination of computational and experimental methods. In Pseudomonas aeruginosa, a ubiquitous Gram-negative bacterium and opportunistic human pathogen, the GacS/GacA two-component system positively controls the transcription of two sRNAs (RsmY, RsmZ), which are crucial for the expression of genes involved in virulence. In the biocontrol bacterium Pseudomonas fluorescens CHA0, three GacA-controlled sRNAs (RsmX, RsmY, RsmZ) regulate the response to oxidative stress and the expression of extracellular products including biocontrol factors. RsmX, RsmY and RsmZ contain multiple unpaired GGA motifs and control the expression of target mRNAs at the translational level, by sequestration of translational repressor proteins of the RsmA family. RESULTS: A combined computational and experimental approach enabled us to identify 14 intergenic regions encoding sRNAs in P. aeruginosa. Eight of these regions encode newly identified sRNAs. The intergenic region 1698 was found to specify a novel GacA-controlled sRNA termed RgsA. GacA regulation appeared to be indirect. In P. fluorescens CHA0, an RgsA homolog was also expressed under positive GacA control. This 120-nt sRNA contained a single GGA motif and, unlike RsmX, RsmY and RsmZ, was unable to derepress translation of the hcnA gene (involved in the biosynthesis of the biocontrol factor hydrogen cyanide), but contributed to the bacterium's resistance to hydrogen peroxide. In both P. aeruginosa and P. fluorescens the stress sigma factor RpoS was essential for RgsA expression. CONCLUSION: The discovery of an additional sRNA expressed under GacA control in two Pseudomonas species highlights the complexity of this global regulatory system and suggests that the mode of action of GacA control may be more elaborate than previously suspected. Our results also confirm that several GGA motifs are required in an sRNA for sequestration of the RsmA protein.

FAM-MDR: a flexible family-based multifactor dimensionality reduction technique to detect epistasis using related individuals

We propose a novel multifactor dimensionality reduction method for epistasis detection in small or extended pedigrees, FAM-MDR. It combines features of the Genome-wide Rapid Association using Mixed Model And Regression approach (GRAMMAR) with Model-Based MDR (MB-MDR). We focus on continuous traits, although the method is general and can be used for outcomes of any type, including binary and censored traits. When comparing FAM-MDR with Pedigree-based Generalized MDR (PGMDR), which is a generalization of Multifactor Dimensionality Reduction (MDR) to continuous traits and related individuals, FAM-MDR was found to outperform PGMDR in terms of power, in most of the considered simulated scenarios. Additional simulations revealed that PGMDR does not appropriately deal with multiple testing and consequently gives rise to overly optimistic results. FAM-MDR adequately deals with multiple testing in epistasis screens and is in contrast rather conservative, by construction. Furthermore, simulations show that correcting for lower order (main) effects is of utmost importance when claiming epistasis. As Type 2 Diabetes Mellitus (T2DM) is a complex phenotype likely influenced by gene-gene interactions, we applied FAM-MDR to examine data on glucose area-under-the-curve (GAUC), an endophenotype of T2DM for which multiple independent genetic associations have been observed, in the Amish Family Diabetes Study (AFDS). This application reveals that FAM-MDR makes more efficient use of the available data than PGMDR and can deal with multi-generational pedigrees more easily. In conclusion, we have validated FAM-MDR and compared it to PGMDR, the current state-of-the-art MDR method for family data, using both simulations and a practical dataset. FAM-MDR is found to outperform PGMDR in that it handles the multiple testing issue more correctly, has increased power, and efficiently uses all available information.

An allele-specific, stochastic gene expression process controls the expression of multiple Ly49 family genes and generates a diverse, MHC-specific NK cell receptor repertoire.

Mouse NK cells express MHC class I-specific inhibitory Ly49 receptors. Since these receptors display distinct ligand specificities and are clonally distributed, their expression generates a diverse NK cell receptor repertoire specific for MHC class I molecules. We have previously found that the Dd (or Dk)-specific Ly49A receptor is usually expressed from a single allele. However, a small fraction of short-term NK cell clones expressed both Ly49A alleles, suggesting that the two Ly49A alleles are independently and randomly expressed. Here we show that the genes for two additional Ly49 receptors (Ly49C and Ly49G2) are also expressed in a (predominantly) mono-allelic fashion. Since single NK cells can co-express multiple Ly49 receptors, we also investigated whether mono-allelic expression from within the tightly linked Ly49 gene cluster is coordinate or independent. Our clonal analysis suggests that the expression of alleles of distinct Ly49 genes is not coordinate. Thus Ly49 alleles are apparently independently and randomly chosen for stable expression, a process that directly restricts the number of Ly49 receptors expressed per single NK cell. We propose that the Ly49 receptor repertoire specific for MHC class I is generated by an allele-specific, stochastic gene expression process that acts on the entire Ly49 gene cluster.

Determinants of science-based cooperation: evidence in a sample of small and micro firms

We study the determining factors of cience-based cooperation in the case of small and micro firms. In this research, we propose an analytical framework based on the resource-based view of the firm and we identify a set of organisational characteristics, which we classify as internal, external and structural factors. Each factor can be linked to at least one reason, from the firm¿s point of view, to cooperate with universities and public research centres. Each reason can, in turn, be used as an indicator of a firm¿s organisational needs or organisational capacities. In order to validate the theoretical model, we estimate a logistic regression that models the propensity to participate in science-based cooperation activities within a sample of 285 small and micro firms located in Barcelona. The results show the key role played by the absorptive capacity of new and small companies.

1,2,3,4-Tetrahydrobenzo[h][1,6]naphthyridines as a new family of potent peripheral-to-midgorge-site inhibitors of acetylcholinesterase: synthesis, pharmacological evaluation and mechanistic studies

A series of 1,2,3,4-tetrahydrobenzo[h][1,6]naphthyridines differently substituted at positions 1, 5, and 9 have been designed from the pyrano[3,2-c]quinoline derivative 1, a weak inhibitor of acetylcholinesterase (AChE) with predicted ability to bind to the AChE peripheral anionic site (PAS), at the entrance of the catalytic gorge. Fourteen novel benzonaphthyridines have been synthesized through synthetic sequences involving as the key step a multicomponent Povarov reaction between an aldehyde, an aniline and an enamine or an enamide as the activated alkene. The novel compounds have been tested against Electrophorus electricus AChE (EeAChE), human recombinant AChE (hAChE), and human serum butyrylcholinesterase (hBChE), and their brain penetration has been assessed using the PAMPA-BBB assay. Also, the mechanism of AChE inhibition of the most potent compounds has been thoroughly studied by kinetic studies, a propidium displacement assay, and molecular modelling. We have found that a seemingly small structural change such as a double O → NH bioisosteric replacement from the hit 1 to 16a results in a dramatic increase of EeAChE and hAChE inhibitory activities (>217- and >154-fold, respectively), and in a notable increase in hBChE inhibitory activity (> 11-fold), as well. An optimized binding at the PAS besides additional interactions with AChE midgorge residues seem to account for the high hAChE inhibitory potency of 16a (IC50 = 65 nM), which emerges as an interesting anti-Alzheimer lead compound with potent dual AChE and BChE inhibitory activities.

1,2,3,4-Tetrahydrobenzo[h][1,6]naphthyridines as a new family of potent peripheral-to-midgorge-site inhibitors of acetylcholinesterase: synthesis, pharmacological evaluation and mechanistic studies

A series of 1,2,3,4-tetrahydrobenzo[h][1,6]naphthyridines differently substituted at positions 1, 5, and 9 have been designed from the pyrano[3,2-c]quinoline derivative 1, a weak inhibitor of acetylcholinesterase (AChE) with predicted ability to bind to the AChE peripheral anionic site (PAS), at the entrance of the catalytic gorge. Fourteen novel benzonaphthyridines have been synthesized through synthetic sequences involving as the key step a multicomponent Povarov reaction between an aldehyde, an aniline and an enamine or an enamide as the activated alkene. The novel compounds have been tested against Electrophorus electricus AChE (EeAChE), human recombinant AChE (hAChE), and human serum butyrylcholinesterase (hBChE), and their brain penetration has been assessed using the PAMPA-BBB assay. Also, the mechanism of AChE inhibition of the most potent compounds has been thoroughly studied by kinetic studies, a propidium displacement assay, and molecular modelling. We have found that a seemingly small structural change such as a double O → NH bioisosteric replacement from the hit 1 to 16a results in a dramatic increase of EeAChE and hAChE inhibitory activities (>217- and >154-fold, respectively), and in a notable increase in hBChE inhibitory activity (> 11-fold), as well. An optimized binding at the PAS besides additional interactions with AChE midgorge residues seem to account for the high hAChE inhibitory potency of 16a (IC50 = 65 nM), which emerges as an interesting anti-Alzheimer lead compound with potent dual AChE and BChE inhibitory activities.

The profile of general practitioners (GPs) who publish in selected family practice journals

Background: Providing support for research is one of the key issues in the ongoing attempts to improve Primary Care. However, when patient care takes up a significant part of a GP's time, conducting research is difficult. In this study we examine the working conditions and profile of GPs who publish in three leading medical journals and propose possible remedial policy actions. Findings: The authors of all articles published in 2006 and 2007 in three international Family Medicine journals - Annals of Family Medicine, Family Practice, and Journal of Family Practice - were contacted by E-mail. They were asked to complete a questionnaire investigating the following variables: availability of specific time for research, time devoted to research, number of patients attended, and university affiliation. Only GPs were included in the study. Three hundred and ten relevant articles published between 2006 and 2007 were identified and the authors contacted using a survey tool. 124 researchers responded to our questionnaire; 45% of respondents who were not GPs were excluded. On average GPs spent 2.52 days per week and 6.9 hours per day on patient care, seeing 45 patients per week. Seventy-five per cent of GPs had specific time assigned to research, on average 13 hours per week; 79% were affiliated to a university and 69% held teaching positions. Conclusions: Most GPs who publish original articles in leading journals have time specifically assigned to research as part of their normal working schedule. They see a relatively small number of patients. Improving the working conditions of family physicians who intend to investigate is likely to lead to better research results.

Risks in R&D Collaboration between Small and Large Firms

The main aim of this thesis was to find out what kinds of risks arise from collabo-ration in R&D between small and large firms. The suitability and gain of some buyer/supplier risk frameworks in examining of R&D collaboration has been in-vestigated. A risk model has been based on the buyer/supplier risks models found in the literature. Its applicability has been tested empirically by means of theme interviews with firm representatives. The risk classification framework received some confirmation. But the study also showed that the theoretical framework was not completely adequate, as a new risk class arose from communication. Collaboration causes risks, and these risks should be taken into account when R&D collaboration is planned. The advantage of risk examination is the possibility to decrease failures and losses, and to in-crease possibilities for success and economical benefits. This study should be used as a managerial analysis tool in trying to understand the form and concept of risk in risk expectancy.

Market Orientation in Rapidly Internationalizing Small Companies — Evidence from the Software Industry

For more than a decade, researchers have been aware of the increased pace of small-firm internationalization and the greater effect of these rapidly growing small businesses on the wealth, international trade, and job-creation opportunities of countries. Due to the small size of the home market, Finnish companies have been generally considered highly interested in internationalization. One particular domain in which rapid internationalization has been considered feasible is the global software business, with its knowledge-intensive nature and high growth potential. However, over time the failure rate of small entrepreneurial firms has remained especially high in high-technology markets. One of the reasons for this seems to lie in the fact that these companies are often formed by people with a strong technological background but limited competences in other areas. Further, research on the marketing capabilities of rapidly internationalizing high-tech firms has been scarce thus far. In addition, while there is much research on the first years of operations of rapidly internationalizing companies, it is not well known what becomes of them later on. Therefore, there is a need for more investigation into the managerial mindset, competences and decision-making in these small companies, especially from the perspective of how they acquire and exploit market knowledge, and enhance their networking capabilities in order to promote international expansion. The present study focuses on market orientation in small software firms that internationalize their operations rapidly in global software markets. It builds on qualitative data to illustrate how these companies develop their market-oriented product-market strategies during the process of increasing international commitment. It also shows how they manage their network relationships in order to be able to offer better customer service and to thrive in the fierce global competition. The study was conducted in the empirical context of Finnish small software companies, and the main data consists of interviews with top managers in these businesses. The interviews were designed to cover a minimum period of five years of the company's international operations, thus offering a retrospective in-depth perspective on market orientation, internationalization and partnerships in the given context. One particular focus is on less successfully internationalized software companies, and the challenges they face when approaching international markets. This study makes a significant contribution to the literature on market orientation for several reasons. First, building on data from the software industry, it clarifies the existing theory in the context of rapid internationalization and network relationships. Secondly, it provides a good body of evidence on market orientation in both successfully and less successfully internationalized companies, and identifies the key related differences between the two company groups. Thirdly, it highlights the importance of inter-firm networks in the rapid internationalization of small software firms, providing companies with important market knowledge and, in some cases, management challenges. Fourthly, this investigation clarifies market orientation in the context of different software-product strategies, thus, combining the perspectives of market orientation in both manufacturing and services. In sum, the results of the study are significant for both small software firms and public-policy makers since they shed light on the market-oriented managerial mindset and the market-information gathering and sharing processes that are needed in successful rapid internationalization.

Corporate Social and Regional Responsibility - The View of Small and Medium-sized Enterprises

The objective of this research was to understand and describe what corpo-rate social and regional responsibility is in SMEs and define the meaning of these concepts to the community and region. Corporate social respon-sibility (CSR) creates a basis for regional responsibility. Regional respon-sibility is a new concept and this research examines it from SMEs’ view-point. This is a theoretical research and the aim is to create a theoretical framework of SMEs’ corporate social and regional responsibility. This framework supports the future research on the subject. The research results show that CSR of SMEs is practical, informal and dependent on the scarce resources of SMEs. CSR is a complex and deep concept and SMEs have their own way of interpreting it. It can be stated that CSR-practises in SMEs are closely connected to employment, envi-ronment, community and supply chain. The challenge is to find motivation to socially and regionally responsible behaviour in SMEs. Benefiting from responsible behaviour and the attitude of SME’s owner-manager are the key reasons for SMEs to involve in CSR and regional responsibility. The benefits of this involvement are for example improved image, reputation and market position. CSR can also be used in SMEs as risk management tool and in cost reduction. This study indicates also that creation of strate-gic partnerships, local government participation, a proper legal system and financial support are the basic issues which support CSR of SMEs. This research showed that regional responsibility of SMEs includes active participation in regional strategy processes, L&RED initiatives and regional philanthropy. For SMEs regional responsibility means good relationships with the community and other related stakeholders, involvement in L&RED initiatives and acting responsibly towards the operating environment. In SMEs’ case this means that they need to understand the benefits of this kind of involvement in order to take action and participate. As regional responsibility includes the relationships between firm and the community, it can be stated that regional responsibility extends CSR’s view of stakeholders and emphasises both, the regional stakeholders and public-private partnerships. Community engagement and responsible be-haviour towards community can be seen as a part of SMEs’ social and regional responsibility. This study indicates that social and regional re-sponsibility of SMEs have a significant influence on the community and region where they are located. Better local and regional relationships with regional and community actors are the positive impacts of social and re-gional responsibility of SMEs. Socially and regionally responsible behav-iour creates a more positive environment and deepens the involvement of SMEs to community and L&RED initiatives.

Gleevec, an Abl family inhibitor, produces a profound change in cell shape and migration (in press)

The issue of how contractility and adhesion are related to cell shape and migration pattern remains largely unresolved. In this paper we report that Gleevec (Imatinib), an Abl family kinase inhibitor, produces a profound change in the shape and migration of rat bladder tumor cells (NBTII) plated on collagen-coated substrates. Cells treated with Gleevec adopt a highly spread D-shape and migrate more rapidly with greater persistence. Accompanying this more spread state is an increase in integrin-mediated adhesion coupled with increases in the size and number of discrete adhesions. In addition, both total internal reflection fluorescence microscopy (TIRFM) and interference reflection microscopy (IRM) revealed a band of small punctate adhesions with rapid turnover near the cell leading margin. These changes led to an increase in global cell-substrate adhesion strength, as assessed by laminar flow experiments. Gleevec-treated cells have greater RhoA activity which, via myosin activation, led to an increase in the magnitude of total traction force applied to the substrate. These chemical and physical alterations upon Gleevec treatment produce the dramatic change in morphology and migration that is observed.