Computational Methods for Reconstruction and Analysis of Genome-Scale Metabolic Networks

Metabolism is the cellular subsystem responsible for generation of energy from nutrients and production of building blocks for larger macromolecules. Computational and statistical modeling of metabolism is vital to many disciplines including bioengineering, the study of diseases, drug target identification, and understanding the evolution of metabolism. In this thesis, we propose efficient computational methods for metabolic modeling. The techniques presented are targeted particularly at the analysis of large metabolic models encompassing the whole metabolism of one or several organisms. We concentrate on three major themes of metabolic modeling: metabolic pathway analysis, metabolic reconstruction and the study of evolution of metabolism. In the first part of this thesis, we study metabolic pathway analysis. We propose a novel modeling framework called gapless modeling to study biochemically viable metabolic networks and pathways. In addition, we investigate the utilization of atom-level information on metabolism to improve the quality of pathway analyses. We describe efficient algorithms for discovering both gapless and atom-level metabolic pathways, and conduct experiments with large-scale metabolic networks. The presented gapless approach offers a compromise in terms of complexity and feasibility between the previous graph-theoretic and stoichiometric approaches to metabolic modeling. Gapless pathway analysis shows that microbial metabolic networks are not as robust to random damage as suggested by previous studies. Furthermore the amino acid biosynthesis pathways of the fungal species Trichoderma reesei discovered from atom-level data are shown to closely correspond to those of Saccharomyces cerevisiae. In the second part, we propose computational methods for metabolic reconstruction in the gapless modeling framework. We study the task of reconstructing a metabolic network that does not suffer from connectivity problems. Such problems often limit the usability of reconstructed models, and typically require a significant amount of manual postprocessing. We formulate gapless metabolic reconstruction as an optimization problem and propose an efficient divide-and-conquer strategy to solve it with real-world instances. We also describe computational techniques for solving problems stemming from ambiguities in metabolite naming. These techniques have been implemented in a web-based sofware ReMatch intended for reconstruction of models for 13C metabolic flux analysis. In the third part, we extend our scope from single to multiple metabolic networks and propose an algorithm for inferring gapless metabolic networks of ancestral species from phylogenetic data. Experimenting with 16 fungal species, we show that the method is able to generate results that are easily interpretable and that provide hypotheses about the evolution of metabolism.

Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): a phase 2B, open-label, randomised controlled trial

Background The irreversible ErbB family blocker afatinib and the reversible EGFR tyrosine kinase inhibitor gefitinib are approved for first-line treatment of EGFR mutation-positive non-small-cell lung cancer (NSCLC). We aimed to compare the efficacy and safety of afatinib and gefitinib in this setting. Methods This multicentre, international, open-label, exploratory, randomised controlled phase 2B trial (LUX-Lung 7) was done at 64 centres in 13 countries. Treatment-naive patients with stage IIIB or IV NSCLC and a common EGFR mutation (exon 19 deletion or Leu858Arg) were randomly assigned (1:1) to receive afatinib (40 mg per day) or gefitinib (250 mg per day) until disease progression, or beyond if deemed beneficial by the investigator. Randomisation, stratified by EGFR mutation type and status of brain metastases, was done centrally using a validated number generating system implemented via an interactive voice or web-based response system with a block size of four. Clinicians and patients were not masked to treatment allocation; independent review of tumour response was done in a blinded manner. Coprimary endpoints were progression-free survival by independent central review, time-to-treatment failure, and overall survival. Efficacy analyses were done in the intention-to-treat population and safety analyses were done in patients who received at least one dose of study drug. This ongoing study is registered with ClinicalTrials.gov, number NCT01466660. Findings Between Dec 13, 2011, and Aug 8, 2013, 319 patients were randomly assigned (160 to afatinib and 159 to gefitinib). Median follow-up was 27·3 months (IQR 15·3–33·9). Progression-free survival (median 11·0 months [95% CI 10·6–12·9] with afatinib vs 10·9 months [9·1–11·5] with gefitinib; hazard ratio [HR] 0·73 [95% CI 0·57–0·95], p=0·017) and time-to-treatment failure (median 13·7 months [95% CI 11·9–15·0] with afatinib vs 11·5 months [10·1–13·1] with gefitinib; HR 0·73 [95% CI 0·58–0·92], p=0·0073) were significantly longer with afatinib than with gefitinib. Overall survival data are not mature. The most common treatment-related grade 3 or 4 adverse events were diarrhoea (20 [13%] of 160 patients given afatinib vs two [1%] of 159 given gefitinib) and rash or acne (15 [9%] patients given afatinib vs five [3%] of those given gefitinib) and liver enzyme elevations (no patients given afatinib vs 14 [9%] of those given gefitinib). Serious treatment-related adverse events occurred in 17 (11%) patients in the afatinib group and seven (4%) in the gefitinib group. Ten (6%) patients in each group discontinued treatment due to drug-related adverse events. 15 (9%) fatal adverse events occurred in the afatinib group and ten (6%) in the gefitinib group. All but one of these deaths were considered unrelated to treatment; one patient in the gefitinib group died from drug-related hepatic and renal failure. Interpretation Afatinib significantly improved outcomes in treatment-naive patients with EGFR-mutated NSCLC compared with gefitinib, with a manageable tolerability profile. These data are potentially important for clinical decision making in this patient population.

Novel application of a discrete choice experiment to identify preferences for a national healthcare-associated infection surveillance programme: A cross-sectional study

Objective: To identify key stakeholder preferences and priorities when considering a national healthcare-associated infection (HAI) surveillance programme through the use of a discrete choice experiment (DCE). Setting: Australia does not have a national HAI surveillance programme. An online web-based DCE was developed and made available to participants in Australia. Participants: A sample of 184 purposively selected healthcare workers based on their senior leadership role in infection prevention in Australia. Primary and secondary outcomes: A DCE requiring respondents to select 1 HAI surveillance programme over another based on 5 different characteristics (or attributes) in repeated hypothetical scenarios. Data were analysed using a mixed logit model to evaluate preferences and identify the relative importance of each attribute. Results: A total of 122 participants completed the survey (response rate 66%) over a 5-week period. Excluding 22 who mismatched a duplicate choice scenario, analysis was conducted on 100 responses. The key findings included: 72% of stakeholders exhibited a preference for a surveillance programme with continuous mandatory core components (mean coefficient 0.640 (p<0.01)), 65% for a standard surveillance protocol where patient-level data are collected on infected and non-infected patients (mean coefficient 0.641 (p<0.01)), and 92% for hospital-level data that are publicly reported on a website and not associated with financial penalties (mean coefficient 1.663 (p<0.01)). Conclusions: The use of the DCE has provided a unique insight to key stakeholder priorities when considering a national HAI surveillance programme. The application of a DCE offers a meaningful method to explore and quantify preferences in this setting.

Designing a blended learning model for primary school language learning

In Finland, there is a desperate need for flexible, reliable and functional multi-e-learning settings for pupils aged 11-13. Southern Finland has several ongoing e-learning projects, but none that develop a multiple setting, with learning and teaching occurring between more than two schools. In 2006, internet connections were not broadband and data transfer was mainly audio data. Connections and technical problems occurred, which were an obstacle to multi-e-learning. Internet connections today enable web-based learning in major parts of
Lapland and by 2015, broadband will reach even the remotest villages up north. Therefore, it is important to research the possibilities of multi-e-learning and to build collaborative, learner-centred, versatile network models for primary school-aged pupils. The resulting model will facilitate distance learning to extend education to rural, sparsely populated areas, and it will give a model of using mobile devices in language portfolios. This will promote regional equality and prevent exclusion. Working with portfolios provides the opportunity to develop mobility from a pedagogical point of view. It is important to study the pros and cons of mobile devices in producing artefacts on portfolios in e-learning and language learning settings.
The current study represents a design-based research approach. The design research approach includes two important aspects concerning the current research: ‘a teacher as researcher’ aspect, which means there is the possibility to be strongly involved in developing processes and an obstacle-aspect, which means that problems while developing, are seen as a
promoter in evolving the designed model, as apposed to negative results.

Designing a blended learning model for primary school language learning

In Finland, there is a desperate need for flexible, reliable and functional multi-e-learning settings for pupils aged 11-13. Southern Finland has several ongoing e-learning projects, but none that develop a multiple setting, with learning and teaching occurring between more than two schools. In 2006, internet connections were not broadband and data transfer was mainly audio data. Connections and technical problems occurred, which were an obstacle to multi-e-learning. Internet connections today enable web-based learning in major parts of Lapland and by 2015, broadband will reach even the remotest villages up north. Therefore, it is important to research the possibilities of multi-e-learning and to build collaborative, learner-centred, versatile network models for primary school-aged pupils. The resulting model will facilitate distance learning to extend education to rural, sparsely populated areas, and it will give a model of using mobile devices in language portfolios. This will promote regional equality and prevent exclusion. Working with portfolios provides the opportunity to develop mobility from a pedagogical point of view. It is important to study the pros and cons of mobile devices in producing artefacts on portfolios in e-learning and language learning settings. The current study represents a design-based research approach. The design research approach includes two important aspects concerning the current research: ‘a teacher as researcher’ aspect, which means there is the possibility to be strongly involved in developing processes and an obstacle-aspect, which means that problems while developing, are seen as a promoter in evolving the designed model, as apposed to negative results.

How Scientists Retrieve Publications: An Empirical Study of How the Internet Is Overtaking Paper Media

The current mainstream scientific-publication process has so far been only marginally affected by the possibilities offered by the Internet, despite some pioneering attempts with free electronic-only journals and electronic preprint archives. Additional electronic versions of traditional paper journals for which one needs a subscription are not a solution. A clear trend, for young researchers in particular, is to go around subscription barriers (both for paper and electronic material) and rely almost exclusively on what they can find free on the Internet, which often includes working versions posted on the home pages of the authors. A survey of how scientists retrieve publications was conducted in February 2000, aimed at measuring to what extent the opportunities offered by the Internet are already changing the scientific information exchange and how researchers feel about this. This paper presents the results based on 236 replies to an extensive Web-based questionnaire, which was announced to around 3,000 researchers in the domains of construction information technology and construction management. The questions dealt with how researchers find, access, and read different sources; how many and what publications they read; how often and to which conferences they travel; how much they publish, and criteria for where they eventually decide to publish. Some of the questions confronted traditional and electronic publishing, with one final section dedicated to opinions about electronic publishing. According to the survey, researchers already download half of the material that they read digitally from the Web. The most popular method for retrieving an interesting publication is downloading it for free from the author's or publisher's Web site. Researchers are not particularly willing to pay for electronic scientific publications. There is much support for a scenario of electronic journals available freely in their entirety on the Web, where the costs could be covered by, for instance, professional societies or the publishing university.

Where to Submit? Journal Choice by Construction Management Authors

Publishers of academic journals can be seen as service providers to authors, in addition to the traditional role of providers of research results to readers. The purpose of this study was to analyse how author choices of journal in construction management are affected by quality and service perceptions. Seven journals were identified and for each 2006 article, one author e-mail address was extracted. A web based questionnaire was sent to 397 authors and 35% responded. It was found that there were three journals regularly followed by at least half the respondents. Most of the other four journals have scopes broader than construction management and receive lower scores for characteristics such as impact on researchers. No open access journals were included, and authors in the field of construction management rarely post openly accessible copies of their manuscripts or publications on the web. Author ranking of journals for their next submission is found to be related to general criteria such as academic status, circulation figures and ISI indexation.

How do Researchers Find and Retrieve Scientific Publications – A Case study of the Impact of the Internet on the Construction IT and Construction Management Research Communities

The World Wide Web provides the opportunity for a radically changed and much more efficient communication process for scientific results. A survey in the closely related domains of construction information technology and construction management was conducted in February 2000, aimed at measuring to what extent these opportunities are already changing the scientific information exchange and how researchers feel about the changes. The paper presents the results based on 236 replies to an extensive Web based questionnaire. 65% of the respondents stated their primary research interest as IT in A/E/C and 20% as construction management and economics. The questions dealt with how researchers find, access and read different sources; how much and what publications they read; how often and to which conferences they travel; how much they publish, and what are the criteria for where they eventually decide to publish. Some of the questions confronted traditional and electronic publishing with one final section dedicated to opinions about electronic publishing. According to the survey researchers already download half of the material that they read digitally from the Web. The most popular method for retrieving an interesting publication is downloading it for free from the author’s or publisher’s website. Researchers are not particularly willing to pay for electronic scientific publications. There is much support for a scenario of electronic journals available totally freely on the Web, where the costs could be covered by for instance professional societies or the publishing university. The shift that the Web is causing seems to be towards the "just in time" reading of literature. Also, frequent users of the Web rely less on scientific publications and tend to read fewer articles. If available with little effort, papers published in traditional journals are preferred; if not, the papers should be on the Web. In these circumstances, the role of paper-based journals published by established publishers is shifting from the core "information exchange" to the building of authors' prestige. The respondents feel they should build up their reputations by publishing in journals and relevant conferences, but then make their work freely available on the Web.

Organisational Responses to Workplace Harassment: An Exploratory Study

Purpose – The aim of this paper is to explore what kind of measures personnel managers have taken to intervene in workplace harassment and to explore how organisational characteristics and the characteristics of the personnel manager affect the choice of response strategies. Design/methodology/approach – The study was exploratory and used a survey design. A web-based questionnaire was sent to the personnel managers of all Finnish municipalities and data on organisational responses and organisational characteristics were collected. Findings – The study showed that the organisations surveyed relied heavily on reconciliatory measures for responding to workplace harassment and that punitive measures were seldom used. Findings indicated that personnel manager gender, size of municipality, use of “sophisticated” human resource management practices and having provided information and training to increase awareness about harassment all influence the organisational responses chosen. Research limitations/implications – Only the effects of organisational and personnel manager characteristics on organisational responses were analysed. Future studies need to include perpetrator characteristics and harassment severity. Practical implications – The study informs both practitioners and policy makers about the measures that have been taken and that can be taken in order to stop harassment. It also questions the effectiveness of written anti-harassment policies for influencing organisational responses to harassment and draws attention to the role of gendered perceptions of harassment for choice of response strategy. Originality/value – This paper fills a gap in harassment research by reporting on the use of different response strategies and by providing initial insights into factors affecting choice of responses.

Implementing virtual collaborative inquiry practises in a middle-school context

The aim of the present study was to investigate the challenges that relate to the implementation of virtual inquiry practises in middle school. The case was a school course in which a group of Finnish students (N = 14) and teachers (N = 7) completed group inquiries through virtual collaboration, using a web-based learning environment. The task was to accomplish a cross-disciplinary inquiry into cultural issues. The students worked mainly at home and took much responsibility for their course achievements. The investigators analysed the pedagogical design of the course and the content of the participants' interaction patterns in the web-based environment, using qualitative content analysis and social network analysis. The findings suggest that the students succeeded in producing distinctive cultural products, and both the students and the teachers adopted novel roles during the inquiry. The web-based learning environment was used more as a coordination tool for organizing the collaborative work than as a forum for epistemic inquiry. The tension between the school curriculum and the inquiry practises was manifest in the participants' discussions of the assessment criteria of the course.

Molecular profiling of indoor microbial communities in moisture damaged and non-damaged buildings

Epidemiological studies have shown an elevation in the incidence of asthma, allergic symptoms and respiratory infections among people living or working in buildings with moisture and mould problems. Microbial growth is suspected to have a key role, since the severity of microbial contamination and symptoms show a positive correlation, while the removal of contaminated materials relieves the symptoms. However, the cause-and-effect relationship has not been well established and knowledge of the causative agents is incomplete. The present consensus of indoor microbes relies on culture-based methods. Microbial cultivation and identification is known to provide qualitatively and quantitatively biased results, which is suspected to be one of the reasons behind the often inconsistent findings between objectively measured microbiological attributes and health. In the present study the indoor microbial communities were assessed using culture-independent, DNA based methods. Fungal and bacterial diversity was determined by amplifying and sequencing the nucITS- and16S-gene regions, correspondingly. In addition, the cell equivalent numbers of 69 mould species or groups were determined by quantitative PCR (qPCR). The results from molecular analyses were compared with results obtained using traditional plate cultivation for fungi. Using DNA-based tools, the indoor microbial diversity was found to be consistently higher and taxonomically wider than viable diversity. The dominant sequence types of fungi, and also of bacteria were mainly affiliated with well-known microbial species. However, in each building they were accompanied by various rare, uncultivable and unknown species. In both moisture-damaged and undamaged buildings the dominant fungal sequence phylotypes were affiliated with the classes Dothideomycetes (mould-like filamentous ascomycetes); Agaricomycetes (mushroom- and polypore-like filamentous basidiomycetes); Urediniomycetes (rust-like basidiomycetes); Tremellomycetes and the family Malasseziales (both yeast-like basidiomycetes). The most probable source for the majority of fungal types was the outdoor environment. In contrast, the dominant bacterial phylotypes in both damaged and undamaged buildings were affiliated with human-associated members within the phyla Actinobacteria and Firmicutes. Indications of elevated fungal diversity within potentially moisture-damage-associated fungal groups were recorded in two of the damaged buildings, while one of the buildings was characterized by an abundance of members of the Penicillium chrysogenum and P. commune species complexes. However, due to the small sample number and strong normal variation firm conclusions concerning the effect of moisture damage on the species diversity could not be made. The fungal communities in dust samples showed seasonal variation, which reflected the seasonal fluctuation of outdoor fungi. Seasonal variation of bacterial communities was less clear but to some extent attributable to the outdoor sources as well. The comparison of methods showed that clone library sequencing was a feasible method for describing the total microbial diversity, indicated a moderate quantitative correlation between sequencing and qPCR results and confirmed that culture based methods give both a qualitative and quantitative underestimate of microbial diversity in the indoor environment. However, certain important indoor fungi such as Penicillium spp. were clearly underrepresented in the sequence material, probably due to their physiological and genetic properties. Species specific qPCR was a more efficient and sensitive method for detecting and quantitating individual species than sequencing, but in order to exploit the full advantage of the method in building investigations more information is needed about the microbial species growing on damaged materials. In the present study, a new method was also developed for enhanced screening of the marker gene clone libraries. The suitability of the screening method to different kinds of microbial environments including biowaste compost material and indoor settled dusts was evaluated. The usability was found to be restricted to environments that support the growth and subsequent dominance of a small number microbial species, such as compost material.

Women, Management and Leadership - Naiset ja johtajuus : NASTA Women's Leadership Project Final Report

Leadership without the full participation of women not only excludes women individually and collectively, but is also a huge waste of talent, knowledge and expertise. And crucially, given the current state of society and the world, this aspect of gender inequality is likely to become even more important in the future. NASTA - Women’s Leadership: A Research and Education Development Project was established in 2005 as a national multi-university project mainly and generously funded by Finnish Ministry of Education. The project aims at producing new knowledge and increasing understanding about women’s leadership, as well as promoting women’s leadership through research, development of teaching, and public outreach. NASTA is a joint effort of three Finnish universities – Hanken School of Economics, University of Jyväskylä School of Business and Economics, and the Helsinki School of Economics (now part of Aalto University) – and has been coordinated by Hanken. This report presents research and activities conducted within and around the project. NASTA activities have been many and various. They have examined the position and experiences of women in relation to leadership, management, organisation and work more generally. They have sought new knowledge about gender and leadership, on women leaders’ values, attitudes and behaviour, as well as about values, attitudes and behaviour in relation to women’s leadership. NASTA activities have included teaching, student supervision, research theses, research projects, publishing, networking, seminars, meetings, an international conference, and knowledge transfer into other sectors of society. The first section of the book introduces NASTA joint projects, including web-based teaching material, a survey of gender staffing and teaching on gender in business schools, critical review of previous research literature, and new empirical research. The next section includes research articles on different aspects of gender, leadership and manage¬¬ment from more individual projects conducted by participating researchers and research groups linked to NASTA across the three universities. The final section includes short presentations of other research in progress. The appendix lists publications by NASTA members – journal articles, research reports, books, chapters, journal special issues, popular journal articles, magazine articles - and masters, licentiate and doctoral theses that have been produced. These matters of women, leadership and management are not simply academic concerns but urgent matters for practice, organisations, management, policy, and society more generally.

Setting up Multilingual Information Repository: A case Study with EPrints.org Software

Today 80 % of the content on the Web is in English, which is spoken by only 8% of the World population and 5% of Indian population. There is wealth of useful content in the various languages of the world other than English, which can be made available on the Internet. But, to date, for various reasons most of it is not yet available on the Internet. India itself has 18 officially recognized languages and scores of dialects. Although the medium of instruction for most of the higher education and research in India is English, substantial amount of literature by way of novels, textbooks, scholarly information are being generated in the other languages in the country. Many of the e-governance initiatives are in the respective state languages. In the past, support for different languages by the operating systems and the software packages were not very encouraging. However, with the advent of Unicode technology, operating systems and software packages are supporting almost all the major languages of the world that have scripts. In the work reported in this paper, we have explained the configuration changes that are needed for Eprints.org software to store multilingual content and to create a multilingual user interface.

Fragment Finder 2.0: a computing server to identify structurally similar fragments

Fragment Finder 2.0 is a web-based interactive computing server which can be used to retrieve structurally similar protein fragments from 25 and 90% nonredundant data sets. The computing server identifies structurally similar fragments using the protein backbone C alpha angles. In addition, the identified fragments can be superimposed using either of the two structural superposition programs, STAMP and PROFIT, provided in the server. The freely available Java plug-in Jmol has been interfaced with the server for the visualization of the query and superposed fragments. The server is the updated version of a previously developed search engine and employs an in-house-developed fast pattern matching algorithm. This server can be accessed freely over the World Wide Web through the URL http://cluster.physics.iisc.ernet.in/ff/.