Discovery and replication of gene influences on brain structure using LASSO regression

We implemented least absolute shrinkage and selection operator (LASSO) regression to evaluate gene effects in genome-wide association studies (GWAS) of brain images, using an MRI-derived temporal lobe volume measure from 729 subjects scanned as part of the Alzheimer's Disease Neuroimaging Initiative (ADNI). Sparse groups of SNPs in individual genes were selected by LASSO, which identifies efficient sets of variants influencing the data. These SNPs were considered jointly when assessing their association with neuroimaging measures. We discovered 22 genes that passed genome-wide significance for influencing temporal lobe volume. This was a substantially greater number of significant genes compared to those found with standard, univariate GWAS. These top genes are all expressed in the brain and include genes previously related to brain function or neuropsychiatric disorders such as MACROD2, SORCS2, GRIN2B, MAGI2, NPAS3, CLSTN2, GABRG3, NRXN3, PRKAG2, GAS7, RBFOX1, ADARB2, CHD4, and CDH13. The top genes we identified with this method also displayed significant and widespread post hoc effects on voxelwise, tensor-based morphometry (TBM) maps of the temporal lobes. The most significantly associated gene was an autism susceptibility gene known as MACROD2.We were able to successfully replicate the effect of the MACROD2 gene in an independent cohort of 564 young, Australian healthy adult twins and siblings scanned with MRI (mean age: 23.8±2.2 SD years). Our approach powerfully complements univariate techniques in detecting influences of genes on the living brain.

Discovery and replication of dopamine-related gene effects on caudate volume in young and elderly populations (N1198) using genome-wide search

The caudate is a subcortical brain structure implicated in many common neurological and psychiatric disorders. To identify specific genes associated with variations in caudate volume, structural magnetic resonance imaging and genome-wide genotypes were acquired from two large cohorts, the Alzheimer's Disease NeuroImaging Initiative (ADNI; N=734) and the Brisbane Adolescent/Young Adult Longitudinal Twin Study (BLTS; N=464). In a preliminary analysis of heritability, around 90% of the variation in caudate volume was due to genetic factors. We then conducted genome-wide association to find common variants that contribute to this relatively high heritability. Replicated genetic association was found for the right caudate volume at single-nucleotide polymorphism rs163030 in the ADNI discovery sample (P=2.36 × 10 -6) and in the BLTS replication sample (P=0.012). This genetic variation accounted for 2.79 and 1.61% of the trait variance, respectively. The peak of association was found in and around two genes, WDR41 and PDE8B, involved in dopamine signaling and development. In addition, a previously identified mutation in PDE8B causes a rare autosomal-dominant type of striatal degeneration. Searching across both samples offers a rigorous way to screen for genes consistently influencing brain structure at different stages of life. Variants identified here may be relevant to common disorders affecting the caudate.

An entrepreneurial music industry education in secondary schooling: The emerging professional learning model

There is widespread agreement that entrepreneurial skills are crucial for young people today, yet there are few studies of high school students engaging in entrepreneurship education that might prepare them for music industry careers. This study has been developed in response to these challenges. It explores a group of high school students (15 – 17 years) who alongside their teacher, have co-designed, developed and driven a new business venture, Youth Music Industries (YMI) since 2010. This venture staged cycles of differently scaled events featuring young artists for a young audience. The project was designed to give students a real business situation for developing their project management skills and a broader understanding of working in the music industry. Informed by concepts of social capital and communities of practice, the study examines the process of learning with and through others. This high-stakes environment increased their sense of presence and participation and made it possible for these young people to distribute expertise and learn from each other in a reciprocal and more democratic way. The ongoing success of this organisation can be attributed to the entrepreneurial competencies students developed. The resulting model and design principles talk to an ongoing challenge that has been identified in music education, and creative industries more generally. These principles offer a way forward for other music and creative industries educators or researchers interested in developing models of, and designs for, nurturing an entrepreneurial mindset.

The impact of international potentials, entrepreneurial motivations and firm stages on new venture internationalisation

Past research on early internationalising firms often examined factors and motivations potentially influencing internationalisation activities separately. The purpose of this paper was to investigate a set of indicators and their interplay with each other. Firstly, the impact of (a) international potential in the form of the depth and diversity of international experience and network contacts was investigated. Secondly, it was examined to what extent (b) motivational factors and (c) firm stages affect the relationship between international potential and internationalisation activities. This paper used longitudinal data from the Comprehensive Australian Study of Entrepreneurial Emergence (CAUSEE). Results suggest that the international potential of a new venture as a whole is a significant determinant of subsequent internationalisation activities. However, having a diverse international experience from a variety of foreign countries appears to be more beneficial than a long-lasting experience from only a limited number of foreign countries. Furthermore, analyses showed that the interplay of high growth ambitions and the depth of international experience positively affect internationalisation activities. Opportunity or necessity driven entrepreneurship, however, neither exaggerate nor weaken the positive relationship between international potentials and internationalisation activities. Similarly, no moderation by firm stages was found.

Five years of GWAS discovery

The past five years have seen many scientific and biological discoveries made through the experimental design of genome-wide association studies (GWASs). These studies were aimed at detecting variants at genomic loci that are associated with complex traits in the population and, in particular, at detecting associations between common single-nucleotide polymorphisms (SNPs) and common diseases such as heart disease, diabetes, auto-immune diseases, and psychiatric disorders. We start by giving a number of quotes from scientists and journalists about perceived problems with GWASs. We will then briefly give the history of GWASs and focus on the discoveries made through this experimental design, what those discoveries tell us and do not tell us about the genetics and biology of complex traits, and what immediate utility has come out of these studies. Rather than giving an exhaustive review of all reported findings for all diseases and other complex traits, we focus on the results for auto-immune diseases and metabolic diseases. We return to the perceived failure or disappointment about GWASs in the concluding section. © 2012 The American Society of Human Genetics.

Genetics of rheumatoid arthritis contributes to biology and drug discovery

A major challenge in human genetics is to devise a systematic strategy to integrate disease-associated variants with diverse genomic and biological data sets to provide insight into disease pathogenesis and guide drug discovery for complex traits such as rheumatoid arthritis (RA)1. Here we performed a genome-wide association study meta-analysis in a total of >100,000 subjects of European and Asian ancestries (29,880 RA cases and 73,758 controls), by evaluating ~10 million single-nucleotide polymorphisms. We discovered 42 novel RA risk loci at a genome-wide level of significance, bringing the total to 101 (refs 2, 3, 4). We devised an in silico pipeline using established bioinformatics methods based on functional annotation5, cis-acting expression quantitative trait loci6 and pathway analyses7, 8, 9—as well as novel methods based on genetic overlap with human primary immunodeficiency, haematological cancer somatic mutations and knockout mouse phenotypes—to identify 98 biological candidate genes at these 101 risk loci. We demonstrate that these genes are the targets of approved therapies for RA, and further suggest that drugs approved for other indications may be repurposed for the treatment of RA. Together, this comprehensive genetic study sheds light on fundamental genes, pathways and cell types that contribute to RA pathogenesis, and provides empirical evidence that the genetics of RA can provide important information for drug discovery.

Discovery of candidate serum proteomic and metabolomic biomarkers in ankylosing spondylitis

Ankylosing Spondylitis (AS) is a common inflammatory rheumatic disease with a predilection for the axial skeleton, affecting 0.2% of the population. Current diagnostic criteria rely on a composite of clinical and radiological changes, with a mean time to diagnosis of 5 to 10 years. In this study we employed nano liquid-chromatography mass spectrometry analysis to detect and quantify proteins and small compounds including endogenous peptides and metabolites in serum from 18 AS patients and nine healthy individuals. We identified a total of 316 proteins in serum, of which 22 showed significant up- or down-regulation (p < 0.05) in AS patients. Receiver operating characteristic analysis of combined levels of serum amyloid P component and inter-α-trypsin inhibitor heavy chain 1 revealed high diagnostic value for Ankylosing Spondylitis (area under the curve = 0.98). We also depleted individual sera of proteins to analyze endogenous peptides and metabolic compounds. We detected more than 7000 molecular features in patients and healthy individuals. Quantitative MS analysis revealed compound profiles that correlate with the clinical assessment of disease activity. One molecular feature identified as a Vitamin D3 metabolite-(23S,25R)-25-hydroxyvitamin D3 26,23-peroxylactone-was down-regulated in AS. The ratio of this vitamin D metabolite versus vitamin D binding protein serum levels was also altered in AS as compared with controls. These changes may contribute to pathological skeletal changes in AS. Our study is the first example of an integration of proteomic and metabolomic techniques to find new biomarker candidates for the diagnosis of Ankylosing Spondylitis

Word Sense Discovery and Disambiguation

The work is based on the assumption that words with similar syntactic usage have similar meaning, which was proposed by Zellig S. Harris (1954,1968). We study his assumption from two aspects: Firstly, different meanings (word senses) of a word should manifest themselves in different usages (contexts), and secondly, similar usages (contexts) should lead to similar meanings (word senses). If we start with the different meanings of a word, we should be able to find distinct contexts for the meanings in text corpora. We separate the meanings by grouping and labeling contexts in an unsupervised or weakly supervised manner (Publication 1, 2 and 3). We are confronted with the question of how best to represent contexts in order to induce effective classifiers of contexts, because differences in context are the only means we have to separate word senses. If we start with words in similar contexts, we should be able to discover similarities in meaning. We can do this monolingually or multilingually. In the monolingual material, we find synonyms and other related words in an unsupervised way (Publication 4). In the multilingual material, we ?nd translations by supervised learning of transliterations (Publication 5). In both the monolingual and multilingual case, we first discover words with similar contexts, i.e., synonym or translation lists. In the monolingual case we also aim at finding structure in the lists by discovering groups of similar words, e.g., synonym sets. In this introduction to the publications of the thesis, we consider the larger background issues of how meaning arises, how it is quantized into word senses, and how it is modeled. We also consider how to define, collect and represent contexts. We discuss how to evaluate the trained context classi?ers and discovered word sense classifications, and ?nally we present the word sense discovery and disambiguation methods of the publications. This work supports Harris' hypothesis by implementing three new methods modeled on his hypothesis. The methods have practical consequences for creating thesauruses and translation dictionaries, e.g., for information retrieval and machine translation purposes. Keywords: Word senses, Context, Evaluation, Word sense disambiguation, Word sense discovery.

On the Origin of Ideas : An Abductivist Approach to Discovery

The purpose of this study is to analyze and develop various forms of abduction as a means of conceptualizing processes of discovery. Abduction was originally presented by Charles S. Peirce (1839-1914) as a "weak", third main mode of inference -- besides deduction and induction -- one which, he proposed, is closely related to many kinds of cognitive processes, such as instincts, perception, practices and mediated activity in general. Both abduction and discovery are controversial issues in philosophy of science. It is often claimed that discovery cannot be a proper subject area for conceptual analysis and, accordingly, abduction cannot serve as a "logic of discovery". I argue, however, that abduction gives essential means for understanding processes of discovery although it cannot give rise to a manual or algorithm for making discoveries. In the first part of the study, I briefly present how the main trend in philosophy of science has, for a long time, been critical towards a systematic account of discovery. Various models have, however, been suggested. I outline a short history of abduction; first Peirce's evolving forms of his theory, and then later developments. Although abduction has not been a major area of research until quite recently, I review some critiques of it and look at the ways it has been analyzed, developed and used in various fields of research. Peirce's own writings and later developments, I argue, leave room for various subsequent interpretations of abduction. The second part of the study consists of six research articles. First I treat "classical" arguments against abduction as a logic of discovery. I show that by developing strategic aspects of abductive inference these arguments can be countered. Nowadays the term 'abduction' is often used as a synonym for the Inference to the Best Explanation (IBE) model. I argue, however, that it is useful to distinguish between IBE ("Harmanian abduction") and "Hansonian abduction"; the latter concentrating on analyzing processes of discovery. The distinctions between loveliness and likeliness, and between potential and actual explanations are more fruitful within Hansonian abduction. I clarify the nature of abduction by using Peirce's distinction between three areas of "semeiotic": grammar, critic, and methodeutic. Grammar (emphasizing "Firstnesses" and iconicity) and methodeutic (i.e., a processual approach) especially, give new means for understanding abduction. Peirce himself held a controversial view that new abductive ideas are products of an instinct and an inference at the same time. I maintain that it is beneficial to make a clear distinction between abductive inference and abductive instinct, on the basis of which both can be developed further. Besides these, I analyze abduction as a part of distributed cognition which emphasizes a long-term interaction with the material, social and cultural environment as a source for abductive ideas. This approach suggests a "trialogical" model in which inquirers are fundamentally connected both to other inquirers and to the objects of inquiry. As for the classical Meno paradox about discovery, I show that abduction provides more than one answer. As my main example of abductive methodology, I analyze the process of Ignaz Semmelweis' research on childbed fever. A central basis for abduction is the claim that discovery is not a sequence of events governed only by processes of chance. Abduction treats those processes which both constrain and instigate the search for new ideas; starting from the use of clues as a starting point for discovery, but continuing in considerations like elegance and 'loveliness'. The study then continues a Peircean-Hansonian research programme by developing abduction as a way of analyzing processes of discovery.

Discovery of genes associated with fruit ripening in arica papaya using expressed sequence tags

To identify genes involved in papaya fruit ripening, a total of 1171 expressed sequence tags (ESTs) were generated from randomly selected clones of two independent fruit cDNA libraries derived from yellow and red-fleshed fruit varieties. The most abundant sequences encoded: chitinase, 1-aminocyclopropane-1-carboxylic acid (ACC) oxidase, catalase and methionine synthase, respectively. DNA sequence comparisons identified ESTs with significant similarity to genes associated with fruit softening, aroma and colour biosynthesis. Putative cell wall hydrolases, cell membrane hydrolases, and ethylene synthesis and regulation sequences were identified with predicted roles in fruit softening. Expressed papaya genes associated with fruit aroma included isoprenoid biosynthesis and shikimic acid pathway genes and proteins associated with acyl lipid catabolism. Putative fruit colour genes were identified due to their similarity with carotenoid and chlorophyll biosynthesis genes from other plant species.

Discovery of genes associated with fruit ripening in Carica papaya using expressed sequence tags

To identify genes involved in papaya fruit ripening, a total of 1171 expressed sequence tags (ESTs) were generated from randomly selected clones of two independent fruit cDNA libraries derived from yellow and red-fleshed fruit varieties. The most abundant sequences encoded:chitinase, 1-aminocyclopropane-1-carboxylic acid (ACC) oxidase, catalase and methionine synthase, respectively. DNA sequence comparisons identified ESTs with significant similarity to genes associated with fruit softening, aroma and colour biosynthesis. Putative cell wall hydrolases, cell membrane hydrolases, and ethylene synthesis and regulation sequences were identified with predicted roles in fruit softening. Expressed papaya genes associated with fruit aroma included isoprenoid biosynthesis and shikimic acid pathway genes and proteins associated with acyl lipid catabolism. Putative fruit colour genes were identified due to their similarity with carotenoid and chlorophyll biosynthesis genes from other plant species.

Kaurimyia gen. nov.: Discovery of Apsilocephalidae (Diptera: Therevoid clade) in New Zealand

A new genus (Kaurimyia thorpei gen. et sp. nov.) of the enigmatic fly family Apsilocephalidae (Asiloidea) is described from New Zealand. Kaurimyia thorpei gen. et sp. nov. is described and figured from male and female specimens, one of which was collected in Kauri forest near Auckland (North Island). While superficially similar to Apsilocephala Krober, this new genus shows closer affinities to Clesthentia White (=Clesthentiella Nagatomi, Saigusa, Nagatomi et Lyneborg syn. nov.) from Tasmania based on genitalic characters such as aedeagus shape and non-articulated surstyli. Apsilocephalidae is presently known from just a few extant species in North America and Tasmania (Australia), although extinct species are recorded from the Holarctic and Oriental regions. This is the first description of the family from New Zealand.

SME international performance in Latin America: The role of entrepreneurial and technological capabilities

SMEs from emerging markets in Latin America are increasingly engaging in internationalization. Nevertheless, there is limited research into how these firms achieve international performance. This study proposes and tests a conceptual model that considers managerial and technology-related capabilities and their impact on international performance of SMEs. The model uses confirmatory factor analysis (CFA) to develop the underlying multi-item constructs and structural equation modeling (SEM) to test the model with data from 233 Chilean SMEs. Specifically, the model considers the role of international entrepreneurial orientation and Internet capabilities on international market performance, taking into account the mediating effect of international entrepreneurial opportunity recognition and technology-related international networks. Results show that international entrepreneurial opportunity recognition and international networks mediate the relationship between international entrepreneurial orientation and Internet marketing capabilities on SME international performance.

Knowledge discovery from tree databases using balanced optimal search

This research is a step forward in discovering knowledge from databases of complex structure like tree or graph. Several data mining algorithms are developed based on a novel representation called Balanced Optimal Search for extracting implicit, unknown and potentially useful information like patterns, similarities and various relationships from tree data, which are also proved to be advantageous in analysing big data. This thesis focuses on analysing unordered tree data, which is robust to data inconsistency, irregularity and swift information changes, hence, in the era of big data it becomes a popular and widely used data model.

Patterns of entrepreneurial career development: An optimal matching analysis approach

Longitudinal studies of entrepreneurial career development are rare, and current knowledge of self-employment patterns and their relationships with individual difference characteristics is limited. In this study, the authors analyzed employment data from a subsample of 514 participants from the German Socio-Economic Panel study (1984–2008). Results of an optimal matching analysis indicated that a continuous self-employment pattern could be distinguished from four alternative employment patterns (change from employment to self-employment, full-time employees, part-time employees, and farmers). Results of a multinomial logistic regression analysis showed that certain socio-demographic characteristics (i.e., age and gender) and personality characteristics (i.e., conscientiousness and risk-taking propensity) were related to the likelihood of following a continuous self-employment pattern compared to the other employment patterns. Implications for future research on entrepreneurial career development are discussed.