Static analysis of unbounded structures in object-oriented programs

In this thesis we investigate different techniques and formalisms to address complexity introduced by unbounded structures in object-oriented programs. We give a representation of a weakest precondition calculus for abstract object creation in dynamic logic. Based on this calculus we define symbolic execution including abstract object creation. We investigate the complex behaviour introduced by multi-threading and give a formalism based on the transformation of multi-threaded reentrant call-graphs to thread automata and the application of context free language reachability to decide deadlock freedom of such programs. We give a formalisation of the observable interface behaviour of a concurrent, object-oriented language with futures and promises. The calculus captures the core of the Creol language and allows for a comparison with the concurrency model of thread-based, object-oriented languages like Java or C#. We give a technique to detect deadlock freedom for an Actor-like subset of the Creol language. LEI Universiteit LeidenThe work in this thesis has been carried out at the Christian-Albrechts--Universität zu Kiel, the Centrum Wiskunde & Informatica (CWI), and the Universiteit Leiden. The research was partially funded by the EU-project IST- 33826 Credo: Modeling and analysis of evolutionary structures for distributed services; the EU-project FP7-231620 HATS: Highly Adaptable and Trustworthy Software using Formal Methods; and the German-Norwegian DAAD-NWO exchange project Avabi (Automated validation for behavioral interfaces of asynchronous active objects).Algorithms and the Foundations of Software technolog

Climate informed engineering: An essential pillar of industry 4.0 transformation

Breakthroughs in computing have led to development of new generations of Earth Systems Models providing detailed information on how our planet may locally respond to the ongoing global warming. Access to such climate information systems presents an unprecedented opportunity for engineers to make tangible contributions to climate adaptation through integration of climate information in their products, designs, and services. We introduce the concept of “Climate Informed Engineering” (CIE) as an emerging interdisciplinary field integrating climatic considerations in engineering products and services. The concept behind CIE is to enable engineers to build infrastructure, devices, sensors or develop new materials and processes that are informed by climate and climate change information. We believe CIE will be an increasingly important dimension of Engineering Science resonating with engineers and scientists with different backgrounds

Chinese L2 learners’ depth of vocabulary knowledge and its role in reading comprehension

This is the author accepted manuscript. The final version is available from the publisher via the DOI in this record.Using a Chinese Word Associates Test (WAT-C), this study examined the vocabulary depth of second language learners of Chinese and its contribution to the learners’ reading comprehension. Results showed no significant effects of word frequency, word class (i.e., adjectives vs. verbs), and type of association relationships (i.e., paradigmatic vs. syntagmatic) on learners’ WAT-C performance. More important, vocabulary depth was found to be a significant and unique predictor of reading comprehension over and above vocabulary size. On the other hand, the relative contributions of vocabulary depth and size depended on what types of texts were read and what comprehension skills were assessed. Specifically, for the long passage comprehension task with questions testing literal comprehension, vocabulary size was a more important predictor, whereas for the short passage comprehension task with questions testing inferencing, vocabulary depth was a more important predictor. These findings were discussed in light of the different levels of lexical complexity between the short and long passages and the different cognitive processing demands the questions of the two comprehension tasks placed on learners

The stiffess of unsaturated railway formations

The rational design of a substructure to support a rail track requires an estimation of the stiffness value of the formation on which it is to be built. Stiffness values derived from back-analyses of deformations of the ground beneath the track have been found by the authors to be much higher than those predicted from laboratory element testing on saturated specimens. This may be because of differences in compaction between field and laboratory, or because suctions created by lack of saturation play a key role in controlling stiffness, and therefore the performance of the track when in use. To test the latter hypothesis a laboratory study has been carried out on material representative of that found in South African railway formations. This was tested at constant dry density and various water contents, with matric suctions determined using different established techniques, and very-small-strain stiffness levels obtained from resonant column testing. A suction stress characteristic curve was developed to identify the contribution of suction to the overall effective stress for this material. The results show that suction can indeed be an important contributing factor to the magnitude of stiffness. For material tested at constant dry density, the stiffness initially increases with reducing compaction water content, and therefore with increasing suction. It subsequently reduces back towards the saturated value as the compaction water content approaches zero, even though the matric suction continues to increase. The relative increase in very-small-strain stiffness due to suction depends, to a large extent, on the net normal stress during the stiffness measurement. The effect of matric suction is proportionately greatest at the low net normal stress levels that apply for shallow infrastructures such as rail formations. Also, the operational stiffness depends not only on the current water content (and therefore suction), but also on the water content at which the material has been compacted.The Engineering and Physical Sciences Research Council’s ‘Rail Research UK’ programmehttp://pif.sagepub.comhb2016Civil Engineerin

Speech rhythm: a metaphor?

Is speech rhythmic? In the absence of evidence for a traditional view that languages strive to coordinate either syllables or stress-feet with regular time intervals, we consider the alternative that languages exhibit contrastive rhythm subsisting merely in the alternation of stronger and weaker elements. This is initially plausible, particularly for languages with a steep ‘prominence gradient’, i.e. a large disparity between stronger and weaker elements; but we point out that alternation is poorly achieved even by a ‘stress-timed’ language such as English, and, historically, languages have conspicuously failed to adopt simple phonological remedies that would ensure alternation. Languages seem more concerned to allow ‘syntagmatic contrast’ between successive units and to use durational effects to support linguistic functions than to facilitate rhythm. Furthermore, some languages (e.g. Tamil, Korean) lack the lexical prominence which would most straightforwardly underpin prominence alternation. We conclude that speech is not incontestibly rhythmic, and may even be antirhythmic. However, its linguistic structure and patterning allow the metaphorical extension of rhythm in varying degrees and in different ways depending on the language, and that it is this analogical process which allows speech to be matched to external rhythms

Agent based modelling helps in understanding the rules by which fibroblasts support keratinocyte colony formation

Background: Autologous keratincoytes are routinely expanded using irradiated mouse fibroblasts and bovine serum for clinical use. With growing concerns about the safety of these xenobiotic materials, it is desirable to culture keratinocytes in media without animal derived products. An improved understanding of epithelial/mesenchymal interactions could assist in this. Methodology/Principal Findings: A keratincyte/fibroblast o-culture model was developed by extending an agent-based keratinocyte colony formation model to include the response of keratinocytes to both fibroblasts and serum. The model was validated by comparison of the in virtuo and in vitro multicellular behaviour of keratinocytes and fibroblasts in single and co-culture in Greens medium. To test the robustness of the model, several properties of the fibroblasts were changed to investigate their influence on the multicellular morphogenesis of keratinocyes and fibroblasts. The model was then used to generate hypotheses to explore the interactions of both proliferative and growth arrested fibroblasts with keratinocytes. The key predictions arising from the model which were confirmed by in vitro experiments were that 1) the ratio of fibroblasts to keratinocytes would critically influence keratinocyte colony expansion, 2) this ratio needed to be optimum at the beginning of the co-culture, 3) proliferative fibroblasts would be more effective than irradiated cells in expanding keratinocytes and 4) in the presence of an adequate number of fibroblasts, keratinocyte expansion would be independent of serum. Conclusions: A closely associated computational and biological approach is a powerful tool for understanding complex biological systems such as the interactions between keratinocytes and fibroblasts. The key outcome of this study is the finding that the early addition of a critical ratio of proliferative fibroblasts can give rapid keratinocyte expansion without the use of irradiated mouse fibroblasts and bovine serum

Genetic determinants of cortical structure (thickness, surface area and volumes) among disease free adults in the CHARGE Consortium

Cortical thickness, surface area and volumes (MRI cortical measures) vary with age and cognitive function, and in neurological and psychiatric diseases. We examined heritability, genetic correlations and genome-wide associations of cortical measures across the whole cortex, and in 34 anatomically predefined regions. Our discovery sample comprised 22,824 individuals from 20 cohorts within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the United Kingdom Biobank. Significant associations were replicated in the Enhancing Neuroimaging Genetics through Meta-analysis (ENIGMA) consortium, and their biological implications explored using bioinformatic annotation and pathway analyses. We identified genetic heterogeneity between cortical measures and brain regions, and 160 genome-wide significant associations pointing to wnt/β-catenin, TGF-β and sonic hedgehog pathways. There was enrichment for genes involved in anthropometric traits, hindbrain development, vascular and neurodegenerative disease and psychiatric conditions. These data are a rich resource for studies of the biological mechanisms behind cortical development and aging

ENIGMA and global neuroscience: A decade of large-scale studies of the brain in health and disease across more than 40 countries

This review summarizes the last decade of work by the ENIGMA (Enhancing NeuroImaging Genetics through Meta Analysis) Consortium, a global alliance of over 1400 scientists across 43 countries, studying the human brain in health and disease. Building on large-scale genetic studies that discovered the first robustly replicated genetic loci associated with brain metrics, ENIGMA has diversified into over 50 working groups (WGs), pooling worldwide data and expertise to answer fundamental questions in neuroscience, psychiatry, neurology, and genetics. Most ENIGMA WGs focus on specific psychiatric and neurological conditions, other WGs study normal variation due to sex and gender differences, or development and aging; still other WGs develop methodological pipelines and tools to facilitate harmonized analyses of "big data" (i.e., genetic and epigenetic data, multimodal MRI, and electroencephalography data). These international efforts have yielded the largest neuroimaging studies to date in schizophrenia, bipolar disorder, major depressive disorder, post-traumatic stress disorder, substance use disorders, obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, autism spectrum disorders, epilepsy, and 22q11.2 deletion syndrome. More recent ENIGMA WGs have formed to study anxiety disorders, suicidal thoughts and behavior, sleep and insomnia, eating disorders, irritability, brain injury, antisocial personality and conduct disorder, and dissociative identity disorder. Here, we summarize the first decade of ENIGMA's activities and ongoing projects, and describe the successes and challenges encountered along the way. We highlight the advantages of collaborative large-scale coordinated data analyses for testing reproducibility and robustness of findings, offering the opportunity to identify brain systems involved in clinical syndromes across diverse samples and associated genetic, environmental, demographic, cognitive, and psychosocial factors

Dose response of the 16p11.2 distal copy number variant on intracranial volume and basal ganglia.

Carriers of large recurrent copy number variants (CNVs) have a higher risk of developing neurodevelopmental disorders. The 16p11.2 distal CNV predisposes carriers to e.g., autism spectrum disorder and schizophrenia. We compared subcortical brain volumes of 12 16p11.2 distal deletion and 12 duplication carriers to 6882 non-carriers from the large-scale brain Magnetic Resonance Imaging collaboration, ENIGMA-CNV. After stringent CNV calling procedures, and standardized FreeSurfer image analysis, we found negative dose-response associations with copy number on intracranial volume and on regional caudate, pallidum and putamen volumes (β = -0.71 to -1.37; P < 0.0005). In an independent sample, consistent results were obtained, with significant effects in the pallidum (β = -0.95, P = 0.0042). The two data sets combined showed significant negative dose-response for the accumbens, caudate, pallidum, putamen and ICV (P = 0.0032, 8.9 × 10-6, 1.7 × 10-9, 3.5 × 10-12 and 1.0 × 10-4, respectively). Full scale IQ was lower in both deletion and duplication carriers compared to non-carriers. This is the first brain MRI study of the impact of the 16p11.2 distal CNV, and we demonstrate a specific effect on subcortical brain structures, suggesting a neuropathological pattern underlying the neurodevelopmental syndromes