Genetic architecture of subcortical brain regions: Common and region-specific genetic contributions

Understanding the aetiology of patterns of variation within and covariation across brain regions is key to advancing our understanding of the functional, anatomical and developmental networks of the brain. Here we applied multivariate twin modelling and principal component analysis (PCA) to investigate the genetic architecture of the size of seven subcortical regions (caudate nucleus, thalamus, putamen, pallidum, hippocampus, amygdala and nucleus accumbens) in a genetically informative sample of adolescents and young adults (N=1038; mean age=21.6±3.2years; including 148 monozygotic and 202 dizygotic twin pairs) from the Queensland Twin IMaging (QTIM) study. Our multivariate twin modelling identified a common genetic factor that accounts for all the heritability of intracranial volume (0.88) and a substantial proportion of the heritability of all subcortical structures, particularly those of the thalamus (0.71 out of 0.88), pallidum (0.52 out of 0.75) and putamen (0.43 out of 0.89). In addition, we also found substantial region-specific genetic contributions to the heritability of the hippocampus (0.39 out of 0.79), caudate nucleus (0.46 out of 0.78), amygdala (0.25 out of 0.45) and nucleus accumbens (0.28 out of 0.52). This provides further insight into the extent and organization of subcortical genetic architecture, which includes developmental and general growth pathways, as well as the functional specialization and maturation trajectories that influence each subcortical region. This multivariate twin study identifies a common genetic factor that accounts for all the heritability of intracranial volume (0.88) and a substantial proportion of the heritability of all subcortical structures, particularly those of the thalamus (0.71 out of 0.88), pallidum (0.52 out of 0.75) and putamen (0.43 out of 0.89). In parallel, it also describes substantial region-specific genetic contributions to the heritability of the hippocampus (0.39 out of 0.79), caudate nucleus (0.46 out of 0.78), amygdala (0.25 out of 0.45) and nucleus accumbens (0.28 out of 0.52).

A commonly carried genetic variant in the delta opioid receptor gene, OPRD1, is associated with smaller regional brain volumes: Replication in elderly and young populations

Delta opioid receptors are implicated in a variety of psychiatric and neurological disorders. These receptors play a key role in the reinforcing properties of drugs of abuse, and polymorphisms in OPRD1 (the gene encoding delta opioid receptors) are associated with drug addiction. Delta opioid receptors are also involved in protecting neurons against hypoxic and ischemic stress. Here, we first examined a large sample of 738 elderly participants with neuroimaging and genetic data from the Alzheimer's Disease Neuroimaging Initiative. We hypothesized that common variants in OPRD1 would be associated with differences in brain structure, particularly in regions relevant to addictive and neurodegenerative disorders. One very common variant (rs678849) predicted differences in regional brain volumes. We replicated the association of this single-nucleotide polymorphism with regional tissue volumes in a large sample of young participants in the Queensland Twin Imaging study. Although the same allele was associated with reduced volumes in both cohorts, the brain regions affected differed between the two samples. In healthy elderly, exploratory analyses suggested that the genotype associated with reduced brain volumes in both cohorts may also predict cerebrospinal fluid levels of neurodegenerative biomarkers, but this requires confirmation. If opiate receptor genetic variants are related to individual differences in brain structure, genotyping of these variants may be helpful when designing clinical trials targeting delta opioid receptors to treat neurological disorders.

The tensor distribution function

Diffusion weighted magnetic resonance imaging is a powerful tool that can be employed to study white matter microstructure by examining the 3D displacement profile of water molecules in brain tissue. By applying diffusion-sensitized gradients along a minimum of six directions, second-order tensors (represented by three-by-three positive definite matrices) can be computed to model dominant diffusion processes. However, conventional DTI is not sufficient to resolve more complicated white matter configurations, e.g., crossing fiber tracts. Recently, a number of high-angular resolution schemes with more than six gradient directions have been employed to address this issue. In this article, we introduce the tensor distribution function (TDF), a probability function defined on the space of symmetric positive definite matrices. Using the calculus of variations, we solve the TDF that optimally describes the observed data. Here, fiber crossing is modeled as an ensemble of Gaussian diffusion processes with weights specified by the TDF. Once this optimal TDF is determined, the orientation distribution function (ODF) can easily be computed by analytic integration of the resulting displacement probability function. Moreover, a tensor orientation distribution function (TOD) may also be derived from the TDF, allowing for the estimation of principal fiber directions and their corresponding eigenvalues.

Australian patients using a cardiac-diabetes web-based intervention program: Contributions to person-centered clinical practice

Rationale, aims and objectives: Patients with both cardiac disease and diabetes have poorer health outcomes than patients with only one chronic condition. While evidence indicates that internet based interventions may improve health outcomes for patients with a chronic disease, there is no literature on internet programs specific to cardiac patients with comorbid diabetes. Therefore this study aimed to develop a specific web-based program, then to explore patients’ perspectives on the usefulness of a new program. Methods: The interpretive approach using semi-structured interviews on a purposive sample of eligible patients with type 2 diabetes and a cardiac condition in a metropolitan hospital in Brisbane, Australia. Thematic analysis was undertaken to describe the perceived usefulness of a newly developed Heart2heart webpage. Results: Themes identified included confidence in hospital health professionals and reliance on doctors to manage conditions. Patients found the webpage useful for managing their conditions at home. Conclusions: The new Heart2heart webpage provided a positive and useful resource. Further research on to determine the potential influence of this resource on patients’ self-management behaviours is paramount. Implications for practice include using multimedia strategies for providing information to patients’ comorbidities of cardiac disease and type 2 diabetes, and further development on enhancement of such strategies

Genome-wide association analysis identifies 11 risk variants associated with the asthma with hay fever phenotype

Background To date, no genome-wide association study (GWAS) has considered the combined phenotype of asthma with hay fever. Previous analyses of family data from the Tasmanian Longitudinal Health Study provide evidence that this phenotype has a stronger genetic cause than asthma without hay fever. Objective We sought to perform a GWAS of asthma with hay fever to identify variants associated with having both diseases. Methods We performed a meta-analysis of GWASs comparing persons with both physician-diagnosed asthma and hay fever (n = 6,685) with persons with neither disease (n = 14,091). Results At genome-wide significance, we identified 11 independent variants associated with the risk of having asthma with hay fever, including 2 associations reaching this level of significance with allergic disease for the first time: ZBTB10 (rs7009110; odds ratio [OR], 1.14; P = 4 × 10−9) and CLEC16A (rs62026376; OR, 1.17; P = 1 × 10−8). The rs62026376:C allele associated with increased asthma with hay fever risk has been found to be associated also with decreased expression of the nearby DEXI gene in monocytes. The 11 variants were associated with the risk of asthma and hay fever separately, but the estimated associations with the individual phenotypes were weaker than with the combined asthma with hay fever phenotype. A variant near LRRC32 was a stronger risk factor for hay fever than for asthma, whereas the reverse was observed for variants in/near GSDMA and TSLP. Single nucleotide polymorphisms with suggestive evidence for association with asthma with hay fever risk included rs41295115 near IL2RA (OR, 1.28; P = 5 × 10−7) and rs76043829 in TNS1 (OR, 1.23; P = 2 × 10−6). Conclusion By focusing on the combined phenotype of asthma with hay fever, variants associated with the risk of allergic disease can be identified with greater efficiency.

Genome-wide association study identifies eight loci associated with blood pressure

Elevated blood pressure is a common, heritable cause of cardiovascular disease worldwide. To date, identification of common genetic variants influencing blood pressure has proven challenging. We tested 2.5 million genotyped and imputed SNPs for association with systolic and diastolic blood pressure in 34,433 subjects of European ancestry from the Global BPgen consortium and followed up findings with direct genotyping (N 71,225 European ancestry, N 12,889 Indian Asian ancestry) and in silico comparison (CHARGE consortium, N = 29,136). We identified association between systolic or diastolic blood pressure and common variants in eight regions near the CYP17A1 (P = 7 × 10 24), CYP1A2 (P = 1 × 10 23), FGF5 (P = 1 × 10 21), SH2B3 (P = 3 × 10 18), MTHFR (P = 2 × 10 13), c10orf107 (P = 1 × 10 9), ZNF652 (P = 5 × 10 9) and PLCD3 (P = 1 × 10 8) genes. All variants associated with continuous blood pressure were associated with dichotomous hypertension. These associations between common variants and blood pressure and hypertension offer mechanistic insights into the regulation of blood pressure and may point to novel targets for interventions to prevent cardiovascular disease.

Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants

We have genotyped 14,436 nonsynonymous SNPs (nsSNPs) and 897 major histocompatibility complex (MHC) tag SNPs from 1,000 independent cases of ankylosing spondylitis (AS), autoimmune thyroid disease (AITD), multiple sclerosis (MS) and breast cancer (BC). Comparing these data against a common control dataset derived from 1,500 randomly selected healthy British individuals, we report initial association and independent replication in a North American sample of two new loci related to ankylosing spondylitis, ARTS1 and IL23R, and confirmation of the previously reported association of AITD with TSHR and FCRL3. These findings, enabled in part by increased statistical power resulting from the expansion of the control reference group to include individuals from the other disease groups, highlight notable new possibilities for autoimmune regulation and suggest that IL23R may be a common susceptibility factor for the major 'seronegative' diseases.

Relocating the American Dream : The America of the 1960s as Portrayed by the New Journalists Norman Mailer, Hunter S. Thompson, and Tom Wolfe

The concept of the American Dream was subject to a strong re-evaluation process in the 1960s, as counterculture became a prominent force in American society. A massive generation of young people, moved by the Vietnam War, the hippie movement, and psychedelic experimentation, created substantial social turbulence in their efforts to break out of conventional patterns and to create a new kind of society. This thesis outlines and analyses the concept of the American Dream in popular imagination through three works of new journalism. My primary data consists of Tom Wolfe’s The Electric Kool-Aid Acid Test (1967), Hunter S. Thompson’s Fear and Loathing in Las Vegas: A Savage Journey to the Heart of the American Dream (1971), and Norman Mailer’s Armies of the Night: History as a Novel, the Novel as History (1968). In defining the American Dream, I discuss the history of the concept as well as its manifestations in popular culture. Because of its elusive and amorphous nature, the concept of the American Dream can only be examined in cultural texts that portray the values, sentiments, and customs of a certain era. I have divided the analytical section of my thesis into three parts. In the first part I examine how the authors discuss the American society of their time in relation to ideology, capitalism, and the media. In the second part I focus on the Vietnam War and the controversy it creates in relation to the notions of freedom and patriotism. In the third part I discuss how the authors portray the countercultural visions of a better America that challenged the traditional interpretations of the American Dream. I also discuss the dark side of the new dream: the problems and disillusions that came with the effort to change the world. This thesis is an effort to trace the relocation of the American Dream in the context of the 1960s counterculture and new journalism. It hopes to provide a valuable addition to the cultural history of the sixties and to the effort of conceptualizing the American Dream.

Konstruktiivisen linjakkuuden perusteita etsimässä : Systemaattinen analyysi John Biggsin esittämistä yliopisto-opetuksen lähtökohdista

The aim of this study is to explore by systematic textual analysis the crucial conceptions of constructive alignment and to reconstruct the concept of constructive alignment and examine the relation between conceptual relationships in John Biggs’s texts. In this study, I have also analyzed the presuppositions of the concept of constructive alignment and its possible implications. The research material includes Biggs’s (1996b; 2003) article entitled Enhancing Teaching through Constructive Alignment and book entitled Teaching for Quality Learning at University. The primary purpose of the systematic textual analysis is to reconstruct concepts and gain access to a new or more profound understanding of the concepts. The main purpose of the constructive alignment is to design a teaching system that supports and encourages students to adopt a deep approach learning. At the center of the constructive alignment are two concepts: constructivism in learning and alignment in teaching. A tension was detected between these concepts. Biggs assumes that students’ learning activities are primed by the teaching. Because of this it is not important what the teacher does. At the same time he emphasizes that teaching interacts with learning. The teacher’s task is to support student’s appropriate learning activities. On the basis of the analysis, I conclude these conceptions are not mutually exclusive. Interaction between teaching and learning has an effect on student’s learning activities. The most essential benefit of the model of constructive alignment is that Biggs brings together and considers teaching at the same level with learning. A weakness of Biggs’s model relates to the theoretical basis and positions of the concept of constructive alignment. There are some conflicts between conceptions of epistemology in Biggs’s texts. In addition, Biggs writes about constructivism also as conceptions of epistemology, but doesn’t consider implications of that position or what follows or doesn’t follow from that commitment. On the basis of the analysis, I suggest that constructivism refers in Biggs’s texts rather to constructivism in learning than philosophical constructivism. In light of this study, constructive alignment doesn´t lead to philosophical constructivism. That’s why constructive alignment stays out of idealism. Biggs’s way of thinking about teachers possibility to confronting students’ misconceptions and evaluate and assess students’ constructions support a realist purpose in terms of philosophical stance. Realism does not drift toward general problems of relativism, like lack of criteria for assessing or evaluate these constructions.

John and Ursula Schlosstein nee Gottschalk with their infant son Ralph. portraits family

Digital Image

Australian Property Institute Inc, Submission to the Productivity Commission on Intellectual Property Arrangements – Issues Paper

This submission responds to the document Intellectual Property Arrangements Issues Paper (Issues Paper) released by the Productivity Commission in October 2015 for public consultation and input by 30 November 2015. The API is grateful for the extension of time granted by the Commission to complete and lodge this submission. The overall need for an inquiry into intellectual property is supported by API. In particular it is noted with approval that the Commission states in its Issues Paper that it is to consider the appropriate balance between “incentives for innovation and investments, and the interests of both individuals and businesses in assessing products”.1 However, API is of the view that intellectual property in the area of real property presents a number of issues which are not fully canvassed in the abovementioned Issues Paper. Intellectual property embedded in valuation and other property-related reports of API members involves the acquisition of information which may possibly be confidential. Yet, when engaged in banks and financial institutions the intellectual property in such valuations and/ or reports is commonly required to be passed to the client bank or financial institution. In the Issues Paper it is proposed that there are seven different forms of intellectual property rights.2 It is the view of API that an eight form exists, namely private agreements. The Issues Paper, however, regards private agreements between firms as alternatives to intellectual property rights. The API considers that “secrecy or confidentiality arrangements”3 as identified in the Issues Paper form a much larger part of the manner in which intellectual property is maintained in Australia for the purposes of trade secrecy or more often, financial confidentiality...

John Ettinger Collection 1941-1946

John Ettinger, 1987.

Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index

Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and approximately 2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 x 10(-)(8)), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.