Association of heparan sulfate proteoglycans SDC1 and SDC4 polymorphisms with breast cancer in an Australian Caucasian population

Breast cancer is a common disease in both developing and developed countries with early identification and treatment improving prognosis and survival. Heparan sulfate proteoglycans (HSPGs) are key components of the extracellular matrix (ECM) that mediate cell adhesion, motility, proliferation, invasion and cell signalling. Members of the syndecan family of HSPGs have been identified to be involved in breast cancer progression through their varied interactions with a number of growth factors, ligands and receptors. Specifically, high expression levels of syndecan-1 (SDC1) have been demonstrated in more invasive breast tumours while elevated syndecan-4 (SDC4) levels have been identified to correspond with improved prognosis. With genetic changes in the syndecans and their association with breast cancers plausible, we examined two single nucleotide polymorphisms in SDC1 (rs1131351) and SDC4 (rs67068737) within an Australian Caucasian breast cancer case/control population. No association was found with SDC4 and breast cancer in our population. However, a significant association between SDC1 and breast cancer was identified in both our case/control population and in a replication cohort. When both populations were combined for analysis, this association became more significant (genotype, p = 0.0003; allele, p = 0.0001). This data suggests an increased risk of developing breast cancer associated with the presence of the C allele of the SDC1 rs1131351 single nucleotide polymorphism (SNP) and may provide a marker toward early breast cancer detection.

Neurobiological correlates of encoding strength of Pavlovian fear conditioned memory

Emotionally significant memories, especially those induced in conjunction with physical and mental trauma, are frequently retained for an individual’s lifetime. How these memories are organized and encoded within neural networks is a fundamental question. The lateral amygdala (LA) is a key nucleus for acquisition and maintenance of associative emotional memories. We used Pavlovian fear conditioning to study how ‘weaker’ and ‘stronger’ memories are encoded in neural networks of the LA. In Pavlovian fear conditioning a neutral stimulus, in this case a tone, is temporally paired with an aversive unconditioned stimulus (US), such as a foot shock. The previously neutral stimulus becomes a conditioned stimulus (CS) capable of eliciting defensive responses. We used time spent freezing when the CS is presented in a neutral context as a dependent variable measure of memory ‘strength’.

Symmetry is an organizing principle in neuronal dendrotaxis

Symmetry is a fundamental property found in both the physical and natural worlds. Bilateral symmetry is also present in the organization of the brain, however the degree to which symmetry is also an organizing principal between and within the key constituent elements of the nervous system, neurons, is not known. We compared and contrasted the structural organization of principal neurons (PN) in the three subnuclei of the lateral amygdala (LA) of the rat and for comparison also from the infralimbic cortex (IL)...

Biophysical correlates of intrinsic and stress-induced morphological variability in lateral amygdaloid neurons: A computational study

Morphological and physiological characteristics of neurons located in the dorsolateral and two ventral subdivisions of the lateral amygdala (LA) have been compared in order to differentiate their roles in the formation and storage of fear memories (Alphs et al, SfN abs 623.1, 2003). Briefly, in these populations, significant differences are observed in input resistance, membrane time constant, firing frequency, dendritic tortuosity, numbers of primary dendrites, dendritic segments and dendritic nodes...

Quantification of the total neuronal structure of the fear conditioning circuit of the lateral amygdala of the rat

During Pavlovian auditory fear conditioning a previously neutral auditory stimulus (CS) gains emotional significance through pairing with a noxious unconditioned stimulus (US). These associations are believed to be formed by way of plasticity at auditory input synapses on principal neurons in the lateral nucleus of the amygdala (LA). In order to begin to understand how fear memories are stored and processed by synaptic changes in the LA, we have quantified both the entire neural number and the sub-cellular structure of LA principal neurons.We first used stereological cell counting methods on Gimsa or GABA immunostained rat brain. We identified 60,322+/-1408 neurons in the LA unilaterally (n=7). Of these 16,917+/-471 were GABA positive. The intercalated nuclei were excluded from the counts and thus GABA cells are believed to represent GABAergic interneurons. The sub-nuclei of the LA were also independently counted. We then quantified the morphometric properties of in vitro electrophysiologically identified principal neurons of the LA, corrected for shrinkage in xyz planes. The total dendritic length was 9.97+/-2.57mm, with 21+/-4 nodes (n=6). Dendritic spine density was 0.19+/-0.03 spines/um (n=6). Intra-LA axon collaterals had a bouton density of 0.1+/-0.02 boutons/um (n=5). These data begin to reveal the finite cellular and sub-cellular processing capacity of the lateral amygdala, and should facilitate efforts to understand mechanisms of plasticity in LA.

The pet factor - Companion animals as a conduit for getting to know people, friendship formation and social support

BACKGROUND: While companion animals have been previously identified as a direct source of companionship and support to their owners, their role as a catalyst for friendship formation or social support networks among humans has received little attention. This study investigated the indirect role of pets as facilitators for three dimensions of social relatedness; getting to know people, friendship formation and social support networks. METHODS: A telephone survey of randomly selected residents in four cities, one in Australia (Perth; n = 704) and three in the U.S. (San Diego, n = 690; Portland, n = 634; Nashville, n = 664) was conducted. All participants were asked about getting to know people within their neighborhood. Pet owners were asked additional questions about the type/s of pet/s they owned, whether they had formed friendships as a result of their pet, and if they had received any of four different types of social support from the people they met through their pet. RESULTS: Pet owners were significantly more likely to get to know people in their neighborhood than non-pet owners (OR 1.61; 95%CI: 1.30, 1.99). When analyzed by site, this relationship was significant for Perth, San Diego and Nashville. Among pet owners, dog owners in the three U.S. cities (but not Perth) were significantly more likely than owners of other types of pets to regard people whom they met through their pet as a friend (OR 2.59; 95%CI: 1.94, 3.46). Around 40% of pet owners reported receiving one or more types of social support (i.e. emotional, informational, appraisal, instrumental) via people they met through their pet. CONCLUSION: This research suggests companion animals can be a catalyst for several dimensions of human social relationships in neighborhood settings, ranging from incidental social interaction and getting to know people, through to formation of new friendships. For many pet owners, their pets also facilitated relationships from which they derived tangible forms of social support, both of a practical and emotionally supportive nature. Given growing evidence for social isolation as a risk factor for mental health, and, conversely, friendships and social support as protective factors for individual and community well-being, pets may be an important factor in developing healthy neighborhoods.

Fine-mapping of the HNF1B multicancer locus identifies candidate variants that mediate endometrial cancer risk

Common variants in the hepatocyte nuclear factor 1 homeobox B (HNF1B) gene are associated with the risk of Type II diabetes and multiple cancers. Evidence to date indicates that cancer risk may be mediated via genetic or epigenetic effects on HNF1B gene expression. We previously found single-nucleotide polymorphisms (SNPs) at the HNF1B locus to be associated with endometrial cancer, and now report extensive fine-mapping and in silico and laboratory analyses of this locus. Analysis of 1184 genotyped and imputed SNPs in 6608 Caucasian cases and 37 925 controls, and 895 Asian cases and 1968 controls, revealed the best signal of association for SNP rs11263763 (P = 8.4 × 10−14, odds ratio = 0.86, 95% confidence interval = 0.82–0.89), located within HNF1B intron 1. Haplotype analysis and conditional analyses provide no evidence of further independent endometrial cancer risk variants at this locus. SNP rs11263763 genotype was associated with HNF1B mRNA expression but not with HNF1B methylation in endometrial tumor samples from The Cancer Genome Atlas. Genetic analyses prioritized rs11263763 and four other SNPs in high-to-moderate linkage disequilibrium as the most likely causal SNPs. Three of these SNPs map to the extended HNF1B promoter based on chromatin marks extending from the minimal promoter region. Reporter assays demonstrated that this extended region reduces activity in combination with the minimal HNF1B promoter, and that the minor alleles of rs11263763 or rs8064454 are associated with decreased HNF1B promoter activity. Our findings provide evidence for a single signal associated with endometrial cancer risk at the HNF1B locus, and that risk is likely mediated via altered HNF1B gene expression.

Problems with the coronial determination of ‘suicide’

After over 100 years of constant dissatisfaction with the accuracy of suicide data, this paper suggests that the problem may actually lie with the category of suicide itself. In almost all previous research, ‘suicide’ is taken to be a self-evidently valid category of death, not an object of study in its own right. Instead, the focus in this paper is upon the presupposition that how a social fact like suicide is counted depends upon norms for its governmental regulation, leading to a reciprocal relationship between social norms and statistical norms. Since this relationship is centred almost entirely in the coroner’s office, this paper examines governmental, definitional and categorisational issues relating to how coroners reach findings of suicide. The intention of this paper is to contribute to international debates over how suicide can best be conceptualised and adjudged.

RuleOMS: A rule-based online management system

We propose an architecture for a rule-based online management systems (RuleOMS). Typically, many domain areas face the problem that stakeholders maintain databases of their business core information and they have to take decisions or create reports according to guidelines, policies or regulations. To address this issue we propose the integration of databases, in particular relational databases, with a logic reasoner and rule engine. We argue that defeasible logic is an appropriate formalism to model rules, in particular when the rules are meant to model regulations. The resulting RuleOMS provides an efficient and flexible solution to the problem at hand using defeasible inference. A case study of an online child care management system is used to illustrate the proposed architecture.

Improving fluid registration through white matter segmentation in a twin study design

Robust and automatic non-rigid registration depends on many parameters that have not yet been systematically explored. Here we determined how tissue classification influences non-linear fluid registration of brain MRI. Twin data is ideal for studying this question, as volumetric correlations between corresponding brain regions that are under genetic control should be higher in monozygotic twins (MZ) who share 100% of their genes when compared to dizygotic twins (DZ) who share half their genes on average. When these substructure volumes are quantified using tensor-based morphometry, improved registration can be defined based on which method gives higher MZ twin correlations when compared to DZs, as registration errors tend to deplete these correlations. In a study of 92 subjects, higher effect sizes were found in cumulative distribution functions derived from statistical maps when performing tissue classification before fluid registration, versus fluidly registering the raw images. This gives empirical evidence in favor of pre-segmenting images for tensor-based morphometry.

A new combined surface and volume registration

3D registration of brain MRI data is vital for many medical imaging applications. However, purely intensitybased approaches for inter-subject matching of brain structure are generally inaccurate in cortical regions, due to the highly complex network of sulci and gyri, which vary widely across subjects. Here we combine a surfacebased cortical registration with a 3D fluid one for the first time, enabling precise matching of cortical folds, but allowing large deformations in the enclosed brain volume, which guarantee diffeomorphisms. This greatly improves the matching of anatomy in cortical areas. The cortices are segmented and registered with the software Freesurfer. The deformation field is initially extended to the full 3D brain volume using a 3D harmonic mapping that preserves the matching between cortical surfaces. Finally, these deformation fields are used to initialize a 3D Riemannian fluid registration algorithm, that improves the alignment of subcortical brain regions. We validate this method on an MRI dataset from 92 healthy adult twins. Results are compared to those based on volumetric registration without surface constraints; the resulting mean templates resolve consistent anatomical features both subcortically and at the cortex, suggesting that the approach is well-suited for cross-subject integration of functional and anatomic data.