Fine-mapping identifies multiple prostate cancer risk loci on 5p15 some associating with TERT expression

Associations between single nucleotide polymorphisms (SNPs) at 5p15 and multiple cancer types have been reported. We have previously shown evidence for a strong association between prostate cancer (PrCa) risk and rs2242652 at 5p15, intronic in the telomerase reverse transcriptase (TERT) gene that encodes TERT. To comprehensively evaluate the association between genetic variation across this region and PrCa, we performed a fine-mapping analysis by genotyping 134 SNPs using a custom Illumina iSelect array or Sequenom MassArray iPlex, followed by imputation of 1094 SNPs in 22 301 PrCa cases and 22 320 controls in The PRACTICAL consortium. Multiple stepwise logistic regression analysis identified four signals in the promoter or intronic regions of TERT that independently associated with PrCa risk. Gene expression analysis of normal prostate tissue showed evidence that SNPs within one of these regions also associated with TERT expression, providing a potential mechanism for predisposition to disease.

Fine-mapping the HOXB region detects common variants tagging a rare coding allele : evidence for synthetic association in prostate cancer

The HOXB13 gene has been implicated in prostate cancer (PrCa) susceptibility. We performed a high resolution fine-mapping analysis to comprehensively evaluate the association between common genetic variation across the HOXB genetic locus at 17q21 and PrCa risk. This involved genotyping 700 SNPs using a custom Illumina iSelect array (iCOGS) followed by imputation of 3195 SNPs in 20,440 PrCa cases and 21,469 controls in The PRACTICAL consortium. We identified a cluster of highly correlated common variants situated within or closely upstream of HOXB13 that were significantly associated with PrCa risk, described by rs117576373 (OR 1.30, P = 2.62×10(-14)). Additional genotyping, conditional regression and haplotype analyses indicated that the newly identified common variants tag a rare, partially correlated coding variant in the HOXB13 gene (G84E, rs138213197), which has been identified recently as a moderate penetrance PrCa susceptibility allele. The potential for GWAS associations detected through common SNPs to be driven by rare causal variants with higher relative risks has long been proposed; however, to our knowledge this is the first experimental evidence for this phenomenon of synthetic association contributing to cancer susceptibility.

The highly abundant urinary metabolite urobilin interferes with the bicinchoninic acid assay

Estimation of total protein concentration is an essential step in any protein- or peptide-centric analysis pipeline. This study demonstrates that urobilin, a breakdown product of heme and a major constituent of urine, interferes considerably with the bicinchoninic acid (BCA) assay. This interference is probably due to the propensity of urobilin to reduce cupric ions (Cu2+) to cuprous ions (Cu1+), thus mimicking the reduction of copper by proteins, which the assay was designed to do. In addition, it is demonstrated that the Bradford assay is more resistant to the influence of urobilin and other small molecules. As such, urobilin has a strong confounding effect on the estimate of total protein concentrations obtained by BCA assay and thus this assay should not be used for urinary protein quantification. It is recommended that the Bradford assay be used instead.

Determinants of second row passenger comfort

China is becoming an increasingly important automotive market. Customer’s vehicle usage, preferences and requirements differ from traditional western markets in a number of aspects – rear seat usage rates are higher, vehicles are used for business purposes as well as for private transport and rear seat usage is generally more important to Chinese customers compared to their western counterparts. The purpose of this project is to dimension and investigate these differences from an ergonomics perspective and use these results to guide the design of future products. The focus for this project will be specific to vehicles in the CD segment. More specifically, this project focuses on the second row ‘ambience’. Ambience refers to the global feeling perceived by second row passengers, and the main factors contributing to ambience are: ingress and egress comfort, seat comfort, roominess, and ease of use of the controls. In order to investigate the aforementioned parameters, an experimental study has been conducted in Shanghai, China. This experiment involved 80 healthy Chinese CD- and D-car customers. These subjects were asked to evaluate different features present in the second row environment of three different cars: A Ford Mondeo, Toyota Camry and Mercedes S-class. Various data has been collected during this experiment: First, the anthropometric dimensions of the subjects have been measured. The subjects were also asked to fill a questionnaire about demographics, their own car usage, and their perception of a various number of features present in the three tested cars. A great amount of technical data was also collected. The first part of this report presents the results given by the questionnaires. It includes Chinese demographics, vehicle usage habits, and the subjective perception of the features present in the tested cars. It also presents the results of the anthropometric measurements. This gives a first insight into Chinese customers’ habits and preferences. The second part deals with the technical data recorded during the experiment: second row seat adjustment ranges, roominess, optimal location of controls, and pressure mapping analysis. Analysis of technical data allows a deeper understanding of the factors contributing to comfort and ambience perception. Using the technical data together with the comfort ratings given by the subjects in the questionnaire, recommendations on several design parameters were provided. Finally, an experimental study of car ingress-egress has been conducted in a University laboratory controlled environment. During this study, the ingress and egress motion of 20 customers from Chinese origin was recorded using a motion capture system. The last part of this report presents the protocol and data processing that led to building an ingress-egress motion database that was provided to Ford.

GIS-based mapping and statistical analysis of air pollution and mortality in Brisbane, Australia

In this thesis, the relationship between air pollution and human health has been investigated utilising Geographic Information System (GIS) as an analysis tool. The research focused on how vehicular air pollution affects human health. The main objective of this study was to analyse the spatial variability of pollutants, taking Brisbane City in Australia as a case study, by the identification of the areas of high concentration of air pollutants and their relationship with the numbers of death caused by air pollutants. A correlation test was performed to establish the relationship between air pollution, number of deaths from respiratory disease, and total distance travelled by road vehicles in Brisbane. GIS was utilized to investigate the spatial distribution of the air pollutants. The main finding of this research is the comparison between spatial and non-spatial analysis approaches, which indicated that correlation analysis and simple buffer analysis of GIS using the average levels of air pollutants from a single monitoring station or by group of few monitoring stations is a relatively simple method for assessing the health effects of air pollution. There was a significant positive correlation between variable under consideration, and the research shows a decreasing trend of concentration of nitrogen dioxide at the Eagle Farm and Springwood sites and an increasing trend at CBD site. Statistical analysis shows that there exists a positive relationship between the level of emission and number of deaths, though the impact is not uniform as certain sections of the population are more vulnerable to exposure. Further statistical tests found that the elderly people of over 75 years age and children between 0-15 years of age are the more vulnerable people exposed to air pollution. A non-spatial approach alone may be insufficient for an appropriate evaluation of the impact of air pollutant variables and their inter-relationships. It is important to evaluate the spatial features of air pollutants before modeling the air pollution-health relationships.

Oscar Pistorius and the death of Reeva Steenkamp : mapping public opinions on Twitter using frame analysis and data mining

This paper uses innovative content analysis techniques to map how the death of Oscar Pistorius' girlfriend, Reeva Steenkamp, was framed on Twitter conversations. Around 1.5 million posts from a two-week timeframe are analyzed with a combination of syntactic and semantic methods. This analysis is grounded in the frame analysis perspective and is different than sentiment analysis. Instead of looking for explicit evaluations, such as “he is guilty” or “he is innocent”, we showcase through the results how opinions can be identified by complex articulations of more implicit symbolic devices such as examples and metaphors repeatedly mentioned. Different frames are adopted by users as more information about the case is revealed: from a more episodic one, highly used in the very beginning, to more systemic approaches, highlighting the association of the event with urban violence, gun control issues, and violence against women. A detailed timeline of the discussions is provided.

Comparative analysis reveals loss of the appetite-regulating peptide hormone ghrelin in falcons

Ghrelin and leptin are key peripherally secreted appetite-regulating hormones in vertebrates. Here we consider the ghrelin gene (GHRL) of birds (class Aves), where it has been reported that ghrelin inhibits rather than augments feeding. Thirty-one bird species were compared, revealing that most species harbour a functional copy of GHRL and the coding region for its derived peptides ghrelin and obestatin. We provide evidence for loss of GHRL in saker and peregrine falcons, and this is likely to result from the insertion of an ERVK retrotransposon in intron 0. We hypothesise that the loss of anorexigenic ghrelin is a predatory adaptation that results in increased food-seeking behaviour and feeding in falcons.

Automated 3D mapping & shape analysis of the lateral ventricles via fluid registration of multiple surface-based atlases

We developed and validated a new method to create automated 3D parametric surface models of the lateral ventricles, designed for monitoring degenerative disease effects in clinical neuroscience studies and drug trials. First we used a set of parameterized surfaces to represent the ventricles in a manually labeled set of 9 subjects' MRIs (atlases). We fluidly registered each of these atlases and mesh models to a set of MRIs from 12 Alzheimer's disease (AD) patients and 14 matched healthy elderly subjects, and we averaged the resulting meshes for each of these images. Validation experiments on expert segmentations showed that (1) the Hausdorff labeling error rapidly decreased, and (2) the power to detect disease-related alterations monotonically improved as the number of atlases, N, was increased from 1 to 9. We then combined the segmentations with a radial mapping approach to localize ventricular shape differences in patients. In surface-based statistical maps, we detected more widespread and intense anatomical deficits as we increased the number of atlases, and we formulated a statistical stopping criterion to determine the optimal value of N. Anterior horn anomalies in Alzheimer's patients were only detected with the multi-atlas segmentation, which clearly outperformed the standard single-atlas approach.

Conformational epitopes on the diabetes autoantigen GAD65 identified by peptide phage display and molecular modeling

The major diabetes autoantigen, glutamic acid decarboxylase (GAD65), contains a region of sequence similarity, including six identical residues PEVKEK, to the P2C protein of coxsackie B virus, suggesting that cross-reactivity between coxsackie B virus and GAD65 can initiate autoimmune diabetes. We used the human islet cell mAbs MICA3 and MICA4 to identify the Ab epitopes of GAD65 by screening phage-displayed random peptide libraries. The identified peptide sequences could be mapped to a homology model of the pyridoxal phosphate (PLP) binding domain of GAD65. For MICA3, a surface loop containing the sequence PEVKEK and two adjacent exposed helixes were identified in the PLP binding domain as well as a region of the C terminus of GAD65 that has previously been identified as critical for MICA3 binding. To confirm that the loop containing tile PEVKEK sequence contributes to the MICA3 epitope, this loop was deleted by mutagenesis. This reduced binding of MICA3 by 70%. Peptide sequences selected using MICA4 were rich in basic or hydroxyl-containing amino acids, and the surface of the GAD65 PLP-binding domain surrounding Lys358, which is known to be critical for MICA4 binding, was likewise rich in these amino acids. Also, the two phage most reactive width MICA4 encoded the motif VALxG, and the reverse of this sequence, LAV, was located in this same region. Thus, we have defined the MICA3 and MICA4 epitopes on GAD65 using the combination of phage display, molecular modeling, and mutagenesis and have provided compelling evidence for the involvement of the PEVKEK loop in the MICA3 epitope.

Characterization of epitopes for virus-neutralizing monoclonal antibodies to Ross River virus E2 using phage-displayed random peptide libraries

Ross River virus (RRV) is the predominant cause of epidemic polyarthritis in Australia, yet the antigenic determinants are not well defined. We aimed to characterize epitope(s) on RRV-E2 for a panel of monoclonal antibodies (MAbs) that recognize overlapping conformational epitopes on the E2 envelope protein of RRV and that neutralize virus infection of cells in vitro. Phage-displayed random peptide libraries were probed with the MAbs T1E7, NB3C4, and T10C9 using solution-phase and solid-phase biopanning methods. The peptides VSIFPPA and KTAISPT were selected 15 and 6 times, respectively, by all three of the MAbs using solution-phase biopanning. The peptide LRLPPAP was selected 8 times by NB3C4 using solid-phase biopanning; this peptide shares a trio of amino acids with the peptide VSIFPPA. Phage that expressed the peptides VSIFPPA and LRLPPAP were reactive with T1E7 and/or NB3C4, and phage that expressed the peptides VSIFPPA, LRLPPAP, and KTAISPT partially inhibited the reactivity of T1E7 with RRV. The selected peptides resemble regions of RRV-E2 adjacent to sites mutated in neutralization escape variants of RRV derived by culture in the presence of these MAbs (E2 210-219 and 238-245) and an additional region of E2 172-182. Together these sites represent a conformational epitope of E2 that is informative of cellular contact sites on RRV.

Investigating limitations of SURF approach for thermal imaging analysis and mapping

Wildlife conservation involves an understanding of a specific animal, its environment and the interaction within a local ecosystem. Unmanned Aerial Vehicles (UAVs) present cost effective, non-intrusive solution for detecting animals over large areas and the use thermal imaging cameras offer the ability detect animals that would otherwise be concealed to visible light cameras. This report examines some of limitations on using SURF for the development of large maps using multiple stills images extracted from the thermal imaging video camera which contain wildlife (eg. Koala in them).