Molecular dynamics and principal components analysis of human telomeric quadruplex multimers.

Guanine-rich DNA repeat sequences located at the terminal ends of chromosomal DNA can fold in a sequence-dependent manner into G-quadruplex structures, notably the terminal 150–200 nucleotides at the 3' end, which occur as a single-stranded DNA overhang. The crystal structures of quadruplexes with two and four human telomeric repeats show an all-parallel-stranded topology that is readily capable of forming extended stacks of such quadruplex structures, with external TTA loops positioned to potentially interact with other macromolecules. This study reports on possible arrangements for these quadruplex dimers and tetramers, which can be formed from 8 or 16 telomeric DNA repeats, and on a methodology for modeling their interactions with small molecules. A series of computational methods including molecular dynamics, free energy calculations, and principal components analysis have been used to characterize the properties of these higher-order G-quadruplex dimers and tetramers with parallel-stranded topology. The results confirm the stability of the central G-tetrads, the individual quadruplexes, and the resulting multimers. Principal components analysis has been carried out to highlight the dominant motions in these G-quadruplex dimer and multimer structures. The TTA loop is the most flexible part of the model and the overall multimer quadruplex becoming more stable with the addition of further G-tetrads. The addition of a ligand to the model confirms the hypothesis that flat planar chromophores stabilize G-quadruplex structures by making them less flexible.

Validation of Next Generation Sequencing Technologies in Comparison to Current Diagnostic Gold Standards for BRAF, EGFR and KRAS Mutational Analysis

Next Generation Sequencing (NGS) has the potential of becoming an important tool in clinical diagnosis and therapeutic decision-making in oncology owing to its enhanced sensitivity in DNA mutation detection, fast-turnaround of samples in comparison to current gold standard methods and the potential to sequence a large number of cancer-driving genes at the one time. We aim to test the diagnostic accuracy of current NGS technology in the analysis of mutations that represent current standard-of-care, and its reliability to generate concomitant information on other key genes in human oncogenesis. Thirteen clinical samples (8 lung adenocarcinomas, 3 colon carcinomas and 2 malignant melanomas) already genotyped for EGFR, KRAS and BRAF mutations by current standard-of-care methods (Sanger Sequencing and q-PCR), were analysed for detection of mutations in the same three genes using two NGS platforms and an additional 43 genes with one of these platforms. The results were analysed using closed platform-specific proprietary bioinformatics software as well as open third party applications. Our results indicate that the existing format of the NGS technology performed well in detecting the clinically relevant mutations stated above but may not be reliable for a broader unsupervised analysis of the wider genome in its current design. Our study represents a diagnostically lead validation of the major strengths and weaknesses of this technology before consideration for diagnostic use.

Some concepts and models usefulninthe analysis of discrete life time data

This thesis entitled Reliability Modelling and Analysis in Discrete time Some Concepts and Models Useful in the Analysis of discrete life time data.The present study consists of five chapters. In Chapter II we take up the derivation of some general results useful in reliability modelling that involves two component mixtures. Expression for the failure rate, mean residual life and second moment of residual life of the mixture distributions in terms of the corresponding quantities in the component distributions are investigated. Some applications of these results are also pointed out. The role of the geometric,Waring and negative hypergeometric distributions as models of life lengths in the discrete time domain has been discussed already. While describing various reliability characteristics, it was found that they can be often considered as a class. The applicability of these models in single populations naturally extends to the case of populations composed of sub-populations making mixtures of these distributions worth investigating. Accordingly the general properties, various reliability characteristics and characterizations of these models are discussed in chapter III. Inference of parameters in mixture distribution is usually a difficult problem because the mass function of the mixture is a linear function of the component masses that makes manipulation of the likelihood equations, leastsquare function etc and the resulting computations.very difficult. We show that one of our characterizations help in inferring the parameters of the geometric mixture without involving computational hazards. As mentioned in the review of results in the previous sections, partial moments were not studied extensively in literature especially in the case of discrete distributions. Chapters IV and V deal with descending and ascending partial factorial moments. Apart from studying their properties, we prove characterizations of distributions by functional forms of partial moments and establish recurrence relations between successive moments for some well known families. It is further demonstrated that partial moments are equally efficient and convenient compared to many of the conventional tools to resolve practical problems in reliability modelling and analysis. The study concludes by indicating some new problems that surfaced during the course of the present investigation which could be the subject for a future work in this area.

Autoconcepto académico y toma de decisiones en el alumnado de bachillerato. 'Academic self-concept and decision making of secondary school students'.

Resumen tomado de la publicación. Con el apoyo económico del departamento MIDE de la UNED. Contiene anexo de preguntas

Judgments, forecasts and decisions: an analysis of fund managers over time

Decision theory is the study of models of judgement involved in, and leading to, deliberate and (usually) rational choice. In real estate investment there are normative models for the allocation of assets. These asset allocation models suggest an optimum allocation between the respective asset classes based on the investors’ judgements of performance and risk. Real estate is selected, as other assets, on the basis of some criteria, e.g. commonly its marginal contribution to the production of a mean variance efficient multi asset portfolio, subject to the investor’s objectives and capital rationing constraints. However, decisions are made relative to current expectations and current business constraints. Whilst a decision maker may believe in the required optimum exposure levels as dictated by an asset allocation model, the final decision may/will be influenced by factors outside the parameters of the mathematical model. This paper discusses investors' perceptions and attitudes toward real estate and highlights the important difference between theoretical exposure levels and pragmatic business considerations. It develops a model to identify “soft” parameters in decision making which will influence the optimal allocation for that asset class. This “soft” information may relate to behavioural issues such as the tendency to mirror competitors; a desire to meet weight of money objectives; a desire to retain the status quo and many other non-financial considerations. The paper aims to establish the place of property in multi asset portfolios in the UK and examine the asset allocation process in practice, with a view to understanding the decision making process and to look at investors’ perceptions based on an historic analysis of market expectation; a comparison with historic data and an analysis of actual performance.

Healing the wounds of war: memories of violence and the making of history in Zimbabwe's most recent past.

How does a society less than two decades after a liberation war which involved large sections of the population come to terms with the memories of violence and war — a war in which there was no clear distinction between insurgent and counter‐insurgent, liberator and oppressor and in which the majority of the casualties can be found among the rural civilian population? This was a predicament not exclusive to Zimbabwe, but one which also applies to Mozambique, South Africa and, more recently, to Rwanda. Since its independence Zimbabwe has been a prime example of successful reconciliation. Ranger has argued that spiritual healing has contributed importantly to coming to terms with the trauma of war through turning violence into history. Here it will be argued that an analysis of the intersections between memories of violence, healing, and history reveals a twofold process. Social healing is made possible by a shift from conviction and compensation to revealing without convicting. At the same time healing provides an arena for communities in which competing and contesting memories of violence are renegotiated. Through these processes sense is being made of the past; history is being made.

Adolescent girls in physical education and sport : an analysis of influences on participation

This study investigates the influences on participation in physical activity of thirty adolescent girls from a metropolitan secondary school in Victoria. It seeks to understand how they perceived, experienced and explained their involvement or non involvement in both competitive and non competitive physical activity during four years of their secondary schooling. Participants experienced physical education as both a single sex group in Years 7 and 9 and a coeducational group in Years 8 and 10. They were exposed to a predominantly competitive curriculum in Years 7 to 9 and a less structured, more social, recreational program in Year 10. These experiences enabled them to compare the differences between class structures and activity programs and identify the significant issues which impacted on their participation. Large Australian population studies have revealed that fewer girls participated in sport and regular physical activity than boys. An important consequence is that girls miss out on the health benefits associated with participating in physical activity. Other research has found adolescence is the time that girls drop out of competitive sport. However, an important issue is whether girls who drop out of competitive sport cease to be involved in any physical activity. There are some studies which have reported good participation rates by adolescent girls in non competitive, recreational forms of physical activity and the possibility exists that they may drop out of competitive and into non competitive physical activity. This study primarily utilises a qualitative approach in contrast to previous studies which have largely relied upon the use of surveys and questionnaires. Whilst quantitative research has provided useful information about the bigger picture, there are limitations caused by reliance on the researchers' own interpretations of the data. Additionally there is no opportunity for any clarification and explanation of findings and trends by the respondents themselves. The current study utilized qualitative individual and collective interviews in three stages. Questions were asked in the broad areas of coeducation and single sex classes, preferences for competitive or recreational activity and body image issues. Some quantitative information focusing on nature and extent of current activity patterns was also gathered in the first stage. Thirty Year 10 girls participated in individual first interviews. Nine selected girls then took part in the second (individual) and third (collective) interview stages. Results revealed three groups based on the nature of physical activity involvement: [1] competitive activity group, [2] social activity group and [3] transition group. The transition group represented those who were in the process of withdrawing from competitive sport to take up more non competitive, recreational activity. The most significant difference between groups was skill level. On the whole those entering adolescence with the highest skill levels, such as those in the competitive group, were the most confident and relished competing against others. The social group was low in skill and confidence and had predominantly negative experiences in physical education and sport because their deficiencies were plainly visible to all. Similarly, a lack of skill improvement relative to those of 'better performers' affected the interest and confidence levels of those in the transition group. Boys' domination in coeducational classes through verbal and physical intimidation of the less competent and confident girls and exclusion of very competent girls was a major issue. Social and transition group members demonstrated compliance with boys' power by hanging back and sitting out of competitive activities. Conversely, the competitive group resisted boy's attempts to dominate but had to work hard to demonstrate their athletic capabilities in order to do so. Body image issues such as the skimpy physical education and sport uniform along with body revealing activities such as swimming and gymnastics, heightened feelings of self-consciousness and embarrassment for most girls. When strategies were adopted by social and transition group members to avoid any body exposure or physical humiliation, participation levels were subsequently affected. However, where girls felt confident about their physical abilities and body image, they were able to ignore their unflattering uniforms and thus participation was unaffected. Specific teaching practices such as giving more attention to boys, for example by segregating the sexes in mixed classes to focus attention on boys, reinforced stereotypical notions of gender and contributed to the inequities for girls in physical education. The competitive group were frustrated with having to prove themselves as capable as boys in order to receive greater teacher attention. The transition group rejected teacher's attempts to coerce them into participating in the inter school sports program. The social group believed that teachers viewed and treated them less favourably than others because of their limited skills. Girls were not passive in the face of these obstacles. Rather than give up physical activity they disengaged from competitive sport and took up other forms of activity which they had the confidence to perform. These activity choices also reflected their expanding social interests such as spending time with male and female friends outside school and increased demands on their time by study and part time work commitments. This study not only highlighted the diversity and complexity of attitudes and behaviours of girls towards physical activity but also demonstrated that they display agency in making conscious, sensible decisions about their physical activity choices. Plain Language Summary of Thesis Adolescent girls in physical education and sport; An analysis of influences on participation by Julia Whitty Submitted for the degree of Master of Applied Science Deakin University Supervisor: Dr Judy Ann Jones This study investigates the influences on participation in physical activity of thirty adolescent girls from a metropolitan secondary school in Victoria in order to understand how girls' perceived, experienced and explained their involvement or non involvement in both competitive and non competitive physical activity. Qualitative individual and collective interviews were conducted. Questions focussed on attitudes about coeducation and single sex classes, preferences for competitive or recreational activity and feelings about body image. Some quantitative information about the nature and extent of current activity patterns was also gathered in the first stage. Thirty Year 10 girls participated in individual first interviews. Nine selected girls then took part in the second (individual) and third (collective) interview stages. Results revealed three clearly different groups based on the nature of physical activity involvement (1) Competitive, (2) Social and (3) Transition (those in the process of withdrawing from competitive sport to take up more non competitive, recreational activity). The major difference between groups was skill level. Those entering adolescence with the highest skill levels were more competent and confident in the coeducational and competitive sport setting. Other significant issues included boys' domination, body image and teaching behaviours and practices.

The determination of bioactive compounds using HPLC with chemiluminescence detection

This dissertation investigated the selectivity and sensitivity of high performance liquid chromatography with various chemiluminescence detection protocols for the determination of biologically important compounds in beverages, wines and biomedical matrices. The work showed conclusively that this technology could successfully identify wines from different geographic locations and also monitor their maturation.

Outsourcing the risks : alcohol licensing, risk and the making of the night time economy

Mariana Valverde argues that in the late twentieth century, the British state contracted out the prevention of disorder and monitoring of risks produced by widespread alcohol use to the private sector through the process of liquor licensing. This paper will argue that this scenario was duplicated in Victoria at the same time. It will do so by an analysis of four government-instigated inquiries into liquor licensing regimes from 1965 to 1998. The inquiries were distinguished by the subtly different emphases in their terms of reference. In 1965, the Phillips Royal Commission was directed to inquire into the best ways of dealing with the problems alcohol produced and how best to regulate it for the benefit of the population as a whole. By the time the Nieuwenhuysen Report was commissioned in 1985, the emphasis had changed, and he was directed to inquire how best to serve the interests of alcohol consumers and to produce the licensing regulatory regime which would enable the construction of a 24-hour city. Any anomalies that still existed in the revised Act were eliminated in the 1998 review which was instigated as a direct response to the National Competition Policy. A consequence of these changes over 30 years was the development of particular risk groups, such as ‘binge-drinking young people’, whose violence and nuisance must be controlled to enable all other ‘reasonable’ and ‘moderate’ drinkers be allowed to keep drinking. Thus the notion of risk had been redefined and the responsibility for dealing with these risks had been directed from the state to individual licensees and individual drinkers.

Stakeholder analysis in urban development : the application of stakeholder circle methodology and social network analysis

The increasing research interest on stakeholder analysis in urban planning reflects a growing recognition that stakeholders can and should influence the decision-making. This paper concentrates on exploring the techniques for analysing stakeholders, especially the application of the Stakeholder Circle tool and Social Network Analysis. An urban renewal project and an infrastructure project in Australia are presented as case studies to verify the use of these two techniques. The stakeholders are identified and prioritized from two different points of view, namely, the attribute evaluations in the Stakeholder Circle tool, and the relationship network analysis. The paper ends with a discussion on the strengths and limitations of the techniques for stakeholder analysis. No method for stakeholder identification and prioritization is perfect. The selection of the approaches is an art with extensive considerations of ‘when, what, and how’ to choose methods to achieve the project objectives. Each method has its own strengths and limitations. Combining several methods when necessary is the best way to analyse stakeholders.

Midwifery work and the making of narrative

This paper draws on a study of birth support conducted across three Melbourne maternity units. Midwife informants were asked to participate in semistructured interviews with two researchers and describe the activity and role of lay birth support people. In the course of the study, the activity of the midwives themselves became a research focus. The study found that one of the key tasks midwives described was assisting birthing women to develop and negotiate satisfactory birth narratives that could encompass the intense and sometimes difficult experience of birth. Midwife informants offered strategies for the development of such narratives as part of their professional and personal labour in the birth room.

Rapid discrimination and determination of polyunsaturated fatty acid composition in marine oils by FTIR Spectroscopy and Multivariate Data Analysis

A rapid analytical approach for discrimination and quantitative determination of polyunsaturated fatty acid (PUFA) contents, particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), in a range of oils extracted from marine resources has been developed by using attenuated total reflection Fourier transform infrared spectroscopy and multivariate data analysis. The spectral data were collected without any sample preparation; thus, no chemical preparation was involved, but data were rather processed directly using the developed spectral analysis platform, making it fast, very cost effective, and suitable for routine use in various biotechnological and food research and related industries. Unsupervised pattern recognition techniques, including principal component analysis and unsupervised hierarchical cluster analysis, discriminated the marine oils into groups by correlating similarities and differences in their fatty acid (FA) compositions that corresponded well to the FA profiles obtained from traditional lipid analysis based on gas chromatography (GC). Furthermore, quantitative determination of unsaturated fatty acids, PUFAs, EPA and DHA, by partial least square regression analysis through which calibration models were optimized specifically for each targeted FA, was performed in both known marine oils and totally independent unknown n - 3 oil samples obtained from an actual commercial product in order to provide prospective testing of the developed models towards actual applications. The resultant predicted FAs were achieved at a good accuracy compared to their reference GC values as evidenced through (1) low root mean square error of prediction, (2) good coefficient of determination close to 1 (i.e., R 2≥ 0.96), and (3) the residual predictive deviation values that indicated the predictive power at good and higher levels for all the target FAs. © 2014 Springer Science+Business Media New York.

Expertise and the making of world heritage policy

This paper contributes to two emergent areas of scholarship: first, the role of expertise within the domain of cultural heritage practice; and second, international heritage institutions and their processes of governance. It does so by exploring expertise within the context of World Heritage Committee meetings. These forums of international heritage policy formulation have undergone significant changes in recent years, with larger geopolitical forces increasingly shaping process and decisions. This paper foregrounds the idea of these annual meetings as ‘locales’ in order to explore the inflows of expertise that help constitute authoritative decision-making, how expert knowledge is crafted for and by bureaucratic structure, and how the interplay between technical knowledge and politics via an ‘aesthetics of expertise’ bears upon future directions. In offering such an analysis, the paper seeks to add nuance and conceptual depth to our understanding of international conservation policy and the regulatory, governmental practices of organisations such as UNESCO.