The unrooted set covering connected subgraph problem differentiating between HIV envelope sequences

This is the author accepted manuscript. The final version is available from the publisher via the DOI in this recordThis paper presents a novel application of operations research techniques to the analysis of HIV Env gene sequences, aiming to identify key features that are possible vaccine targets. These targets are identified as being critical to the transmission of HIV by being present in early transmitted (founder) sequences and absent in later chronic sequences. Identifying the key features of Env involves two steps: first, calculating the covariance of amino acid combinations and positions to form a network of related and compensatory mutations; and second, developing an integer program to identify the smallest connected subgraph of the constructed covariance network that exhibits a set covering property. The integer program developed for this analysis, labelled the unrooted set covering connected subgraph problem (USCCSP), integrates a set covering problem and connectivity evaluation, the latter formulated as a network flow problem. The resulting integer program is very large and complex, requiring the use of Benders’ decomposition to develop an efficient solution approach. The results will demonstrate the necessity of applying acceleration techniques to the Benders’ decomposition solution approach and the effectiveness of these techniques and heuristic approaches for solving the USCCSP

Mutational networks of escape from transmitted HIV-1 infection

This is the final version. Available on open access from the Public Library of Science via the DOI in this recordData availability: The sequence data are available in the Dryad Data Depository, DOI: doi:10.5061/dryad.r19c2 Data files: HIV envelope sequences Seroconverter HIV subtype B envelope sequences.Human immunodeficiency virus (HIV) is subject to immune selective pressure soon after it establishes infection at the founder stage. As an individual progresses from the founder to chronic stage of infection, immune pressure forces a history of mutations that are embedded in envelope sequences. Determining this pathway of coevolving mutations can assist in understanding what is different with the founder virus and the essential pathways it takes to maintain infection. We have combined operations research and bioinformatics methods to extract key networks of mutations that differentiate founder and chronic stages for 156 subtype B and 107 subtype C envelope (gp160) sequences. The chronic networks for both subtypes revealed strikingly different hub-and-spoke topologies compared to the less structured transmission networks. This suggests that the hub nodes are impacted by the immune response and the resulting loss of fitness is compensated by mutations at the spoke positions. The major hubs in the chronic C network occur at positions 12, 137 (within the N136 glycan), and 822, and at position 306 for subtype B. While both founder networks had a more heterogeneous connected network structure, interestingly founder B subnetworks around positions 640 and 837 preferentially contained CD4 and coreceptor binding domains. Finally, we observed a differential effect of glycosylation between founder and chronic subtype B where the latter had mutational pathways significantly driven by N-glycosylation. Our study provides insights into the mutational pathways HIV takes to evade the immune response, and presents features more likely to establish founder infection, valuable for effective vaccine design.Australian Research Council (ARC

Differentiating founder and chronic HIV envelope sequences

This is the final version. Available from Public Library of Science via the DOI in this record.The sequence data are available in the Dryad Data Depository. Data package title: Data from: Differentiating founder and chronic HIV envelope sequences Provisional DOI: doi:10.5061/dryad.r19c2 Data files: HIV envelope sequences Seroconverter HIV subtype B envelope sequences.Significant progress has been made in characterizing broadly neutralizing antibodies against the HIV envelope glycoprotein Env, but an effective vaccine has proven elusive. Vaccine development would be facilitated if common features of early founder virus required for transmission could be identified. Here we employ a combination of bioinformatic and operations research methods to determine the most prevalent features that distinguish 78 subtype B and 55 subtype C founder Env sequences from an equal number of chronic sequences. There were a number of equivalent optimal networks (based on the fewest covarying amino acid (AA) pairs or a measure of maximal covariance) that separated founders from chronics: 13 pairs for subtype B and 75 for subtype C. Every subtype B optimal solution contained the founder pairs 178–346 Asn-Val, 232–236 Thr-Ser, 240–340 Lys-Lys, 279–315 Asp-Lys, 291–792 Ala-Ile, 322–347 Asp-Thr, 535–620 Leu-Asp, 742–837 Arg-Phe, and 750–836 Asp-Ile; the most common optimal pairs for subtype C were 644–781 Lys-Ala (74 of 75 networks), 133–287 Ala-Gln (73/75) and 307–337 Ile-Gln (73/75). No pair was present in all optimal subtype C solutions highlighting the difficulty in targeting transmission with a single vaccine strain. Relative to the size of its domain (0.35% of Env), the α4β7 binding site occurred most frequently among optimal pairs, especially for subtype C: 4.2% of optimal pairs (1.2% for subtype B). Early sequences from 5 subtype B pre-seroconverters each exhibited at least one clone containing an optimal feature 553–624 (Ser-Asn), 724–747 (Arg-Arg), or 46–293 (Arg-Glu).University of New South Wales (UNSW) Goldstar Gran

Criminology, Gender and Security in the Australian Context: Making Women’s Lives Matter

This article examines how it might be possible to make women’s lives matter in contemporary criminological understandings of security. In doing so it considers the conceptual complexity of security, and reflects on the criminological engagement with that complexity and the feminist contribution to it paying particular attention to current concerns with everyday security. The article deploys the contemporary Australian policy agenda on family violence to illustrate the paradoxes to be found within these current pre-occupations. Drawing on feminist informed work that situates violence against women within the conceptual framework of everyday terrorism, it concludes by offering further consideration to the meaning of everyday security and the implications that this has for contemporary criminological concerns with security

Victim stories and victim policy: Is there a case for a narrative victimology?

Since the 1980s, victims’ voices have been increasingly heard and have been influential in policy debates. Since that time, the nature and presence of those voices has changed shape and form from the influence and presence of victim centred organizations to the rise of the high profile individual victim. The purpose of this article is to explore the presence of one victim’s story, Rosie Batty, and to examine her influence on the rise of the policy agenda on family violence in Australia. This article considers the ways in which this story gained traction and influenced the reform of family violence policy in Australia, and considers the extent to which an understanding of this process contributes to an (emergent) narrative victimology

Bayesian Conditioning, the Reflection Principle, and Quantum Decoherence

The probabilities a Bayesian agent assigns to a set of events typically change with time, for instance when the agent updates them in the light of new data. In this paper we address the question of how an agent's probabilities at different times are constrained by Dutch-book coherence. We review and attempt to clarify the argument that, although an agent is not forced by coherence to use the usual Bayesian conditioning rule to update his probabilities, coherence does require the agent's probabilities to satisfy van Fraassen's [1984] reflection principle (which entails a related constraint pointed out by Goldstein [1983]). We then exhibit the specialized assumption needed to recover Bayesian conditioning from an analogous reflection-style consideration. Bringing the argument to the context of quantum measurement theory, we show that "quantum decoherence" can be understood in purely personalist terms---quantum decoherence (as supposed in a von Neumann chain) is not a physical process at all, but an application of the reflection principle. From this point of view, the decoherence theory of Zeh, Zurek, and others as a story of quantum measurement has the plot turned exactly backward.Comment: 14 pages, written in memory of Itamar Pitowsk

A systematic review of randomised controlled trials on the effectiveness of exercise programs on lumbo pelvic pain among postnatal women

Background: A substantial number of women tend to be affected by Lumbo Pelvic Pain (LPP) following child birth. Physical exercise is indicated as a beneficial method to relieve LPP, but individual studies appear to suggest mixed findings about its effectiveness. This systematic review aimed to synthesise evidence from randomised controlled trials on the effectiveness of exercise on LPP among postnatal women to inform policy, practice and future research. Methods: A systematic review was conducted of all randomised controlled trials published between January 1990 and July 2014, identified through a comprehensive search of following databases: PubMed, PEDro, Embase, Cinahl, Medline, SPORTDiscus, Cochrane Pregnancy and Childbirth Group’s Trials Register, and electronic libraries of authors’institutions. Randomised controlled trials were eligible for inclusion if the intervention comprised of postnatal exercise for women with LPP onset during pregnancy or within 3 months after delivery and the outcome measures included changes in LPP. Selected articles were assessed using the PEDro Scale for methodological quality and findings were synthesised narratively as meta-analysis was found to be inappropriate due to heterogeneity among included studies. Results: Four randomised controlled trials were included, involving 251 postnatal women. Three trials were rated as of ‘good’ methodological quality. All trials, except one, were at low risk of bias. The trials included physical exercise programs with varying components, differing modes of delivery, follow up times and outcome measures. Intervention in one trial, involving physical therapy with specific stabilising exercises, proved to be effective in reducing LPP intensity. An improvement in gluteal pain on the right side was reported in another trial and a significant difference in pain frequency in another. Conclusion: Our review indicates that only few randomised controlled trials have evaluated the effectiveness of exercise on LPP among postnatal women. There is also a great amount of variability across existing trials in the components of exercise programs, modes of delivery, follow up times and outcome measures. While there is some evidence to indicate the effectiveness of exercise for relieving LPP, further good quality trials are needed to ascertain the most effective elements of postnatal exercise programs suited for LPP treatment

The underpotential deposition that should not be : Cu(1x1) on Au(111)

Peer reviewedPostprin

Cross-species gene expression analysis of species specific differences in the preclinical assessment of pharmaceutical compounds

Animals are frequently used as model systems for determination of safety and efficacy in pharmaceutical research and development. However, significant quantitative and qualitative differences exist between humans and the animal models used in research. This is as a result of genetic variation between human and the laboratory animal. Therefore the development of a system that would allow the assessment of all molecular differences between species after drug exposure would have a significant impact on drug evaluation for toxicity and efficacy. Here we describe a cross-species microarray methodology that identifies and selects orthologous probes after cross-species sequence comparison to develop an orthologous cross-species gene expression analysis tool. The assumptions made by the use of this orthologous gene expression strategy for cross-species extrapolation is that; conserved changes in gene expression equate to conserved pharmacodynamic endpoints. This assumption is supported by the fact that evolution and selection have maintained the structure and function of many biochemical pathways over time, resulting in the conservation of many important processes. We demonstrate this cross-species methodology by investigating species specific differences of the peroxisome proliferatoractivator receptor (PPAR) a response in rat and human