Mechanisms of retroviral reverse transcription and assembly

The work described in these dissertation studies examines three aspects of retrovirus replication and dissects the uncovered phenomena to increase understanding of how retroviruses thrive in complex host environments. The first aspect of replication discussed is the mechanisms behind minus-strand DNA transfer, a crucial step of reverse transcription. We proved for the first time that non-viral sequences can be utilized to carry out this step of the replication process, and that the minus-strand DNA transfer step can be exploited to reconstitute a functional gene in the infected host cell. This finding serves as a proof-of-principle for a new class of self-activating gene therapy vectors. In the second study, mechanisms of trans-complementation were studied between two distantly related retroviruses, murine leukemia virus (MLV) and spleen necrosis virus. We showed that two different species of pol proteins can be incorporated into virions and cooperate to complete the reverse transcription and integration steps of replication. This finding highlights how different species of retroviruses could possibly interact and combine to form new and possibly more virulent or pathogenic species. Finally, in the third work, a previously uninvestigated region of MLV capsid protein was examined. Specifically, the contribution of the 33 carboxyl-terminal amino acids of MLV CA were found to consist of highly charged residues. The contribution of these residues to virus assembly was investigated via deletion analysis. A new phenotype of MLV CA assembly defect was demonstrated, and a structural model was proposed to explain the possible role of this region, termed the charged assembly helix, in MLV assembly. In summary, the work presented in this dissertation has revealed new properties of retroviral replication as well as further clarified previous knowledge of retroviral biology

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Multiple reassortment events in the evolutionary history of H1N1 influenza A virus since 1918

The H1N1 subtype of influenza A virus has caused substantial morbidity and mortality in humans, first documented in the global pandemic of 1918 and continuing to the present day. Despite this disease burden, the evolutionary history of the A/H1N1 virus is not well understood, particularly whether there is a virological basis for several notable epidemics of unusual severity in the 1940s and 1950s. Using a data set of 71 representative complete genome sequences sampled between 1918 and 2006, we show that segmental reassortment has played an important role in the genomic evolution of A/H1N1 since 1918. Specifically, we demonstrate that an A/H1N1 isolate from the 1947 epidemic acquired novel PB2 and HA genes through intra-subtype reassortment, which may explain the abrupt antigenic evolution of this virus. Similarly, the 1951 influenza epidemic may also have been associated with reassortant A/H1N1 viruses. Intra-subtype reassortment therefore appears to be a more important process in the evolution and epidemiology of H1N1 influenza A virus than previously realized

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Height and body-mass index trajectories of school-aged children and adolescents from 1985 to 2019 in 200 countries and territories: a pooled analysis of 2181 population-based studies with 65 million participants

Summary Background Comparable global data on health and nutrition of school-aged children and adolescents are scarce. We aimed to estimate age trajectories and time trends in mean height and mean body-mass index (BMI), which measures weight gain beyond what is expected from height gain, for school-aged children and adolescents. Methods For this pooled analysis, we used a database of cardiometabolic risk factors collated by the Non-Communicable Disease Risk Factor Collaboration. We applied a Bayesian hierarchical model to estimate trends from 1985 to 2019 in mean height and mean BMI in 1-year age groups for ages 5–19 years. The model allowed for non-linear changes over time in mean height and mean BMI and for non-linear changes with age of children and adolescents, including periods of rapid growth during adolescence. Findings We pooled data from 2181 population-based studies, with measurements of height and weight in 65 million participants in 200 countries and territories. In 2019, we estimated a difference of 20 cm or higher in mean height of 19-year-old adolescents between countries with the tallest populations (the Netherlands, Montenegro, Estonia, and Bosnia and Herzegovina for boys; and the Netherlands, Montenegro, Denmark, and Iceland for girls) and those with the shortest populations (Timor-Leste, Laos, Solomon Islands, and Papua New Guinea for boys; and Guatemala, Bangladesh, Nepal, and Timor-Leste for girls). In the same year, the difference between the highest mean BMI (in Pacific island countries, Kuwait, Bahrain, The Bahamas, Chile, the USA, and New Zealand for both boys and girls and in South Africa for girls) and lowest mean BMI (in India, Bangladesh, Timor-Leste, Ethiopia, and Chad for boys and girls; and in Japan and Romania for girls) was approximately 9–10 kg/m2. In some countries, children aged 5 years started with healthier height or BMI than the global median and, in some cases, as healthy as the best performing countries, but they became progressively less healthy compared with their comparators as they grew older by not growing as tall (eg, boys in Austria and Barbados, and girls in Belgium and Puerto Rico) or gaining too much weight for their height (eg, girls and boys in Kuwait, Bahrain, Fiji, Jamaica, and Mexico; and girls in South Africa and New Zealand). In other countries, growing children overtook the height of their comparators (eg, Latvia, Czech Republic, Morocco, and Iran) or curbed their weight gain (eg, Italy, France, and Croatia) in late childhood and adolescence. When changes in both height and BMI were considered, girls in South Korea, Vietnam, Saudi Arabia, Turkey, and some central Asian countries (eg, Armenia and Azerbaijan), and boys in central and western Europe (eg, Portugal, Denmark, Poland, and Montenegro) had the healthiest changes in anthropometric status over the past 3·5 decades because, compared with children and adolescents in other countries, they had a much larger gain in height than they did in BMI. The unhealthiest changes—gaining too little height, too much weight for their height compared with children in other countries, or both—occurred in many countries in sub-Saharan Africa, New Zealand, and the USA for boys and girls; in Malaysia and some Pacific island nations for boys; and in Mexico for girls. Interpretation The height and BMI trajectories over age and time of school-aged children and adolescents are highly variable across countries, which indicates heterogeneous nutritional quality and lifelong health advantages and risks

Heterogeneous contributions of change in population distribution of body mass index to change in obesity and underweight NCD Risk Factor Collaboration (NCD-RisC)

From 1985 to 2016, the prevalence of underweight decreased, and that of obesity and severe obesity increased, in most regions, with significant variation in the magnitude of these changes across regions. We investigated how much change in mean body mass index (BMI) explains changes in the prevalence of underweight, obesity, and severe obesity in different regions using data from 2896 population-based studies with 187 million participants. Changes in the prevalence of underweight and total obesity, and to a lesser extent severe obesity, are largely driven by shifts in the distribution of BMI, with smaller contributions from changes in the shape of the distribution. In East and Southeast Asia and sub-Saharan Africa, the underweight tail of the BMI distribution was left behind as the distribution shifted. There is a need for policies that address all forms of malnutrition by making healthy foods accessible and affordable, while restricting unhealthy foods through fiscal and regulatory restrictions

Efficacy and cost-effectiveness of an online mindfulness program (MindOnLine) to reduce fear of recurrence among people with cancer:Study protocol for a randomised controlled trial

INTRODUCTION: Fear of cancer recurrence (FCR) is a common condition among cancer survivors that can lead to significant levels of distress, anxiety and depression. Online mindfulness programmes may provide the mechanism to support cancer survivors manage FCR and distress, and improve people’s well-being over the short, medium and long term. The primary aim of this study is to determine the potential efficacy of MindOnLine, a 9 session mindfulness-based programme for survivors of breast, prostate and colorectal cancer. A formal economic programme will also be conducted. METHODS AND ANALYSIS: A single-blind randomised controlled trial to determine the efficacy and cost-efficacy of a MindOnLine programme for cancer survivors. A total of 400 people living with cancer will be recruited via online advertisements on social media platforms, peak consumer advocacy groups or through outpatient services at healthcare providers across Victoria, Australia. People will be randomly allocated to either the MindOnLine programme (n=200) or waitlist control (n=200). Participant assessments will occur at baseline, at 9 weeks and 9-month follow-up. The primary outcome is change in Fear of Recurrence Index Score total score between baseline and 9 weeks; secondary outcomes are changes in depression and anxiety, quality of life and mindfulness. The economic analysis comprises a cost-consequences analysis where all outcomes will be compared with costs. ETHICS AND DISSEMINATION: Ethics approval was obtained from the Peter MacCallum Cancer Centre (20-53) and Deakin University (2020-284). All participants will be required to provide written informed consent. Findings will be disseminated in peer reviewed journals and among key stakeholder organisations including hospitals, cancer and community organisations and Government. If successful the project will be rolled out nationally with a formal implementation plan. TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry (12620000645954); Pre-results. Registered 6 June 2020, https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=379520&isReview=true