Virus host shifts in Drosophila: The influences of virus genotype and coinfection on susceptibility within and across host species

Virus host shifts are a major source of outbreaks and emerging infectious diseases, and continue to cause considerable damage to public health, society, and the global economy. Predicting and preventing future virus host shifts has become a primary goal of infectious disease research, and multiple tools and approaches are being developed to work towards this goal. In this thesis, I examine three key aspects of infection that have implications for our wider understanding of virus host shifts and their predictability in natural systems: whether the outcome of infections across species is correlated between related viruses, whether the presence of a coinfecting virus can alter the outcomes of cross-species transmission, and the influence of host genetics and immunity on the outcomes of coinfection. These experiments make use of a large and evolutionarily diverse panel of Drosphilidae host species, and infections with two insect Cripaviruses: Drosophila C virus (DCV) and Cricket Paralysis virus (CrPV), with the outcomes of infection quantified throughout as viral loads via qRT-PCR. In Chapter Two, phylogenetic generalised linear mixed models are applied to data on the outcome of single infections with three isolates of DCV (DCV-C, DCV-EB, DCV-M) and one isolate of CrPV, to look for correlations in viral load across host species. Strong positive corrections were found between DCV isolates and weaker positive correlations between DCV and CrPV, with evidence of host species by virus interactions on the outcome of infection. Of the four viruses tested, the most closely related isolates tended to be the most strongly correlated, with correlation strength deteriorating with the evolutionary distance between isolates, although we lacked the diversity or sample size of viruses to properly determine any effect of evolutionary distance on correlation strength. Together, this suggests that hosts susceptible to one virus are also susceptible to closely related viruses, and that knowledge of one virus may be extrapolated to closely related viruses, at least within the range of evolutionary divergence tested here. In the remainder of this thesis, I examine the outcome of coinfection with DCV-C and CrPV across host species (Chapter Three) and across genotypes and immune mutants of Drosophila melanogaster (Chapter Four). These chapters aim to assess the potential for coinfection to alter the outcomes of cross-species transmission – and so interfere with predictions of virus host shifts – and the potential influence of host genetics and immunity on the outcome of coinfection. Chapter Three finds little evidence of systematic changes in the outcome of single and coinfection for both viruses across species, suggesting that coinfection may not be a required consideration in predictive models of every host-virus system. Effects of coinfection were found in a subset of species but were not recapitulated in a follow-up experiment looking at tissue tropism during coinfection on a subset of host species. Together, this suggests that any effects of coinfection across species with DCV and CrPV are due to stochastic effects within individual hosts. Chapter Four finds small but credible effects of coinfection across genotypes of D. melanogaster, but these effects showed little host genetic basis or effect on the genetic basis of susceptibility to each virus separately. Mutations in several immune genes caused virus-specific changes in viral load between single and coinfection, suggesting that coinfection interactions between viruses can be moderated by the host immune response. This thesis has aimed to explore several fundamental features of cross-species transmission that are relevant to our understanding – and ability to predict – virus host shifts. Both the finding that correlations exist between viruses and the approach used to characterise coinfection across and within host species would now benefit from an increased diversity of experimental pathogens, to better investigate the influence of virus evolutionary relationships on the outcomes of virus host shifts and present a broader understanding of the potential impact of coinfection on the outcomes of cross-species transmission.Natural Environment Research Council (NERC

The spatial experiences of dwarfs in public spaces

Dwarfism is commonly defined as anyone 4ft 10″ (147.32 cm) or below and whose short stature involves a medical condition [Adelson, M. B. 2005. The Lives of Dwarfs, xv. NJ: Rutgers University Press]. Whilst it recognized that the built environment is unsuitable for dwarfs [see Kruse, R. 2002. “Social Spaces of Little People: The Experiences of the Jamisons.” Social and Cultural Geography 3 (2): 175–191, Kruse, R. 2010. “Placing Little People: Dwarfism and Geographies of Everyday Life.” In Towards Enabling Geographies, edited by V. Chouinard, E. Hall, and R. Wilton, 183–198. Surrey: Ashgate; Shakespeare, T., M. Wright, and S. Thompson. 2007. A Small Matter of Equality: Living with Restricted Growth. Newcastle: Newcastle University], this paper critically examines how spaces and facilities designed with other users in mind, including disabled people and children, can have unintended consequences for dwarfs. The data used in this paper are taken from semi-structured interviews and photo elicitation exercises conducted with 22 dwarfs living in the UK. Overall this paper shows the spatial experiences of dwarfs, which are a result of the unintended consequences of disabled child spaces and facilities, and suggests how Universal Design may be a more appropriate design concept

Sexually transmitted infection risk exposure among black and minority ethnic youth in northwest London: findings from a study translating a sexually transmitted infection risk-reduction intervention to the UK setting.

OBJECTIVES: Young black women are disproportionately affected by sexually transmitted infections (STI) in the UK, but effective interventions to address this are lacking. The Young Brent Project explored the nature and context of sexual risk-taking in young people to inform the translation of an effective clinic-based STI reduction intervention (Project SAFE) from the USA to the UK. METHODS: One-to-one in-depth interviews (n = 37) and group discussions (n = 10) were conducted among men and women aged 15-27 years from different ethnic backgrounds recruited from youth and genitourinary medicine clinic settings in Brent, London. The interviews explored the context within which STI-related risks were assessed, experienced and avoided, the skills needed to recognise risk and the barriers to behaviour change. RESULTS: Concurrent sexual partnerships, mismatched perceptions and expectations, and barriers to condom use contributed to STI risk exposure and difficulties in implementing risk-reduction strategies. Women attempted to achieve monogamy, but experienced complex and fluid sexual relationships. Low risk awareness, flawed partner risk assessments, negative perceptions of condoms and lack of control hindered condom use. Whereas men made conscious decisions, women experienced persuasion, deceit and difficulty in requesting condom use, particularly with older partners. CONCLUSIONS: Knowledge of STI and condom use skills is not enough to equip young people with the means to reduce STI risk. Interventions with young women need to place greater emphasis on: entering and maintaining healthy relationships; awareness of risks attached to different forms of concurrency and how concurrency arises; skills to redress power imbalances and building self-esteem

Follow-up of patients with Hodgkin's disease following curative treatment: the routine CT scan is of little value

A total of 10-40% of patients with Hodgkin's disease relapse following initial curative therapy. Intensive follow-up is resource intensive and may identify false relapses. We performed a retrospective review of all patients with Hodgkin's disease treated at our centre between 1990 and 1999 to evaluate the utility of the components of follow-up. A total of 107 patients met the inclusion and exclusion criteria. The median age was 33 years and the median duration of follow-up 38 months. The total number of follow-up visits was 1209 and total number of CT scans 283. There were 109 suspected relapses of which 22 proved to be true relapses. Of the latter, 14 were identified clinically, six radiologically and two via lab testing. The routine CT scan detected only two relapses (9%), yet accounted for 29% of the total follow-up costs. Based on data from our centre, the cost per true relapse was $6000 US, 49% incurred by radiological tests. The majority of the cost of follow-up was incurred by routine follow-up (84%) as opposed to the investigation of suspected relapses (16%). We conclude that most true relapses are clinically symptomatic and that the routine CT is an expensive and inefficient mode of routine follow-up

Testing the limits of SMILES-based de novo molecular generation with curriculum and deep reinforcement learning

Deep reinforcement learning methods have been shown to be potentially powerful tools for de novo design. Recurrent-neural-network-based techniques are the most widely used methods in this space. In this work we examine the behaviour of recurrent-neural-network-based methods when there are few (or no) examples of molecules with the desired properties in the training data. We find that targeted molecular generation is usually possible, but the diversity of generated molecules is often reduced and it is not possible to control the composition of generated molecular sets. To help overcome these issues, we propose a new curriculum-learning-inspired recurrent iterative optimization procedure that enables the optimization of generated molecules for seen and unseen molecular profiles, and allows the user to control whether a molecular profile is explored or exploited. Using our method, we generate specific and diverse sets of molecules with up to 18 times more scaffolds than standard methods for the same sample size; however, our results also point to substantial limitations of one-dimensional molecular representations, as used in this space. We find that the success or failure of a given molecular optimization problem depends on the choice of simplified molecular-input line-entry system (SMILES)

Assessing the number of users who are excluded by domestic heating controls

This is the pre-print version of the Article. This Article is also referred to as: "Assessing the 'Design Exclusion' of Heating Controls at a Low-Cost, Low-Carbon Housing Development". - Copyright @ 2011 Taylor & FrancisSpace heating accounts for almost 60% of the energy delivered to housing which in turn accounts for nearly 27% of the total UK's carbon emissions. This study was conducted to investigate the influence of heating control design on the degree of ‘user exclusion’. This was calculated using the Design Exclusion Calculator, developed by the Engineering Design Centre at the University of Cambridge. To elucidate the capability requirements of the system, a detailed hierarchical task analysis was produced, due to the complexity of the overall task. The Exclusion Calculation found that the current design placed excessive demands upon the capabilities of at least 9.5% of the UK population over 16 years old, particularly in terms of ‘vision’, ‘thinking’ and ‘dexterity’ requirements. This increased to 20.7% for users over 60 years old. The method does not account for the level of numeracy and literacy and so the true exclusion may be higher. Usability testing was conducted to help validate the results which indicated that 66% of users at a low-carbon housing development could not programme their controls as desired. Therefore, more detailed analysis of the cognitive demands placed upon the users is required to understand where problems within the programming process occur. Further research focusing on this cognitive interaction will work towards a solution that may allow users to behave easily in a more sustainable manner

Mind the gap? The persistence of pathological discourses in urban regeneration policy

Urban regeneration policy has historically framed policy problems using a discourse that pathologises areas and spatial communities. Since 2001 in England, and 2002 in Scotland a structural change in policy has occurred where citywide partnerships are now meant overcome structural spatial inequalities, countering pathological explanations. This paper uses historical and discourse analysis to evaluate one of the major community regeneration strategies developed by the Scottish Executive in 2002: Better Communities in Scotland: Closing the Gap. It seeks to ask whether structural change in policy was paralleled by discursive change; what discursive path dependence is evidenced? The text is placed in the historic context of UK urban renewal policies dating back to the launch of the Urban Programme in 1968 and particularly the policy discourse created by the influential Conservative government policy of 1988 New Life for Urban Scotland and the wider discourses of poverty and neighbourhood renewal policy created by Labour governments since 1997. The close textual analysis of the text shows that Better Communities in Scotland continues to pathologise spatial communities. Although this suggests a degree of historical path dependency, the historic breadth of the analysis also problematises simple historical determinism

Chikungunya virus infection in Indonesia: a systematic review and evolutionary analysis

Abstract Background Despite the high number of chikungunya cases in Indonesia in recent years, comprehensive epidemiological data are lacking. The systematic review was undertaken to provide data on incidence, the seroprevalence of anti-Chikungunya virus (CHIKV) IgM and IgG antibodies, mortality, the genotypes of circulating CHIKV and travel-related cases of chikungunya in the country. In addition, a phylogenetic and evolutionary analysis of Indonesian CHIKV was conducted. Methods A systematic review was conducted to identify eligible studies from EMBASE, MEDLINE, PubMed and Web of Science as of October 16th 2017. Studies describing the incidence, seroprevalence of IgM and IgG, mortality, genotypes and travel-associated chikungunya were systematically reviewed. The maximum likelihood phylogenetic and evolutionary rate was estimated using Randomized Axelerated Maximum Likelihood (RAxML), and the Bayesian Markov chain Monte Carlo (MCMC) method identified the Time to Most Recent Common Ancestors (TMRCA) of Indonesian CHIKV. The systematic review was registered in the PROSPERO database (CRD42017078205). Results Chikungunya incidence ranged between 0.16-36.2 cases per 100,000 person-year. Overall, the median seroprevalence of anti-CHIKV IgM antibodies in both outbreak and non-outbreak scenarios was 13.3% (17.7 and 7.3% for outbreak and non-outbreak events, respectively). The median seroprevalence of IgG antibodies in both outbreak and non-outbreak settings was 18.5% (range 0.0–73.1%). There were 130 Indonesian CHIKV sequences available, of which 120 (92.3%) were of the Asian genotype and 10 (7.7%) belonged to the East/Central/South African (ECSA) genotype. The ECSA genotype was first isolated in Indonesia in 2008 and was continually sampled until 2011. All ECSA viruses sampled in Indonesia appear to be closely related to viruses that caused massive outbreaks in Southeast Asia countries during the same period. Massive nationwide chikungunya outbreaks in Indonesia were reported during 2009–2010 with a total of 137,655 cases. Our spatio-temporal, phylogenetic and evolutionary data suggest that these outbreaks were likely associated with the introduction of the ECSA genotype of CHIKV to Indonesia. Conclusions Although no deaths have been recorded, the seroprevalence of anti-CHIKV IgM and IgG in the Indonesian population have been relatively high in recent years following re-emergence in early 2001. There is sufficient evidence to suggest that the introduction of ECSA into Indonesia was likely associated with massive chikungunya outbreaks during 2009–2010.https://deepblue.lib.umich.edu/bitstream/2027.42/148282/1/12879_2019_Article_3857.pd