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Genetics of gout - Progression from hyperuricaemia to gout
Full text linkGout is an inflammatory arthritis that is prevalent in New Zealand (NZ) populations, with a higher frequency in Māori (6.06%) and Pacific Islanders (7.60%) in comparison to NZ Europeans (3.24%). This inflammatory arthritis arises from an innate immune response to monosodium urate (MSU) crystals that accumulate in joints and surrounded tissues. MSU crystals are formed in the presence of hyperuricaemia (elevated serum urate levels). Hyperuricaemia (HU) is a prerequisite for gout, but not sufficient. Therefore, it suggests the contribution of other factors that are causal to gout. Genome-wide association studies, an indispensable approach in population genetics, have reported dozens of loci associated with serum urate levels and confirm the importance of urate excretion in controlling urate levels and gout. However, genetic contribution to the progression from hyperuricaemia to gout is poorly understood. Some candidate gene studies have identified genes encoding proteins that are involved in the NLRP3 (NOD-LRR and pyrin domain-containing 3) inflammasome activation that is a key regulator in gout pathogenesis. Thereby, the current research project aims to investigate causal association between non-urate, inflammatory loci and gout.
The current study provides evidence of association between non-urate transporters CNIH2, CUX2, FAM35A and NIPAL1 and inflammatory loci PPARGC1B, IL37 and IL23R with gout in NZ Polynesian and European populations. Recent studies reported association of some of these loci with gout in the Japanese population such as CUX2 (rs4766566), CNIH2 (rs4073582), NIPAL1 (rs11733284), FAM35A (rs7903456), PPARGC1B (rs45520937) and IL23R (rs7517847). The causal role that these variants have in gout pathogenesis in NZ populations has not been reported before and is important for understanding disease mechanisms and developing effective therapeutic stratigies to cure gout.
Population-specific genetic effects on gout are also evident but are not being explored as much as in other complex phenotypes. With the help of an in-silico resequencing approach applied to whole genome sequencing (WGS) gout data, several novel population-specific association signals were found and among these CACNA1S (rs13374149), TAP2 (rs2071) and IL37 (rs17521135) were successfully validated for their association with gout in the New Zealand Polynesian cohort. They were identified with a high prevalence and increasing risk of gout only in a Polynesian sample set. Notably the IL37 (rs17521135) G-allele increased the risk of gout using hyperuricaemic controls compared to gout cases (OR= 1.81, P = 0.031), indicating that this locus is involved in the progression from hyperuricaemia to gout in a population-dependent manner.
Lastly, the current study attempted to evaluate the cause-effect relationship between mitochondria and gout susceptibility through influencing mitochondrial copy number. The hypothesis was generated based on a recent report of identification of low mitochondrial DNA (mtDNA) copy number in Polynesian (Māori and Pacific) gout individuals (Gosling et al. 2018). My study replicated the Gosling et al. (2018) association but did not find association of mtDNA copy number with gout in European. My study evidenced the association of nuclear genome encoded variant rs149132393 (in a FCRL6 gene) with increased mtDNA copy number (in the Eastern Polynesian group) and protected from risk of gout in the Polynesian (Western Polynesian group) population using HU controls versus gout cases. In addition, a previously identified mitochondrial variant 16189C in Polynesian gout patients (Gosling et al. 2018) was associated with gout risk (OR = 0.45, P = 0.045) through mitochondrial-wide association analysis among this NZ Polynesian cohort. Collectively my study indicates a potential contribution of mitochondrial genome variation in gout pathophysiology by affecting mitochondrial copy number
The Role of Large Extracellular Vesicles in Human Papillomavirus-Associated Immune Modulation of Langerhans Cells
No full textHuman papillomavirus type 16 (HPV16) is an oncogenic virus that infects basal keratinocytes of stratified squamous epithelium. Langerhans cells (LCs) reside within the stratified squamous epithelium and initiate immune responses against invading pathogens. The suppression of LC function is one of the many mechanisms of HPV immune evasion, which can contribute to viral persistence and cancer development. Extracellular vesicles (EVs) are small, cell-derived particles that are key players to carcinogenesis, immunity and viral spread. Previous work in the Hibma laboratory has attributed impairment of LC activation and suppression of the cytotoxic T cell response to interactions with large EVs (lEVs) shed by keratinocytes expressing HPV16 E7.
The present study aimed to understand the effects of both HPV16 E6 and E7 (E6/E7) genes on the production of lEVs by keratinocytes and investigate the regulatory roles of lEVs produced by keratinocytes expressing HPV16 E6/E7 on the activation of and cross-presentation by LCs.
Mouse (C57Bl/6) immortalised keratinocyte (PDV) cell lines expressing HPV16 E6/E7 or empty vector control were established following lentivirus transduction. Cell lines were validated, and lEVs from the cell culture supernatants of PDV cells expressing HPV16 E6/E7 (E6/E7 lEVs) or empty vector control (Ctrl lEVs) were purified by differential centrifugation. The purification step was followed by a number of methods to characterise the protein profile, morphology, size and numbers of lEVs. In addition, co-culture experiments were conducted to investigate the effects of E6/E7 lEVs on the activation of LC-like cells (LCLCs) differentiated from the bone marrow progenitors of C57Bl/6 mice.
We found that the overall amounts of lEVs determined by counts and total protein were increased from PDV cells expressing HPV16 E6/E7 compared with empty vector control. Following co-culture with E6/E7 lEVs, LCLCs expressing intracellular IL-12 were markedly downregulated when compared with Ctrl lEVs. In contrast, expression of cell surface co- stimulatory molecules, CD40, CD80 and CD86, on LCLCs was not affected. Furthermore, the effect of E6/E7 lEVs on cross-presentation by LCLCs was examined by measuring the proliferation of CD8+ T cells in response to LCLC-presented ovalbumin. Co-incubations with E6/E7 lEVs resulted to a significantly reduced proliferation of CD8+ T cells when compared with Ctrl lEVs. This effect was ablated when LCLCs derived from Transporter associated with Antigen Processing (TAP1) knockout mice were used, suggesting the involvement of TAP-dependent cross-presentation pathways.
In conclusion, lEVs produced by keratinocytes expressing HPV16 E6/E7 impair LCLC activation and function. A better understanding of E6/E7 lEVs may translate to the production of drugs to inhibit their release and synergise with therapeutic vaccines in development to improve their efficacy in treating HPV-associated malignancies
New Zealand Deprivation Index 2018 - TA50: South Wairarapa District
No full textFor further information about data sources, interpretation of the graphs, and cautions, please see the separate Introduction Chapter
All data relating to the 2018 census is provided by Stats NZ, https://www.stats.govt.nz/
New Zealand Deprivation Index 2018 - TA67: Chatham Islands Territory
No full textFor further information about data sources, interpretation of the graphs, and cautions, please see the separate Introduction Chapter
All data relating to the 2018 census is provided by Stats NZ, https://www.stats.govt.nz/
New Zealand Deprivation Index 2018 - TA43: Kapiti Coast District
No full textFor further information about data sources, interpretation of the graphs, and cautions, please see the separate Introduction Chapter
All data relating to the 2018 census is provided by Stats NZ, https://www.stats.govt.nz/
Investigating the roles of specific amino acid substitutions found in the D1' and far-red forms of the Photosystem II reaction centre D1 protein
No full textPhotosystem II is a highly conserved membrane-protein complex that plays an integral role in oxygenic photosynthesis as a light-driven water-plastoquinone oxidoreductase. One of the most important proteins within Photosystem II that contributes to oxygenic photosynthesis is the psbA-encoded D1 protein. The psbA gene encoding D1 is highly conserved in plants and all photosynthetic eukaryotes; however, multiple copies of psbA encoding different forms of the D1 protein are present in cyanobacteria. These copies have been shown to be upregulated under specific conditions, thus allowing them to respond to changing environmental stimuli. Seven distinct isoforms of D1 have been identified by phylogenetic studies. Of these, the current investigation focused on two: the D1' isoform that is expressed under low-oxygen conditions, and the far-red D1 isoform, which is expressed as part of a far-red light acclimation response. Point and combined mutants conveying amino acid changes associated with D1' and far-red D1 were constructed in Synechocystis sp. PCC 6803 and characterised to determine how the structural and physiological function of D1 changed. The D1'-associated point mutants were A81T, N87A, P162S and P173M. Results from these mutants found the introduced amino acid changes impaired electron movement through PS II, decreasing oxygen-evolving activity. Results supported the conclusion that potential advantages for the expression of D1' would be the ability to adapt to a changing aerobic/anaerobic environment or the ability to produce oxygen at the same rate it is consumed in an environment. The far-red D1-associated combined mutants were L114M, L114M:V115I, L114M:V115I:V116G, L114M:V115I:V116G:F119Y and L114M:V115I:V116G:F119Y:L120I. Results showed these mutants all had impaired PS II activity, which resulted in decreased oxygen evolution and ultimately decreased the photoautotrophic growth rates of some strains. The far-red D1-associated point mutants were L120I and I121P, which showed a similar but less pronounced phenotype to the combined mutants. These results supported the conclusion that amino acid substitutions found in the far red form of D1 likely convey a conserved purposed and function. Lastly, a spontaneous double mutant L114M:A251V was characterised. Results showed the L114M mutant had incorporated a deleterious secondary mutation (Ala251 to Val) and potential explanations for why this occurred were explored. The current investigation successfully identified changes to the function of D1 introduced by conserved amino acid substitutions found in the sequence of the D1' and far-red D1 isoforms of D1
The impact of anti-CRISPRs on horizontal gene transfer (HGT) and their regulation in mobile genetic elements
No full textCRISPR-Cas systems are common in bacterial genomes, providing adaptive immunity against bacterial viruses (bacteriophages). CRISPR-Cas systems are diverse, with two classes, six types and thirty-three subtypes. Bacteriophages circumvent this host defence by using anti-CRISPRs. Anti-CRISPR proteins may have a massive impact on microbial evolution and bacteriophage biology.
This thesis explores the potential of anti-CRISPRs for the horizontal transmission of acquired traits (e.g. antibiotic resistance) across microbiomes. We hypothesized that selection for antibiotic resistance might have resulted in an accumulation of anti-CRISPR genes in genomes that harbour CRISPR-Cas systems and horizontally-acquired antibiotic resistance genes. Our genome-wide correlation analysis of over 100,000 bacterial genomes, with a focus on pathogens, found a significant positive association between the presence of anti-CRISPRs and acquired antibiotic resistance in Pseudomonas aeruginosa.
Furthermore, genome mining identified novel type I anti-CRISPRs from human and plant pathogens. We, along with our collaborators uncovered 11 type I-F and/or I-E anti-CRISPR genes encoded on chromosomal and extrachromosomal mobile genetic elements (MGEs) within Enterobacteriaceae and Pseudomonas. These were cloned and tested experimentally in Pectobacterium and Serratia systems, validating the anti-CRISPR activity of some. The new acr genes cluster with genes encoding inhibitors of other distinct bacterial defence systems.
In most cases, anti-CRISPR genes are located before of DNA binding helix-turn-helix (HTH) transcription factors, named anti-CRISPR associated proteins (Aca). Recent studies had shown three of these Acas act as repressors of anti-CRISPR expression. Here, we computationally analysed bacterial, phage, and plasmid genomes to determine the possible mode of actions of Aca families. The investigation of the promoter regions of acr genes suggests a widespread DNA repression mechanism of regulation by the Aca proteins in the control of anti-CRISPR expression.
Overall, the study has broadened our knowledge of anti-CRISPR mediated HGT and its regulation in MGEs
Determining the Geographical Origin of Cocoa Beans in Chocolate using Stable Isotope Ratios
Full text linkSustainability of cocoa bean farms is becoming an increasingly important matter. With more chocolate showing more sustainability labels, there needs to be confidence in the consumer's mind on these labels. One way in which to build this confidence is to ensure traceability of the cocoa bean from farm to the final chocolate product.
The stable isotope ratio of cocoa bean samples were measured using IRMS to see if their isotope ratio profile reflects their country of origin. δ2H, δ13C and δ15N were all measured on the bulk unshelled cocoa bean, along with δ2H and δ13C of the three most abundant fatty acids within cocoa beans; Palmitic acid, Stearic acid and Oleic acid. The results were analysed using PCA and showed that the samples tended to split into two groups. Nicaragua, Ghana and Vietnam and Papua New Guinea, The Solomon Islands and Samoa.
Two chocolate samples were made from cocoa beans which originated from Ghana. The δ13C and δ2H of extracted fatty acids were analysed as their methyl esters (FAMEs) and compared to the results of the cocoa bean fatty acids. These results showed that the chocolate samples had isotope ratio values closer to that of Vietnam than Ghana. However, the samples from Ghana were also found to be close to those of Vietnam. As an investigative study, this study showed that the method of FAME isotope ratios could potentially be used in future to determine origin of cocoa beans. With some more samples and research, this could lead to the possibility of using it on cocoa beans within a mixture to determine origin.
This study also investigated the gas chromatography stable isotope analysis of underivatized fatty acids extracted from cocoa beans samples. This method is a way to analyse the fatty acids without the need to conduct mass balance calculations needed for FAME analysis. Although the chromatographic responses were found to be much lower than that of the FAME, results seen from one chromatographic peak showed similar trends observed for the δ13C in bulk and FAME analyses. Thereby indicating the potential for this technique to be in traceability studies
Everyday resilience: How has the journey of internet usage among Palestinians in the West Bank affected and reflected their political subjectivity?
No full textPalestinians live in a conflict zone where they experience isolation, lack of freedom and political repression. In this context, Palestinians are increasingly utilising digital spaces to facilitate interaction within and beyond Palestine. This project examines how this journey of engagement in and dependence on digital spaces by Palestinians has affected and reflected their political subjectivity. An in-depth analysis of their involvement in this daily internet usage, allows for a deeper understanding of how Palestinians re-arrange their social order as a result of this integration of internet usage in their everyday lives in the context of entrenched and seemingly intractable conflict. It illuminates how internet usage has been negotiated and incorporated in the long-standing Palestinian struggle.
Since the beginning of Palestinians’ internet usage in the mid-1990s, the digital spaces have challenged their spatial and temporal exclusion and opened them to the world. At the same time, this journey of internet usage has mirrored and shaped their subjectivities since it emphasised their understanding of their position and it gave them a tool to transcend their confinement. Digital spaces have been utilised to bypass their exclusion and build a transnational space of ‘Palestine Online’ according to Miriyam Aouragh (2012). Since the end of the 2000s, internet usage has been integrated as a daily practice as a result of a combination of technological advancements and political factors, such as the Arab Spring, in which digital tactics of contention have been applied. The emergence of social media has facilitated inter-personal connections and provided ordinary people with a tool of protest, resistance and reflexivity. The everydayness of digitisation enables Palestinians to be in dialogue with their identities and subjectivities. In the recent past, amidst the chaos of the Arab Spring and the tightening of political and social digital surveillance, the political subjectivity of Palestinians has been challenged once again. A new cybercrime law was enacted in 2017, enabling Palestinian security systems to spy on the social media accounts of Palestinians and bring charges against them on the basis of their digital utterances. The digital spaces have been confiscated from them. They are aware of the digital surveillance that limits their internet usage. This has not prevented them from continuing to use the internet, although they do not use it to express themselves as they did when social media first emerged. To use the internet nowadays, they need to bargain and manoeuvre the gatekeeping powers in digital spaces. Internet usage by Palestinians demonstrates their everyday resilience. This study documents Palestinians’ journey of internet usage and analyses their understanding of their digital practice and experience and the implications thereof for their political subjectivities. Data for the study was generated by means of a qualitative approach that relied on semi-structured, in-depth interviews with activists, journalists, students, and university academics
The Māori conversion and four early converts
Full text linkThis thesis seeks to understand the extent and nature of the Māori Conversion that occurred during the first half of the nineteenth century in Aotearoa New Zealand. In the absence of an agreed scholarly definition of conversion, this thesis formulates an original definition to serve as an important interpretative tool:
Conversion is a profoundly religious experience of reorientation in which an individual or group embraces a gradual, though at times appearing sudden, process of change in patterns of belief, identity and practice, resulting in a stable and viable way of communal life that has recognisable continuity with the past, yet is distinctly new.
This definition is then used as a model to analyse the conversion of four early converts: Ruatara, Māui, Te Rangi, and Taiwhanga.
The extent of the Māori Conversion is estimated using the statistical information reported to the Church Missionary Society by their missionaries and is shown to be more extensive than previously acknowledged by historians, with some 90 percent of Māori having converted to Christianity by 1852. The nature of the Māori Conversion is assessed by considering the lives of the four early converts. The thesis draws on a number of previously underutilised archival sources, including autobiographical material written by Māui in 1816, a series of transcripts of conversations held with Waitangi Māori by Henry Williams from 1823–1825, and four letters written by Taiwhanga before his baptism in 1830. This bottom-up approach has the advantage of highlighting the active agency of these Māori converts in the conversion process and provides an important indigenous perspective on the Māori Conversion. By identifying common themes and connecting narratives, these four converts are also shown to be far from exceptional or isolated cases, but typical of the wider movement of which they were a part.
The thesis concludes that the Māori Conversion was indeed a profoundly religious movement that can be understood and conceptualised around three interwoven strands of belief, identity and practice. Māori converts were attracted to Christian ideas because they provided them with a satisfying and alternative way of living in the changing world opening up to them through Western contact. Christianity enabled Māori converts to form new allegiances and identities based on the Bible as a source of spiritual authority, allowing them to dispense with the divisions and animosities of the past and to pursue new forms of peace. The practice of Sabbath
iv observance, Christian prayer, and baptism (among others) reinforced for Māori converts their new Christian beliefs and identities, leading to the transformation of traditional Māori society and the emergence of a distinctly Māori expression of Christianity