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Two applications of the Cauchy problem in general relativity
Get PDFThe Cauchy problem plays an important role in both analytical and numerical studies of the Einstein field equations. Here we discuss two particular applications of the Cauchy problem within the framework of General Relativity. In the first of the two problems, we investigate how one can solve the Einstein constraint equations as an initial value problem. For this, our primary focus is on the asymptotic behaviour of the unknowns and how it may be ``controlled''. In particular, we provide analytical and numerical evidence that it is possible to control the asymptotic behaviour of the unknowns. In the second of the two problems, we investigate the asymptotic behaviour of solutions of the Einstein equations with a minimally coupled scalar field near the Big Bang. Our primary focus here is on understanding what effect the addition of a potential has on the asymptotic behaviour of the scalar field
Characterizing the Role of Long Non-Coding RNA CAN3 in Colorectal Cancer
No full textColorectal cancer (CRC) has been ranked among the leading cause of cancer-related mortality, accounting for 19.5% of cancer incidence, globally. Over the years, while there have been advancements with therapeutic treatments to improve cancer management, CRC burden remains high especially for metastatic CRC patients. In recent years, extensive research has discovered many cancer-associated mutations within non-coding regions of our genome, including long non-coding RNAs (lncRNAs). LncRNAs are classified as transcripts with >200 nucleotides and do not encode for a protein, however, still have regulatory functions. They have emerged as potential therapeutic targets with a majority being identified as key players in the development and progression of cancer hallmarks. While there are more than 100,000 lncRNA transcripts that have been identified to date, many remain largely uncharacterized.
Therefore, in this study, we sought to characterize a novel lncRNA, termed CAN3, and its role in CRC progression. LncRNA CAN3 was initially identified as a regulator of cell growth in a CRISPR-interference (CRISPRi) depletion screen in a CRC cell line. From this, we hypothesized that CAN3 plays a role in driving cell proliferation in CRC. We first aimed to generate a loss-of-function model in the HCT116 (human colorectal carcinoma) cell line using the CRISPRi approach. Validation of expression levels showed successful CAN3 repression with >50% knockdown efficiency. Our second aim was to generate a loss-of-function model in the HCT116 cell line using antisense oligonucleotides (ASOs) as a means of comparing phenotypical changes between a transcriptional loss-of-function model (CRISPRi) and a post-transcriptional silencing model (ASOs). Similarly, the loss-of-function models generated using ASOs resulted in >50% knockdown efficiencies. The third aim of this study was to elucidate the role of CAN3 on cell proliferation in CRC using the loss-of-function models that had been generated. Our findings showed no significant changes to the rate of cell proliferation upon CAN3 repression, thus, rejecting the hypothesis that was initially proposed.
Taken together, our success with generating knockdown models using CRISPRi and ASOs suggest that both approaches are useful tools for generating loss-of-function models targeting lncRNA genes. Findings from our interrogation of CAN3 suggest that it does not play a role in driving cell proliferation in CRC. However, we propose that further investigations into validating the results observed and mitigating any limitations from this project may be beneficial to further evaluate its potential as a therapeutic target for CRC treatment
Twelfth Annual Report of the Perinatal and Maternal Mortality Review Committee
Get PDFThe twelfth annual report of the Perinatal and Maternal Mortality Review Committee (PMMRC) has a new format from previous reports. It addresses neonatal mortality and neonatal encephalopathy in depth. The perinatal mortality section includes a slightly reduced selection of tables and figures compared to previous years. Maternal mortality includes a core selection of tables and figures only. Both of these sections include limited commentary that aims to address any new data or issues of particular importance in the current year. The PMMRC plans to analyse and report maternal mortality in detail every three years. Specific topics will be chosen each year for in-depth analysis and commentary
Human arbovirus diseases in New Zealand: Risk factors and outbreak scenarios
Get PDFBackground: Although New Zealand has not yet reported local transmission of a mosquito-borne virus (arbovirus), several risk factors are present. While current literature is inconsistent on the risk status, to date, no evidence-based approach has been used to assess major risk factors and elements likely to facilitate local transmission.
Aims: 1) To identify and evaluate the current status of major risk factors and favourable conditions likely to facilitate local transmission of arbovirus infections in New Zealand
2) To outline likely scenarios and identify combinations of circumstances under which the elements of arbovirus transmission and related risk factors might coincide to trigger a local outbreak
Methods: Information on arbovirus notified cases and traveller arrivals were used to evaluate the risk of arbovirus introduction via viraemic travellers by describing trends in importation rates, seasonality and route of travel and likely origins of infection. Information on mosquito interception records and air and sea freight imports, and international passenger flight arrivals was obtained to assess the risk of exotic mosquito introduction and establishment by describing trends in the border interceptions and the role of imported goods and air travel as a mean of transport. Using occurrence records obtained from biosecurity surveillance programmes, country-scale environmental suitability maps for Aedes notoscriptus were created to evaluate the role of this species in potential local Ross River virus (RRV) transmission. Trap surveillance mosquito counts were examined for association with selected environmental factors to identify the environmental conditions favourable for local mosquito biting activity and, therefore, disease transmission.
Results: The risk of an arbovirus outbreak in New Zealand exists and is exacerbated. This is supported by the following findings:
i. The increases in imported arbovirus cases: a total of 1912 reported cases between 2001-2017, with more than half of these were reported in the final four years and dengue cases comprised 81.1%.
ii. Regular interception of exotic mosquitoes at the borders: Aedes (Stegomyia) aegypti (Linnaeus) and Ae. (Stegomyia) albopictus (Skuse) were the two most commonly intercepted species,
iii. Ongoing growth of international trade and travel with arbovirus endemic and/or mosquito vector-established countries: a 71% increase in the number of international flights to New Zealand between 2001-2017 and a ten-fold increase in the number of flights from Queensland, where Ae. aegypti is established and RRV is endemic.
iv. Ongoing expansion and widespread distribution of Ae. (Finlaya) notoscriptus (Skuse) and its occurrence in relatively high counts in different types of habitats of New Zealand.
Conclusions: Dengue and Ross River virus diseases are the most likely infections to cause local outbreaks. All requirements to initiate a local Ross River virus epidemic exist, while the absence of a competent vector is the limiting factor for dengue virus transmission. Auckland is the most likely point of virus and vector entry. The most likely mode of virus introduction is viraemic travellers entering the country through Auckland from Australia and/or the Pacific Islands, while Australia, the Pacific Islands and Japan are the most likely source of the vector. The northern North Island (where the number of adult Aedes notoscriptus collected was 40 times more than that collected from all other areas) is the most likely receptive location for introduction of RRV, while Auckland (where Ae. albopictus and Ae. aegypti were intercepted) would be receptive to dengue. Raised awareness among travellers, medical and public health authorities on arbovirus diseases, country-scale mosquito surveillance programmes, and a national early warning system would reduce the risk of a local epidemic
High resolution lacustrine records of Late Holocene climate change from southern New Zealand
No full textNew Zealand freshwater ecosystems are directly impacted by temperature and precipitation variations controlled by the strength and position of the Southern Hemisphere Westerly Winds. Understanding westerly wind controls on hydroclimate is essential for predicting ecosystem response to future warming projections. However, New Zealand lacks this context due to short duration of our instrumental records and poorly resolved paleoclimate records that span the last 1000 years. Sedimentary paleoclimate records developed from remote alpine lakes are sensitive recorders of temperature and precipitation change and offer an opportunity to provide highly resolved records of present and past climate. This study presents two highly resolved (centennial-scale) sedimentary records from southern New Zealand alpine lakes that can be used to evaluate the last ~13,600 years of hydrologic change associated with Southern Hemisphere Westerly Winds. Highly resolved proxy records obtained from non-destructive scanning are assessed together with biogenic silica concentration, δ13C and δ15N isotope data, bulk organic carbon and nitrogen concentrations, and 14C and 210Pb dates, to reveal temporal trends linked to temperature and precipitation change. High-resolution non-destructive μX-ray fluorescence core scanning and hyperspectral imaging produce continuous, sub-millimetre elemental and pigment profiles, respectively. Principal component analysis of elemental data indicates elements that track lithogenic change (Ti, K, Fe, Ca, Si, = PC1) are leading contributors of geochemical variance in both records. Elemental proxies that track lithogenic variation (PC1) and biosiliceous sediment (Si/Ti) are assessed with hyperspectral imaging
indices that track productivity (Chl a; RABD660-670) and minerogenic (R570/R630) change. Early Holocene evidence for enhanced productivity with limited lithogenic contribution indicate lower lake level and warm, dry conditions. Consistent with previous studies, these observations are attributed to southward-shifted and/or weaker westerly winds. Results of Early Holocene millennial-scale trends inform assessment of Late Holocene hydroclimate. A long-term cooling trend, linked to strengthening of the westerly winds, is overprinted by centennial-scale trends. These records provide insight into how Late Holocene climate mechanisms influence westerly wind in southern New Zealand. Present trends toward increasing temperature and increased aquatic productivity suggest these mechanisms are critical to the understanding and prediction of how forecasted future climate will affect southern New Zealand lakes
Internalin proteins, the weapons wielded by Listeria monocytogenes
Get PDFListeria monocytogenes (Lm) is a bacterial pathogen capable of causing meningitis, septicaemia and fetoplacental infections in the immunocompromised, elderly, and pregnant women. Disease caused by Lm (listeriosis) manifests as self-limiting gastroenteritis in immunocompetent individuals. Lm is a facultative intracellular pathogen that can survive extracellularly or adopt an intracellular lifecycle within a host cell. Lm has a family of structurally related proteins called ‘Internalin’ proteins, some of which are known virulence factors. Most strains of Lm have 25 Internalin proteins, with only five of these proteins (InlA, InlB, InlC, InlF, and InlP) being well-characterised in terms of biological function. Internalin proteins have a conserved leucine-rich repeat (LRR) region that adopts a horseshoe structure. In the case of the five well-characterised Internalin proteins, the concave surface mediates interaction with different human receptors. The majority of Internalin proteins have not been extensively studied.
The hypothesis that drove this project is that most or all Internalin proteins promote disease by interacting with human receptors. The overarching aim of this work was to identify human receptors of the three Internalin proteins Inl671, Inl369, and Inl2595. A yeast two-hybrid screen of a human cDNA library was previously performed by others in the Ireton laboratory to identify the human protein Ring1B as a potential receptor of Inl671. Riing1B is an E3 ubiquitin ligase that is known to regulate gene expression by mediating monoubiquitination of the histone 2A (H2A) protein. Western blotting and laser scanning confocal microscopy analysis was used to assess the effect of Listeria infection on Ring1B expression and activity. Although infection was correlated with decreased levels of Ring1B expression in some experiments, these effects were inconsistent among multiple experiments, making it difficult to conclude if Listeria affects Ring1B protein levels. Ring1B activity was assessed via Western blotting to detect monoubiquitinated H2AK119 (ubiquityl-H2AK119). However, difficulty in preserving H2A ubiquitination after solubilization of human cells prevented conclusions about whether Listeria infection affects monoubiquitination of H2A.
The Ireton laboratory previously performed a yeast two-hybrid screen to isolate two human proteins that potentially interact with the Internalin protein Inl369. However, the amino acid sequences of these human proteins were not characterized and their interaction with Inl369 was not validated through control experiments. In this Honours project, the interactions were validated by co-transforming, into a naïve strain of yeast, plasmids expressing Inl369 fused to the DNA binding domain of GAL4 and each of the two human proteins fused to the Gal4 transcription activation domain. Results showed that expression of yeast genes reporting interaction required both Inl671 and each of the two human proteins. It was therefore not due to promoter mutations in the reporter genes of the yeast strain where interaction was first detected. After validation of interaction, human cDNAs were sent for sequencing, leading to the identification of the human proteins centriolin and dynein axonemal assembly factor 11 (DNAAF11) as potential host receptors for Inl369. In addition to work with Inl671 and Inl369, the Internalin protein Inl2595 was studied for its suitability for yeast two-hybrid screens by determining if this protein lacked toxicity and the ability autoactivate gene expression in yeast. Unfortunately, Inl2595 constructs with the DNA binding domain of GAL4 fused to the N- or C-terminus of Inl2595 were found to autoactivate gene expression, indicating that they were not appropriate for yeast two-hybrid screening. The findings in this thesis suggest future work that may help assess the roles of Inl671 and Inl369 and their potential host receptors in Lm infection
The evolution of composition for the classical guitar in New Zealand
Get PDFThis study offers a coherent account of the evolution of composition for the classical guitar in New Zealand, which is exemplified through the performance component of the DMA. The exegesis reveals this evolution through the critical analysis of archival material, the examination of historical developments, and the interviewing of twelve key people who were active in the classical guitar scene from the late 1950s to the present day. It also reflects on the author’s commissioning and/or performing of fifteen major works for guitar by nine New Zealand composers. It examines the drivers that shaped the development of New Zealand guitar music, the factors that led to the creation of key compositions and the role performers have played through collaboration with composers in an attempt to create a significant body of distinctive works. Key findings include identifying that certain important New Zealand composers were, in fact, ahead of their counterparts in other comparable countries in embracing the classical guitar as a viable medium to write for early in their careers, despite there being very few guitarists present to perform their music at the time they wrote it; the importance of the role performers have played in shaping the nature, scope and scale of the repertoire written through collaboration with composers; the importance of the influence of the first New Zealand-born or resident guitarists who laid the foundation for the next generation of performers, particularly for the author; and the development of those early initiatives that has resulted in a substantial and internationally recognised repertoire in the 21st century, continuing a tradition established by Andrés Segovia, cemented by Julian Bream and emulated by many guitarists around the world
Neural correlates of categorisation in the forebrain of pigeons (Columba Livia)
Get PDFThe objective of this thesis is to examine neural activity in the pigeon brain during a wide range of categorisation tasks. Single-unit electrophysiology will be used to record from neurons in a prefrontal area (NCL) and an intermediary visual area (ENTO), in an attempt to understand how neurons in both of these areas are involved in the categorisation process, and how neurons from these areas use reward/behavioural information and visual information about categories during discrimination. We then present an integrated model of the neural correlates of categorisation in the pigeon brain based on our findings.
This thesis starts with an exploration into the second intermediary visual area and the termination point of the thalamofugal pathway, the visual Wulst (Chapter 3). While we found some interesting evidence of the Wulst being a highly reward-driven visual area, we decided not to continue recording from this area for the remainder of the studies as further research is needed to understand the Wulst’s primary mode of processing.
The first of the categorisation tasks was a semi-symbolic categorisation task, in which birds learned to distinguish several English four-letter words from four-letter nonwords (Chapter 4). Neural activity was recorded while the pigeons discriminated their learned “vocabularies” from an extensive pool of nonwords. We found that there were no differences between activity to words and non-words, except in birds who were potentially still learning the task. We argue that behavioural information such as reward helps guide categorisation in NCL and ENTO before learning but is likely no longer used after learning.
In the second categorisation task, we trained birds to respond to either Monet or Picasso paintings using an S+/S- paradigm (Chapter 5). We recorded neural activity from an additional area of interest known as the mesopallium ventrolaterale (MVL), a higher order visual area. In both NCL and ENTO, we found a significant left-hemisphere dominance for both reward and visual-based categorisation, while no such asymmetry was found in MVL. Furthermore, both NCL and ENTO appear to use reward information during categorisation when there is the opportunity to (i.e. differential rewards), but MVL does not.
The third categorisation task involved more complex stimuli, in which category exemplars are comprised of four smaller stimuli (Chapter 6). Exemplars from both categories share some features (irrelevant features), while other features are unique to each category (relevant features). We found that both excitatory and inhibitory ENTO neurons use visual (colour) and behavioural (relevancy) information to aid categorisation, and we posit that these neurons relay this information onto excitatory NCL neurons.
Inhibitory NCL neurons then use the information encoded and received by ENTO and excitatory NCL neurons to execute a behavioural decision.
The final categorisation task involved the same stimuli as the Monet/Picasso study in Chapter 5, but in a delayed matching-to-category (DMC) paradigm instead of the original S+/S- paradigm (Chapter 7). We present preliminary results indicating that NCL, ENTO, and MVL share information about categories with each other via reciprocal projections
Development and analysis of a novel bovine hydroxyapatite calcium silicate cement for conservative pulp therapy
No full textAim: To develop an experimental endodontic cement using bovine bone-derived hydroxyapatite (BHA), Portland cement (PC), and a radiopacifier and to characterize its physicochemical and biological properties for use in endodontic treatment.
Methods: BHA was manufactured from waste bovine bone and milled to form a powder. Four BHA supplemented PCs (BHA 10%/20%/30%/40%), a 10% nanohydroxyapatite (NHA) supplemented PC and an unsupplemented PC (PC65) were manufactured. A radiopacifier, either zirconia (ZrO) or tantalum (TaO) and a plasticizing agent were also included. The raw materials and synthesized cements were chemically characterized and cements were tested to evaluate their radiopacity, compressive strength, setting time, solubility, pH, and biocompatibility (using Saos-2 osteosarcoma cells). The radiopacity and biocompatibility of these cements were also compared with ProRoot MTA (PR-MTA). Compressive strength, solubility and pH were evaluated over a 4-week curing period.
Results: The compressive strength of all cements increased with the extended curing times, with a significant increase in all groups from day 1 to day 28. The BHA10% group exhibited significantly higher compressive strength than: PC65, NHA & BHA30/40% at day 1; NHA, BHA30/40% at day 7; and PC65, NHA & BHA30/40% at day 28. The BHA10/20% groups exhibited significantly longer setting times than BHA 30/40% and PC65. NHA exhibited a longer setting time than any other material. No significant difference was observed between cements in terms of solubility and pH during 4-weeks of observation. ZrO was a more effective radiopacifier by weight than TaO. BHA did not alter radiopacity of cements. BHA 10/20% demonstrated significantly higher cell counts compared with BHA 30/40% and MTA at 72 h exposure.
Conclusions: The addition of 10% and 20% BHA to an experimental PC-based cement containing 35% ZrO improved the material’s mechanical strength while enabling similar radiopacity and biocompatibility to PR-MTA. BHA is a cost effective additive which has the potential to improve the properties of calcium silicate endodontic cements
Brain blood flow and breathing control in extreme environments
No full textOne’s ability to survive and thrive in diverse environments relies on both behavioural and physiological responses, which act together to maintain a suitable internal environment. Physiological responses occur automatically in proportion to the degree of strain imparted by the stimulus, whereas behavioural responses are learned and require adequate cognitive capacity to perceive, interpret and respond to threatening situations. As it is central to both physiological and behavioural responses, understanding how the brain tolerates various environmental stressors is essential in predicting how well an individual as a whole will tolerate these stressors.
Study 1 investigated how acute and chronic hypoxia affected cerebral haemodynamics during cold and heat stress. Healthy males were passively cooled by 1 °C and heated by 1.5 °C core temperature at sea level and again after 16 days at high altitude (4330 m). Core cooling reduced global cerebral blood flow, as assessed by duplex ultrasound, by 20-30%, and cerebral oxygen delivery by 12-19% at sea level and high altitude, whereas heat stress did not reliably reduce cerebral blood flow or oxygen delivery. Acclimatisation to 4330 m fully restored arterial oxygen content, but concurrent cold stress reduced cerebral blood flow and thereby cerebral oxygen delivery. Decreases in cerebral blood flow appeared to be driven primarily by cold-induced hypocapnia secondary to hyperventilation. Despite decreases in cerebral oxygen delivery by up to 19%, gross indices of cognition were unaffected. In summary, chronic hypoxia renders the brain susceptible to large reductions in oxygen delivery with concurrent cold stress, however, these impairments appear to be well tolerated short-term.
Study 2 investigated the temporal changes in cerebral blood flow under four different modes of incremental heating, as well as the role of heating in elevating intracranial pressure. Healthy males and females were heated to volitional thermal tolerance via: (1) passive hot water immersion, (2) passive hot, humid air exposure, (3) cycling in the heat, and (4) cycling in the heat with the prevention of heat-induced hypocapnia. The cerebral blood flow response to incremental heat strain was dependent on the mode of heating, decreasing by 30% when passively exposed to hot, humid air, while remaining unchanged or increasing with hot water immersion and both exercise conditions. Despite a consistent blunting of cerebrovascular reactivity to hypocapnia, cerebral blood flow at thermal tolerance appeared to be largely influenced by the magnitude of hypocapnia that developed as a consequence of heat-induced hyperventilation. Thermal tolerance was equally superior in the two passive heating conditions despite a 25% difference in cerebral blood flow, and preventing hypocapnia during cycling increased cerebral blood flow by 25% but had no influence on exercising tolerance. Perception of thermal discomfort and thermal behaviour, i.e., volitional tolerance, did not appear to be affected by cerebral blood flow. Intracranial pressure, as estimated by optic nerve sheath diameter, was increased universally by 18% at volitional thermal tolerance in all modes of heating. In summary, passive hot, humid air exposure poses the greatest challenge to the brain under moderate- to severe- heating due to lower blood flow but similarly increased intracranial pressure.
Instead of further interrogating the cerebrovascular responses to environmental stress, study 3 focussed on the mechanisms that drive hyperventilation – which based on studies 1 and 2 – largely explain the cerebral blood flow responses to both cold and heat stress. The carotid body was targeted because the ventilatory response to acute and chronic hypoxia was profoundly augmented under thermal stress in study 1. Carotid body tonic activity was assessed by transient hyperoxia, and its sensitivity by isocapnic hypoxia under both graded heating and cooling. Carotid body tonic activity was increased in a dose-dependent manner with graded heating, reaching a maximum that was 175% above baseline at +2 °C core temperature. Core cooling increased carotid body activity by up to 250% under mild cooling, i.e., -1 °C core temperature. Despite hypocapnic restraint secondary to heat-induced hyperventilation, carotid body sensitivity to hypoxia was augmented by up to 115% with heat stress. Carotid body sensitivity was minimally increased (~30%) by core cooling under much less hypocapnic restraint. In summary, heat stress increases both the carotid body tonic activity and its sensitivity, providing two interrelated mechanisms by which the carotid body contributes to heat-induced hyperventilation.
This collection of studies exposed the complex interactions involved in maintaining brain allostasis under severe environmental stress and provides evidence that: 1) the balance of arterial carbon dioxide pressure and oxygen content largely dictate the cerebral blood flow response under cold, heat and hypoxic stress - alone and in combination - but cerebrovascular sensitivities to both gases are selectively altered to protect cerebral oxygen delivery; 2) transient elevations in intracranial pressure occur in healthy heated humans and may drive thermal behaviour; and, 3) the carotid body likely plays a dominant role in driving heat-induced hyperventilation. Lastly, it appears that alongside the diverse autonomous responses that act collectively to protect the brain, cognition and perception are still well preserved even when the brain’s internal environment is temporarily compromised under the severest of environments