The neural processes of memory storage are not well understood. It is notable, however, that the hippocampus, a brain region critical for memory, is one of only two regions where new nerve cells are generated throughout life. The precise role of these new nerve cells in memory is unclear, largely due to an inability to selectively manipulate their activity. Here we will develop the critical molecular technology for selectively and reversibly silencing new nerve cells during an animal’s performance of memory tasks. We will genetically modify cells newly generated in adult mice with a protein that inhibits their activity when the animals are given ivermectin. We will then use ivermectin to silence these cells during memory storage or retrieval to assess their importance for memory.
A second series of experiments will compare the participation of older and newer nerve cells in the neural circuitry for memory storage by monitoring their activity during learning, and after “waking them up” with a variety of experimental procedures. Overall, these experiments will provide important new insights into how nerve cells compete for involvement in memory storage. The new genetic technology also has great potential for broader applications in understanding how the brain controls behaviour.
I identify a largely unrecognised philosophical and theological paradox of our literary heritage: the substantial Medieval presence within the Modernist aesthetic (1900-1960), expressed in moments of illumination that deploy religious and mystical traditions to create and/or orchestrate moments of insight that are often secular in effect. The capacity of metaphor to enact the "miracle" of taking one from the "here" of everyday understanding to the "there" of the transcendent plane exemplifies how rhetorical devices and structures generate luminous effects that reconcile these two realms. To identify the "machinery of transcendence" (in Kenneth Burke's celebrated phrase) that translates the ordinary into the extraordinary (to invoke James Joyce's equally celebrated insight) is to familiarise and thus ground those mysterious "moments" that illuminate many Modernist works.
My project, linked intimately (albeit sometimes skeptically) with the "Modernism and Christianity" Institute at the University of Bergen, interrogates the Medieval traditions that inform Modernism, the pragmatic outcomes being: a revaluation of the Modernist tradition and its dialogue with the past; a monograph on the Modernist aesthetic; a Dunedin colloquium (and book of essays) on "unattended moments" and literary epiphany; close work with two emerging AIs; and the training of two young researchers.
p53 is the pre-eminent tumour suppressor gene. Proper p53 functioning is therefore important in the prevention of cancers. Recently, twelve naturally occurring variants or isoforms of human p53 were identified, one of which (Δ133p53) is present at unusually high levels in several human cancers and antagonizes normal p53 function. These data suggest that this isoform might promote rather than prevent cancer forming, thus acting as p53’s ‘nemesis’. We constructed a mouse that makes the equivalent of Δ133p53 (designated Δ122p53) and have shown that the mice are tumour prone. Thus, Δ122p53 (and by implication Δ133p53) can function as a cancer promoting agent (i.e. an oncogene). These mice also show evidence of enhanced cell growth and widespread inflammation that occur prior to the onset of cancer. The inflammation is likely to be due to increased levels of the pro-inflammatory cytokine IL-6 in the blood.
In this proposal we investigate whether reducing inflammation can prevent cancers forming, delay their onset or reduce their severity. We also investigate how Δ122p53 can cause cells to grow faster. These experiments will tell us how Δ122p53 causes cancer which could lead to novels ways of treating cancers in humans.
It has been widely predicted that nanotechnology has the potential to fuel the next industrial revolution. For this to come to fruition humans must develop the ability to exploit controlled molecular-level motion in the same way that biological nanomachines do.
This proposal seeks to use controlled rotational molecular motion in the development of a novel synthetic molecular actuator and investigate ways of extrapolating the effects of motion at the molecular level through to the macroscopic world. The resulting molecular actuators will bring the development of functional synthetic nanomachines one step closer.
The addition of ubiquitin to proteins regulates their abundance and interactions, and has emerged as a major mechanism for the regulation of many cellular events. As expected for such a critical process, dysregulation of ubiquitin mediated events manifests as diseases such as cancer. Attachment of ubiquitin to proteins depends on a cascade of three enzymes (referred to as E1, E2 and E3). Although the activity and regulation of the E2 family of enzymes is critical, less is known about how they function.
Recent studies by the co-applicants and others indicate that the E2 enzymes are regulated in a number of different ways. Using purified proteins, we will determine how sequences within the E2 enzyme can modulate activity. We will also investigate how transfer of ubiquitin from the E2, to the target protein, is regulated by its interaction with the E3 protein. A detailed molecular understanding of E2 enzyme function is important because the E2 enzymes lie at the heart of the enzyme cascade and each E2 works together with a number of E3 proteins. Many diseases are caused by aberrant ubiquitylation and ultimately these studies may suggest novel approaches for the regulation of these processes.
The environment animals experience can affect the way they look and behave– this is called phenotypic plasticity. Phenotypic plasticity is important in many animals, including humans. In humans, the environment you encounter as a fetus may determine how susceptible you are to type II diabetes and heart disease, diseases that don’t affect you until you are 40 or 50 years old! In other animals, such as aphids, the environment can change the way they reproduce. Aphids can switch between sexual and asexual reproduction and this is partly why they are successful pests - reproducing without sex means that they can have a lot more children quickly.
The environment interacting with our DNA brings about all these biological changes. But how does this happen? We think that the DNA is organized within the cell in such a way as to help an animal’s ability to respond to the environment. We propose to look at the way that the DNA is organized in sexual and asexual pea aphids. We hope what we discover in aphids will give us insight into how DNA responds to the environment in other animals, including humans.
Independent dexterity of the left and right hands occurs with normal development. Nerve fibres from each motor cortex cross from their side of origin to communicate with muscles on the opposite side of the body. The genetic and developmental processes that underlie this critical fibre tract crossing are not known. People with Hereditary Congenital Mirror Movements (CMMs) provide a naturally-occurring genetic model to examine this. Whenever people with CMMs attempt to move the fingers or hand on one side of the body, they also exhibit unintentional (mirror) movements on the opposite side.
Our team of NZ experts in neuroimaging, human genetics and neurodevelopment will elucidate the processes that determine this fibre tract crossing in an extended family with CMMs. With specialised ‘movement gloves’ we will conduct detailed clinical analysis, and will apply non-invasive brain mapping techniques to elucidate the neuroanatomical underpinnings of CMMs. We will identify the causative gene, and we will undertake developmental studies to determine how the gene product guides the growth of nerve fibres to the correct side in normal brain development. Our investigations will identify regulators of brain wiring that might also represent novel targets for neuroregenerative or neurorestorative therapies.
An ultra-cold atom trapped in an optical microtrap form an ideal paradigm system for experimental research in quantum mechanics. This setup allows for manipulation and detection of particles that display quantum behavior and are inherently isolated from the uncontrollable environment. I propose to build on our recently demonstrated single atom experiment, by constructing a new type of microtrap, and by using it to study quantum tunnelling and the Zeno effect at the single event level. Quantum mechanics predicts that there is a finite probability of a particle to tunnel through a potential barrier, which is impenetrable according to classical mechanics.
I propose to directly observe this phenomena for tunnelling of a trapped atom across microscopic walls made using laser beams. Tunnelling can be viewed as a decay process characterized by tunnelling time: the typical time for the trapped particle to escape from the trap. Quantum decay processes are thought to be subject to the quantum Zeno effect, which suggest that measurement can modify the time evolution of a quantum system. I propose to experimentally study the quantum Zeno effect by applying a measurement on the atom as it tunnel through a potential barrier.
Cytokines are signalling proteins that coordinate the complex workings of the human immune system. Macrophage migration inhibitory factor (MIF) is a cytokine that helps protect the body from infection, but it also promotes damage in diseases such as sepsis, arthritis and inflammatory bowel disease. MIF acts like other cytokines by binding to specific receptors on cells. However, MIF also has an unusually reactive proline residue. The function of this proline is unclear, but we propose it is a sensor that regulates MIF activity. We recently discovered that this proline could be modified by dietary compounds, causing a conformational change in MIF that blocked receptor binding.
We hypothesize that compounds generated during inflammation act in a similar way to influence MIF activity. In this study we will assess which compounds are able to react with MIF, and determine if modification occurs at sites of inflammation. If correct, we will have discovered a new mechanism for regulating the immune system.
The prehistorian’s task to return extinct human societies from oblivion has always confronted the dilemma of measuring time. Southeast Asia and Southern China is a region central to identifying how civilizations emerged ultimately from bands of hunters and gatherers. Yet the essential chronological scaffolding has not been defined because previous radiocarbon methods have been flawed.
This proposal will lay the foundations for an accurate overall chronology that charts the major transitions: the Neolithic revolution, the adoption of bronze casting, development of complex chiefdoms and finally, the origins of the civilizations. It has been made possible by a radiocarbon dating revolution that is only now opening unprecedented possibilities for the archaeologist. It involves the ultrafiltration pre-treatment of samples of bone, linked to the Bayesian analysis of the resulting determinations. Where formerly, prehistorians were hamstrung by dates with a wide margin of error at best, it is now possible to track cultural changes with almost a generational precision. Having defined the chronological sequence, we will deploy Bayesian analyses to explore in detail the social organization within key sites, thereby establishing a new benchmark in the pursuit of the past in one of the world’s most dynamic regions.
A key component of ambition is the tendency to select high-effort/high-reward pursuits over easier, but less rewarding, alternatives. This willingness to ‘put in the extra effort’ is associated with several positive outcomes, yet very little research has examined how the brain actually encodes and drives effortful choice behaviour. In this project we test the hypothesis that, at the neural level, selecting high-effort/high-reward pursuits depends on activity levels in the Anterior Cingulate Cortex (ACC), a region of prefrontal cortex.
By simultaneously recording brain activity and monitoring behavioural performance in laboratory rats, we will determine whether ACC activity precedes and predicts high-effort choice behaviour, and moreover whether an underlying difference in ACC properties separates ‘low-effort’ from ‘high-effort’ individuals. Together these experiments will delineate specific neural level mechanisms that contribute towards the ambitious mindset.
Do tobacco companies’ claims that smokers' make 'informed' decisions to smoke match young adults' experiences, or is 'informed choice' an oxymoron that inhibits tobacco control?
We will test ‘informed choice’ arguments by implementing a new theoretical framework to explore the circumstances of smoking onset among young adults, the group with the highest smoking prevalence. In-depth interviews will explore general, specific, actual, personal and cumulative risk understanding and how risk understanding, optimism bias, and regret evolve as smoking duration increases. A quantitative phase will use the same theoretical framework to develop measures that estimate risk awareness, knowledge, understanding, and regret.
The final phase will use data from the earlier studies to develop interventions that address factors in participants’ environments impeding ‘informed choice’. We propose undertaking in-depth interviews with policy makers, service providers and commentators to test the feasibility, and likely acceptance and impact of these interventions, and will conduct focus groups with smokers to evaluate their views and likely responses. The findings will provide the first insights into how those at greatest risk understand the 'informed choice' they are assumed to make. They will also suggest how the discrepancies between young adults’ risk understanding, environment and behaviour might be ameliorated.
Professor Hoek and Edwards’ project falls under the umbrella of ASPIRE 2025, a national research collaboration launched earlier this year. ASPIRE 2025 is a partnership between major New Zealand research groups carrying out research to help achieve a tobacco-free Aotearoa by 2025.
Animal domestication was one of the most significant revolutions in human history. Cattle are one of the most important domestic animals, holding tremendous economic, social and cultural value worldwide. Their domestication fuelled significant human population expansions across much of the Old World. The processes of cattle domestication, which began around 10,000 years ago, however, remains obscure. Few of the traits valued in domesticated cattle, such as meat and milk quality, and hide colour preserve in the archaeological record.
Consequently, we understand little about how or when these traits were selected. In fact, we do not even know how many times, or in how many places, domestication occurred. Several genetic markers associated with milk production, coat colour and body fat composition have been identified in studies of modern cattle.
Using recently developed, state of the art DNA sequencing technology we can now obtain DNA from ancient archaeological cattle remains, sequence these gene regions, and observe when and where these genetic traits appeared; thus uncovering the process of domestication through time and across space. In doing so, we can finally understand how, when and where humans began manipulating wild species to “invent” the cattle we know and value so greatly today.
A newly fertilised embryo contains rapidly dividing stem cells with the capacity of developing into all tissues of the body. One of life's biggest mysteries is the process by which these cells decide their fate. It has recently been noted that Cohesin proteins, well known for roles in chromosome stability and in controlling developmental gene expression, also regulate genes that maintain stem cell identity. Therefore, we hypothesise that Cohesin forms a key link between stem cell identity and differentiation.
This project aims to uncover novel Cohesin-dependent mechanisms of cell fate using zebrafish embryos, an ideal model for embryology. Cohesin directly binds genes to control their expression, so we will first identify genes that are cohesin-bound before and after cell fate commitment. Next, we will determine if Cohesin controls expression of fate determination genes, by measuring their levels during cell differentiation, and by examining whether altering Cohesin changes their expression. Finally, as a model for interpreting findings made above, we will investigate how Cohesin controls tissue-specific expression of Runx1, a key developmental gene important for blood stem cell development. Together, these goals will greatly enhance our understanding of how cells of the embryo determine their fate.
Females of many species choose to mate with old males rather than young males, presumably because they have proven survival ability that benefits offspring and female fitness. Paradoxically, sperm production and sperm quality decline with male age; thus females choosing old mates may suffer reduced pregnancy rates, and increased birth defects in offspring, lowering fitness. This apparent paradox has generated much interest, but whether this paradox actually emerges remains equivocal and contentious.
Theory predicts that mechanisms will evolve enabling males to provide honest signals of their quality and that allow females to select the best mates from those available. However, past studies have found mixed support for this prediction, have invariably been observational and have failed to control for mating history, female age and other factors.
Using a series of innovative, well-controlled, experiments in zebrafish we will determine how aging and mating history affect sperm function and female preference, thus whether old males are still good males and if females can tell the difference. Improved knowledge of how fertility alters with age and other life-history factors, and the mechanisms responsible may have important consequences for conservation efforts, breeding programs for agriculture and aquaculture, and treatment of infertility in humans.
Genes are controlled not only by signals contained within the sequence of bases that form DNA, but also by the physical, three dimensional structures that the DNA molecule can adopt. We have evidence which suggests that a novel mechanism of regulation may operate at a gene called MEST, that is involved in mammalian development and behaviour. MEST displays genomic imprinting, whereby the copy of the gene inherited from the mother is permanently switched off and marked by chemical modification (methylation). In purified DNA, this maternal imprinted form of MEST appears to block the activity of enzymes that normally copy DNA.
Our hypothesis is that within the cell methylation of the imprinted MEST copy stabilises unusual DNA structures called G-quadruplexes, that then prevent access by DNA binding proteins and enzymes important for normal biological functions. We will test our hypothesis by in vitro structural studies and in vivo gene expression analyses, and we will explore how commonly such structures occur in the genome. Exploring this phenomenon will extend our understanding of mammalian gene regulation and genomic imprinting, processes of vital importance to normal development and disease.
We propose to build a novel collider to perform high precision atomic physics measurements. Like the high-energy colliders used in particle physics, our apparatus will smash together bunches of atoms and analyze the spatial distribution of the scattered debris. However, our collider will operate in a regime of extreme contrast: it will use samples of atoms at nano-Kelvin temperatures accelerated to pedestrian velocities of up to a meter per second. The full execution of this collider utilizes a unique collaboration with theorists who have developed state-of-the-art calculations to extract key information from the experimental scattering patterns.
The detailed understanding of how atoms interact at ultra-cold temperatures, and how magnetic fields can be used to manipulate these interactions and reversibly associate atoms into molecules, has been at the heart of cutting edge atomic physics and was central to the work awarded the 1997 and 2001 Physics Nobel Prizes. Our work will yield a better understanding of these interactions, which is of crucial importance for a wide range of applications, including the production of ultra-cold molecules, improving atomic clocks, and performing quantum simulations.
The origins and history of the New Zealand terrestrial biota are complex, controversial and poorly understood. During the Miocene (23-10 Ma) large environmental and biotic changes shaped the ancestors of plants and animals we have today, but little is known about what occurred and its impact on the flora and fauna.
We propose to investigate globally significant maar lake, oil shale lake, swamp and river deposits that hold a cornucopia of exquisitely well-preserved Miocene fossils. Flowers with in situ pollen, fruits, seeds, mummified leaves with cuticle, amber inclusions of soft-bodied organisms, insects, spiders, fish and microscopic algae will be identified and analysed to determine phylogenetic and biogeographic relations. Data from sediment and leaf features will enable us to determine environments and climate. These fossils provide a remarkably comprehensive window into the world from which the distinctive modern-day biota originated. We will be able to reconstruct entire Miocene ecosystems and integrate fossil evidence with phylogenetic analysis of the modern flora and fauna.
This research will settle controversial issues around local evolution versus immigration (by long-distance dispersal), and the part played by extinction to provide a new understanding of how Miocene events created the modern biota of New Zealand.
Inorganic nanoparticles with diameters < 100 nm have attracted much recent attention because of the fact that their size, shape and composition can dramatically affect their physical and chemical properties. The possibility of tuning the properties of nanoparticles by simply changing their size and shape is of great importance for technological applications; thus, shape-dependent studies to tune the optical, electronic and catalytic properties of nanoparticles have been an important research focus. Magnetic nanoparticles form an important class of inorganic nanoparticles, and their unique magnetic properties are also size- and shape-dependent. This allows them to be useful in applications beyond technological applications. In particular, they have significant potential for biomedical applications, particularly as magnetic resonance imaging (MRI) contrast agents.
To realise their full potential for this application, however, it is necessary to first understand the effect of shape on the magnetic resonance properties of magnetic nanoparticle dispersions, an understanding which does not currently exist within the scientific community. This project aims to prepare magnetic nanoparticles with well-defined shapes (e.g. cubes, rods, spheres), and use specialised techniques to investigate their magnetic resonance properties in suspension.
Our results will aid in the development of new and improved magnetic materials for use in biomedicine.
Air-sea CO2 flux in the Southern Ocean is controlled by the strength and latitudinal position of the Southern Hemisphere westerly winds. Today, southward-shifting and intensifying winds are thought to reduce the efficiency of the Southern Ocean carbon sink, with direct implications for the rate at which anthropogenic CO2 accumulates in the atmosphere. However, Holocene westerly wind variability is poorly constrained at present, inhibiting our ability to place these modern changes in any long-term context.
We therefore propose to reconstruct past variations in the westerly winds by examining cores obtained from well-positioned lakes and wetlands in southern New Zealand. We have identified a network of sites within the northern margin of the wind field where the precipitation regime is well-coupled to westerly wind intensity. We will apply multiple stable isotope proxy methods to modern water and sediment trap samples, lake sediment cores, and peat cores to evaluate Holocene changes in hydrologic balance, temperature, and lake/vegetation dynamics that are directly attributed to the westerly winds. Comparing our network of sites with high latitude records across the Pacific will identify hemisphere-scale westerly shifts. Results from this research will be used to evaluate current theories on how the westerlies influence the global carbon cycle.
Widely used in disciplines ranging from physics to sociology, network analysis is increasingly employed by ecologists to delve into nature’s complex organization. This method provides a powerful tool to investigate interactions within communities, i.e. existing links between different species such as predation or herbivory, and how these affect the community’s stability and its resilience against change. Treating species as parts of interconnected webs, network analysis can also pinpoint the role of parasites in the structure and function of food webs. We will apply this approach to New Zealand lake ecosystems to determine how an animal’s position in the food web determines its risk of acquiring parasites, how parasites use flows of energy through the web for their transmission, and how a food web’s architecture might mitigate the impact of parasites.
Our research will uncover general patterns of parasite transmission in New Zealand freshwater ecosystems, and use comparisons with other systems to assess the universality of these patterns.
We will make a fundamental contribution to the understanding of rock deformation and the nucleation of earthquakes by investigating the effect of stress cycling, associated with earthquakes in the Earth’s upper crust, on solid-state flow (creep) below the brittle-ductile transition (BDT).
To achieve this we will conduct creep experiments, using ice and ice-mica/ice-graphite mixtures as rock analogues, to quantify the microstructural and mechanical changes that occur during stress cycling. We will use a new experimental approach that tracks the microstructural evolution throughout a high strain experiment and relates microstructural evolution directly to mechanical changes. We will compare ice microstructures with those of experimentally deformed crustal rocks so that we can use rock microstructures to constrain microstructural and mechanical trajectories and we will apply these tools to the interpretation of naturally deformed rocks in the fossil BDT of the Alpine Fault zone. Microstructures of ice and rock will be quantified from electron backscatter diffraction data.
Finally we will use numerical models to extrapolate microstructural and mechanical changes from laboratory data to time and length-scales relevant to the Alpine Fault zone, so that we can quantify the creep response at and below the BDT to stress cycles associated with great earthquake events.
Dynamical systems are mathematical objects used to model change. The time evolution in a system is often modelled by an action of the real line on the states of the system, and measurable quantities, called observables, are modelled by functions on the state space. In models from physics, it is particularly important to understand a family of stationary states called equilibrium states. There is now a generally accepted mathematical formulation of equilibrium state, which makes sense even when the system is not physical, and which is often interesting from a purely mathematical point of view.
The object of this project is to study the equilibrium states of systems of wide interest arising from different areas of mathematics, including number theory, graph theory, combinatorics and algebra. The main techniques will be those of functional analysis: the observables of the system will be realised as transformation on infinite-dimensional vector spaces and the states built from vectors. This project will provide good opportunities for research training because the general approach will be informed by detailed study of key examples.
The oceans provide half of Earth’s primary production. This photosynthetic fixation of carbon by microscopic plants (phytoplankton) is controlled by iron-supply over much of the ocean, making the global iron-cycle central to Earth’s functioning. While phytoplankton in remote regions (e.g. the Southern-Ocean) are anaemic, desert dusts are iron-laden. Long-distance atmospheric transport of this dust helps to alleviate oceanic anaemia, boosting productivity.
The immediate dissolution of iron from this dust into the ocean (2%) has been well studied, yet the fate of the remaining dust has been ignored. Does more of it dissolve and enhance primary production? Or does it just sink into the abyss? With dust storms forecast to increase in the future, understanding the destiny of this remaining 98% will improve predictions of the impact of dust-storms on the ocean’s ability to sequester carbon.
Using iron stable-isotopes (iron atoms with different masses), we will trace the different sources and pathways within the oceanic cycling of iron over the long term. Due to their relatively light mass, these iron-isotopes fractionate through a wide range of natural biotic and abiotic processes, providing the discriminatory power needed to resolve the fate of aerosols as they are altered during weeks and months in the upper ocean.
Since the Helsinki Agreement on ethical principles for human experimentation, ethics committees (ECs) have grown exponentially. International research on ethics review systems claims researchers are frustrated by the evolution of overly bureaucratic ECs which prioritise the protection of host institutions from litigation rather than the original intention of actually protecting human subjects. However, to date, research has focused primarily on developing universal solutions to these shortcomings which have proved less than useful in local contexts or in relation to indigenous values.
This proposal takes a dramatically different approach: looking for sustainable solutions at the local interface between researchers and their ECs. This project uses innovative methodologies to investigate whether post-research, non-hierarchical conversations between researchers and ECs could render a more nuanced understanding of the problems. This opens up an interesting second line of enquiry: how researchers in Aotearoa/New Zealand engage with ethics processes within Treaty of Waitangi contexts. This is particularly relevant given emerging concerns that Maori values and concerns are not being given equal weight to other values in ethical deliberations. The desired research outcomes are to test the worth of local solutions to the global ethics impasse and to enhance conditions for indigenous research.
Recent research suggests that native species can respond rapidly and dynamically to human impacts. Yellow-eyed penguins, for instance, apparently arrived in New Zealand only recently, replacing a prehistoric penguin species that was wiped out shortly after humans arrived here. Intriguing new data also hint at similar extinction-recolonisation scenarios for New Zealand’s sea-lions and little blue penguins. These rapid 'replacement' events, where offshore populations apparently benefitted from the extinction of their mainland relatives, seem unprecedented in the history of ancient-DNA research. This project will use carbon-dating, and state-of-the-art DNA analysis of prehistoric bones, to shed light on New Zealand’s dramatic biological history.
By conducting a biological 'audit' of prehistoric New Zealand, we will test the new idea that human arrival led to the extinction of a previously unrecognised 'treasure trove' of unique coastal animal species around our coast. The study will also determine how many of our iconic coastal species are actually new arrivals from overseas.