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  • 2013-2022
  • UK Research and Innovation
  • OA Publications Mandate: No
  • 2013
  • 2016

10
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  • Funder: UKRI Project Code: ST/L000342/1
    Funder Contribution: 37,099 GBP

    The ET-R&D project is aimed at essential R&D tasks in preparation for a technical design of the Einstein Telescope, a 3rd generation, underground gravitational wave detector. While the basic design mostly relies on techniques well developed and tested for the advanced detectors, several aspects still require R&D with long lead times. We propose to target the most important of these topics in this ET-R&D project via 5 working groups (WGs). WG1 will explore how well astrophysical source models and GR itself can be tested with ET, and how much information on the dynamics of the universe can be extracted from the data. WG2 will collect long term seismic data for various candidate sites and develop methods for measuring the seismic motion which directly couples to the test mass motion, with the goal of developing subtraction techniques. WG3 will investigate properties of cryogenic optics essential for lowering detector thermal noise and providing good low frequency performance. The control of various interferometer degrees of freedom and noise correlations in the data of the three different ET detectors will be studied in WG4. WG5 will focus on overall project management.

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  • Funder: UKRI Project Code: MR/K011480/1
    Funder Contribution: 394,933 GBP

    Endometriosis is a common women's health problem characterised by the presence of deposits resembling endometrium (lining of the uterus) on ectopic sites in the pelvis, causing chronic inflammation, severe pelvic pain and reduced fertility. Family studies indicate that the disease can be inherited. In a recent study comparing genetic information from 5,675 women with endometriosis and 9,331 controls, we found a genetic variant on chromosome 7 associated with moderate-severe endometriosis. In an independent study involving 190,803 individuals, the same genetic region was found to be associated with fat distribution (waist-hip ratio). The signal is located between genes, and it is unclear how the variant - or those in its vicinity - act on transcription of DNA and ultimately on the development of endometriosis or differences in fat distribution. We are collecting endometriotic tissue, endometrium, subcutaneous abdominal fat and blood from women undergoing a laparoscopy for symptoms of endometriosis, or for tubal sterilisation. Using these samples, we will investigate whether DNA transcription in the region of interest is different between women with moderate-severe endometriosis and controls, and between tissues. We will also explore all known genetic variants in the region, and investigate how these affect transcription levels. Implicated variants will be investigated for association with endometriosis risk, and waist-hip ratio, in up to 10,936 women. The proposed work will provide crucial information on gene regulation in the implicated region and its effect on clinical phenotypes, information required for the translation of the genome-wide association findings into clinical meaningful results that can inform the development of new (non-invasive) diagnostic methods and identification of novel drug targets.

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  • Funder: UKRI Project Code: EP/K023349/1
    Funder Contribution: 1,780,200 GBP

    This proposal brings together a critical mass of scientists from the Universities of Cardiff, Lancaster, Liverpool and Manchester and clinicians from the Christie, Lancaster and Liverpool NHS Hospital Trusts with the complementary experience and expertise to advance the understanding, diagnosis and treatment of cervical, oesophageal and prostate cancers. Cervical and prostate cancer are very common and the incidence of oesophageal is rising rapidly. There are cytology, biopsy and endoscopy techniques for extracting tissue from individuals who are at risk of developing these diseases. However the analysis of tissue by the standard techniques is problematic and subjective. There is clearly a national and international need to develop more accurate diagnostics for these diseases and that is a primary aim of this proposal. Experiments will be conducted on specimens from all three diseases using four different infrared based techniques which have complementary strengths and weaknesses: hyperspectral imaging, Raman spectroscopy, a new instrument to be developed by combining atomic force microscopy with infrared spectroscopy and a scanning near field microscope recently installed on the free electron laser on the ALICE accelerator at Daresbury. The latter instrument has recently been shown to have considerable potential for the study of oesophageal cancer yielding images which show the chemical composition with unprecedented spatial resolution (0.1 microns) while hyperspectral imaging and Raman spectroscopy have been shown by members of the team to provide high resolution spectra that provide insight into the nature of cervical and prostate cancers. The new instrument will be installed on the free electron laser at Daresbury and will yield images on the nanoscale. This combination of techniques will allow the team to probe the physical and chemical structure of these three cancers with unprecedented accuracy and this should reveal important information about their character and the chemical processes that underlie their malignant behavior. The results of the research will be of interest to the study of cancer generally particularly if it reveals feature common to all three cancers. The infrared techniques have considerable medical potential and to differing extents are on the verge of finding practical applications. Newer terahertz techniques also have significant potential in this field and may be cheaper to implement. Unfortunately the development of cheap portable terahertz diagnositic instruments is being impeded by the weakness of existing sources of terahertz radiation. By exploiting the terahertz radiation from the ALICE accelerator, which is seven orders of magnitude more intense that conventional sources, the team will advance the design of two different terahertz instruments and assess their performance against the more developed infrared techniques in cancer diagnosis. However before any of these techniques can be used by medical professionals it is essential that their strengths and limitations of are fully understood. This is one of the objectives of the proposal and it will be realised by comparing the results of each technique in studies of specimens from the three cancers that are the primary focus of the research. This will be accompanied by developing data basis and algorithms for the automated analysis of spectral and imaging data thus removing subjectivity from the diagnostic procedure. Finally the team will explore a new approach to monitoring the interactions between pathogens, pharmaceuticals and relevant cells or tissues at the cellular and subcellular level using the instruments deployed on the free electron laser at Daresbury together with Raman microscopy. If this is successful, it will be important in the longer term in developing new treatments for cancer and other diseases.

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  • Funder: UKRI Project Code: NE/J024481/1
    Funder Contribution: 372,389 GBP

    We will examine the genetic basis of sex ratio behaviour in the parasitoid wasp Nasonia vitripennis. Female N. vitripennis facultatively change their offspring sex ratios in line with Hamilton's theory of Local Mate Competition (LMC). LMC arises from competition between related males (e.g. brothers) for mates, and can occur when mating occurs in localised groups, for instance amongst groups of kin. When LMC is intense (e.g. if all males are brothers), the optimal sex ratio is a female-biased one. This bias reduces competition amongst sons and increases the number of mates for those sons. As LMC declines, so does the predicted sex ratio bias. The degree of LMC depends on how many females lay eggs on a patch of hosts (and how many eggs they lay). Over the last decade, we have explored the cues female Nasonia use when allocating sex under LMC. With a robust theoretical framework, we now have a remarkably good understanding of facultative sex allocation under LMC at the phenotypic level in Nasonia. However, our understanding of the genetics of sex ratio is more rudimentary, especially in terms of the mechanism of sex allocation. Thus far, we have some picture of the quantitative genetics of sex ratio in Nasonia (estimates of heritability, input of new mutations, and the identification of four Quantitative Trait Loci, or QTL). We have also begun to explore what genes are expressed during oviposition. In this proposal, we will build on this work to explore the genetic basis of sex ratio variation and control in Nasonia, using three complementary approaches. First, we will first follow-up our recent QTL study using a Restriction Site Associated DNA sequencing ("RAD-seq") approach and a repeat of the cross between High and Low sex ratio lines drawn from the same natural population. RAD-seq can generate thousands of markers across a genome enabling finer-scale QTL mapping projects. We will also use the data we generate to test for clutch size variation QTL, testing for loci pleiotropically influencing both sex ratio and clutch size. Second, we will follow-up our recent gene expression work to explore changes in gene expression associated with exposure to different LMC environments and different combinations of LMC cues. Back in 2004, Shuker & West experimentally showed that female Nasonia vitripennis responded differentially to "host" versus "social" LMC cues. We will follow a similar protocol, assaying the transcriptomes of the focal females using RNA-seq on the Illumina platform. Our aim is to see whether we can link patterns of gene expression to subtle environmental differences which we know have a big effect on the sex ratio phenotype. Third, we will test whether or not epigenetic modifications of DNA (specifically DNA methylation) are associated with the regulation of sex ratio behaviour. The extent to which epigenetic control of gene expression influences behaviour is currently the focus of much interest, both in humans and other vertebrates, but also increasingly in insects. First, we will look for patterns of differential methylation associated with either mating (as females switch from mate-searching to host-searching) and/or interactions with LMC cues whilst ovipositing. Second, we will disrupt DNA methylation and look for changes in sex allocation. If DNA methylation helps regulate gene networks associated with sex ratio behaviour, then we will see patterns of differential methylation across the treatments in the first experiment and changes in sex allocation across the treatments in the second. Taken together, these approaches will address both the genetic architecture of sex ratio variation and also the genes and gene pathways associated with sex allocation, and whether or not the regulation of those pathways involves DNA methylation. They will provide complementary sets of candidate genes, enabling the functional genomic/molecular evolution studies required to fully realise the genotype-phenotype link.

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  • Funder: UKRI Project Code: BB/K01109X/1
    Funder Contribution: 179,781 GBP

    This project will build on the successes of our two projects in phase 1 of the Bioprocessing Research Industry Club (BRIC1) to develop a system for the growth-associated production of commercially important protein products in a commercially-important production organism - the yeast Pichia pastoris. Proteins, particularly antibodies, are now playing a major role in the treatment of human disease. They are usually produced using animal cells in culture, a procedure that is both costly and time-consuming. An attractive alternative is to engineer a yeast cell to produce human proteins of therapeutic value. Pichia pastoris is often used for this purpose since it may be grown at high cell densities and has an efficient secretion system to release the protein product from the cells. Current processes induce protein production by repeatedly adding methanol to the yeast cultures. Our studies in BRIC1 demonstrated that this is exactly the wrong way to go about this since the cells are repeatedly stressed and produced badly folded proteins that have low biological activity and are not secreted out of the cells. What is required is a continuous process for protein production and recovery and this is what our BRIC2 project aims to achieve. The product proteins to be studied will be guided by our contacts within the BRIC member companies and include a number of proteins used in human therapies. Growth-associated production will enable continuous processes and thus increase commercial productivity. Computer models developed in BRIC1 will be improved, extended, and used to control the novel process. Moreover, the fast protein separation methods that we also developed in BRIC1, will permit the continuous retrieval of product, thus obviating the major barrier to the commercial adoption of continuous systems - the mismatch between continuous production and batchwise downstream processing.

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  • Funder: UKRI Project Code: ES/J019402/1
    Funder Contribution: 393,777 GBP

    The research will examine the contribution of labour law reform to poverty alleviation in low and middle-income countries. Since the early 1990s, the World Bank and other international financial institutions have argued that labour laws in developing countries should be made more flexible, with a view to promoting a more 'business friendly' environment in those countries. In some cases, deregulatory labour law reforms have been inititated as a condition of countries receiving financial aid from the World Bank. Recent research suggests that the World Bank's approach understates the role that protective labour laws can play in stimulating economic growth by encouraging investment in human capital and technological upgrading by firms. In addition, labour law institutions such as collective bargaining and social insurance can play a direct role in addressing poverty by redistributing wealth and protecting the least well off in society against workplace hazards and social risks associated with unemployment, sickness and old age. At the same time, this emerging body of evidence suggests that, in order to be effective, labour law rules must be appropriate for developing country contexts. Labour laws which are transplanted from industrialised countries may be inappropriate for emerging and developing labour markets in which only a small part of the labour force has access to regular, waged employment, or where private sector enterprises have limited capacity to comply with labour standards or to adapt to regulatory requirements by increasing their investment in new skills and technologies. Labour laws which do not bed down in a given environment may have the counter-productive effect of increasing informality and casualisation of employment. Thus it is important to have an understanding of the preconditions for the effectiveness of labour laws in practice in developing and emerging markets. The present project proposes to develop a new analytical framework for studying the nature of the 'fit' between labour law institutions and the economic and political context of low and middle income countries. The research will take the form of a series of case studies, based on paired comparisons of countries at roughly equivalent stages of development, but with different institutional, economic and political characteristics: Burkina Faso and Cambodia (which have different experiences of the role of financial conditionality in labour law reform); Chile and South Africa (where the political cycle has taken different forms in the recent past); and India and China (which offer contrasting cases of relative stasis in labour law versus recent reform of labour law institutions, taking place, in both cases, alongside rapid economic growth). The experiences of these countries will be studied using a mix of quantitative and qualitative research techniques, which will allow for a more systematic assessment of the nature of the labour law reform process in the different contexts being studied. The end result of the project will be an analytical template for the evaluation of labour law rules which can be used more widely to assess their contribution to poverty alleviation in low and middle income countries. The template will be developed by the research team in collaboration with officials from the ILO and with the active involvement of users of the research in government, the social partners, global NGOs, and civil society organisations in the case study countries. The project will also make a fundamental contribution to understanding the role that formal, quantitative measures and more qualitative indicators of law and development can play in evaluating policy and reform initiatives in relation to poverty alleviation.

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  • Funder: UKRI Project Code: EP/J010790/1
    Funder Contribution: 613,852 GBP

    String theory is believed to be a theory capable of describing all the known forces of nature, and provides a solution to the venerable problem of finding a theory of gravity consistent with quantum mechanics. To a first approximation, the world we observe corresponds to a vacuum of this theory. String theory admits many of these vacuum states and the class that is most likely to describe the observed world are the so-called `heterotic vacua'. Analysing these vacua requires the application of sophisticated tools drawn from mathematics, particularly from algebraic geometry. If history is any guide, the synthesis of these mathematical tools with observations drawn from physics will lead not only to significant progress in physics, but also important advances in mathematics. An example of such a major insight in mathematics, that arose from string theory, is mirror symmetry. This is the observation that within in a restricted class of string vacua, these arise in `mirror pairs'. This has the consequence that certain mathematical quantities, which are both important and otherwise mysterious, can be calculated in a straightforward manner. The class of heterotic vacua, of interest here, are a wider class of vacua, and an important question is to what extent mirror symmetry generalises and how it acts on this wider class. In a more precise description, the space of heterotic vacua is the parameter space of pairs (X,V) where X is a Calabi-Yau manifold and V is a stable holomorphic vector bundle on X. This space is a major object of study in algebra and geometry. String theory tells us that it is subject to quantum corrections. To understand the nature of these corrections is the key research problem in this proposal and any advance in our understanding will have a important impact in both mathematics and physics. By now it is widely understood that string theory and geometry are intimately related with much to be learned from each other, yet this relationship is relatively unexplored in the heterotic string. This fact, together with recent developments that indicate that longstanding problems have recently become tractable, means that the time is right to revisit the geometry of heterotic vacua.

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  • Funder: UKRI Project Code: ST/K502467/1
    Funder Contribution: 69,046 GBP

    Doctoral Training Partnerships: a range of postgraduate training is funded by the Research Councils. For information on current funding routes, see the common terminology at https://www.ukri.org/apply-for-funding/how-we-fund-studentships/. Training grants may be to one organisation or to a consortia of research organisations. This portal will show the lead organisation only.

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  • Funder: UKRI Project Code: MR/K00042X/1
    Funder Contribution: 362,813 GBP

    Tuberculosis is a global health problem, further compounded due to the rise of multi-drug resistance. The causative bacterium, Mycobacterium tuberculosis has a waxy, protective cell wall which is rich in lipids. One such 'building block' of the cell wall is a group of fatty acids termed mycolic acids. While we know how mycolic acids are made, not much is known about how they are transported to the outside of the cell. This study aims to decipher mycolic acid transport processes by using an array of molecular tools that will identify genes responsible for mycolic acid transport. As mycolic acids are essential for the survival of M. tuberculosis, genes identified in this study have potential to be targeted for drug development. Additionally, as mycolic acids are also required for virulence, these studies will, indirectly, also have implications for our understanding of how M. tuberculosis causes disease.

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  • Funder: UKRI Project Code: MC_PC_13044
    Funder Contribution: 1,720,920 GBP

    The aim of this study to maximise the value of the brain tissue samples available to the research community in the four MRC-funded brain banks by the systematic analysis and integration of data from genomic studies on cases currently available for research in the banks. . All MRC brain banks have ethics approval to function as tissue banks and to collect, store and release tissue samples and data from consented donors. Consent/authorisation for genetic research is recorded and will be used to identify cases for inclusion in this study. Governance mechanisms include local NHS governance, Human Tissue Authority licences and Healthcare Improvement Scotland accreditation, along with MRC policies on research governance. This study will involve the investigation of normal brains from a wide age range and brains from well-characterised disease cohorts in the MRC brain banks. We aim to genetically characterise 1500 representative brains with Alzheimer disease, dementia with Lewy bodies /Parkinson disease, vascular dementia, frontotemporal dementia/motor neurone disease, Creutzfeldt-Jakob disease and controls. The data generated will greatly enrich the clinical and neuropathological data currently associated with these samples. This work will therefore provide major added value to the exiting brain banks, opening up totally new opportunities for mechanistic and translational research in neurodegeneration and brain aging.

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1,477 Projects
  • Funder: UKRI Project Code: ST/L000342/1
    Funder Contribution: 37,099 GBP

    The ET-R&D project is aimed at essential R&D tasks in preparation for a technical design of the Einstein Telescope, a 3rd generation, underground gravitational wave detector. While the basic design mostly relies on techniques well developed and tested for the advanced detectors, several aspects still require R&D with long lead times. We propose to target the most important of these topics in this ET-R&D project via 5 working groups (WGs). WG1 will explore how well astrophysical source models and GR itself can be tested with ET, and how much information on the dynamics of the universe can be extracted from the data. WG2 will collect long term seismic data for various candidate sites and develop methods for measuring the seismic motion which directly couples to the test mass motion, with the goal of developing subtraction techniques. WG3 will investigate properties of cryogenic optics essential for lowering detector thermal noise and providing good low frequency performance. The control of various interferometer degrees of freedom and noise correlations in the data of the three different ET detectors will be studied in WG4. WG5 will focus on overall project management.

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  • Funder: UKRI Project Code: MR/K011480/1
    Funder Contribution: 394,933 GBP

    Endometriosis is a common women's health problem characterised by the presence of deposits resembling endometrium (lining of the uterus) on ectopic sites in the pelvis, causing chronic inflammation, severe pelvic pain and reduced fertility. Family studies indicate that the disease can be inherited. In a recent study comparing genetic information from 5,675 women with endometriosis and 9,331 controls, we found a genetic variant on chromosome 7 associated with moderate-severe endometriosis. In an independent study involving 190,803 individuals, the same genetic region was found to be associated with fat distribution (waist-hip ratio). The signal is located between genes, and it is unclear how the variant - or those in its vicinity - act on transcription of DNA and ultimately on the development of endometriosis or differences in fat distribution. We are collecting endometriotic tissue, endometrium, subcutaneous abdominal fat and blood from women undergoing a laparoscopy for symptoms of endometriosis, or for tubal sterilisation. Using these samples, we will investigate whether DNA transcription in the region of interest is different between women with moderate-severe endometriosis and controls, and between tissues. We will also explore all known genetic variants in the region, and investigate how these affect transcription levels. Implicated variants will be investigated for association with endometriosis risk, and waist-hip ratio, in up to 10,936 women. The proposed work will provide crucial information on gene regulation in the implicated region and its effect on clinical phenotypes, information required for the translation of the genome-wide association findings into clinical meaningful results that can inform the development of new (non-invasive) diagnostic methods and identification of novel drug targets.

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  • Funder: UKRI Project Code: EP/K023349/1
    Funder Contribution: 1,780,200 GBP

    This proposal brings together a critical mass of scientists from the Universities of Cardiff, Lancaster, Liverpool and Manchester and clinicians from the Christie, Lancaster and Liverpool NHS Hospital Trusts with the complementary experience and expertise to advance the understanding, diagnosis and treatment of cervical, oesophageal and prostate cancers. Cervical and prostate cancer are very common and the incidence of oesophageal is rising rapidly. There are cytology, biopsy and endoscopy techniques for extracting tissue from individuals who are at risk of developing these diseases. However the analysis of tissue by the standard techniques is problematic and subjective. There is clearly a national and international need to develop more accurate diagnostics for these diseases and that is a primary aim of this proposal. Experiments will be conducted on specimens from all three diseases using four different infrared based techniques which have complementary strengths and weaknesses: hyperspectral imaging, Raman spectroscopy, a new instrument to be developed by combining atomic force microscopy with infrared spectroscopy and a scanning near field microscope recently installed on the free electron laser on the ALICE accelerator at Daresbury. The latter instrument has recently been shown to have considerable potential for the study of oesophageal cancer yielding images which show the chemical composition with unprecedented spatial resolution (0.1 microns) while hyperspectral imaging and Raman spectroscopy have been shown by members of the team to provide high resolution spectra that provide insight into the nature of cervical and prostate cancers. The new instrument will be installed on the free electron laser at Daresbury and will yield images on the nanoscale. This combination of techniques will allow the team to probe the physical and chemical structure of these three cancers with unprecedented accuracy and this should reveal important information about their character and the chemical processes that underlie their malignant behavior. The results of the research will be of interest to the study of cancer generally particularly if it reveals feature common to all three cancers. The infrared techniques have considerable medical potential and to differing extents are on the verge of finding practical applications. Newer terahertz techniques also have significant potential in this field and may be cheaper to implement. Unfortunately the development of cheap portable terahertz diagnositic instruments is being impeded by the weakness of existing sources of terahertz radiation. By exploiting the terahertz radiation from the ALICE accelerator, which is seven orders of magnitude more intense that conventional sources, the team will advance the design of two different terahertz instruments and assess their performance against the more developed infrared techniques in cancer diagnosis. However before any of these techniques can be used by medical professionals it is essential that their strengths and limitations of are fully understood. This is one of the objectives of the proposal and it will be realised by comparing the results of each technique in studies of specimens from the three cancers that are the primary focus of the research. This will be accompanied by developing data basis and algorithms for the automated analysis of spectral and imaging data thus removing subjectivity from the diagnostic procedure. Finally the team will explore a new approach to monitoring the interactions between pathogens, pharmaceuticals and relevant cells or tissues at the cellular and subcellular level using the instruments deployed on the free electron laser at Daresbury together with Raman microscopy. If this is successful, it will be important in the longer term in developing new treatments for cancer and other diseases.

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  • Funder: UKRI Project Code: NE/J024481/1
    Funder Contribution: 372,389 GBP

    We will examine the genetic basis of sex ratio behaviour in the parasitoid wasp Nasonia vitripennis. Female N. vitripennis facultatively change their offspring sex ratios in line with Hamilton's theory of Local Mate Competition (LMC). LMC arises from competition between related males (e.g. brothers) for mates, and can occur when mating occurs in localised groups, for instance amongst groups of kin. When LMC is intense (e.g. if all males are brothers), the optimal sex ratio is a female-biased one. This bias reduces competition amongst sons and increases the number of mates for those sons. As LMC declines, so does the predicted sex ratio bias. The degree of LMC depends on how many females lay eggs on a patch of hosts (and how many eggs they lay). Over the last decade, we have explored the cues female Nasonia use when allocating sex under LMC. With a robust theoretical framework, we now have a remarkably good understanding of facultative sex allocation under LMC at the phenotypic level in Nasonia. However, our understanding of the genetics of sex ratio is more rudimentary, especially in terms of the mechanism of sex allocation. Thus far, we have some picture of the quantitative genetics of sex ratio in Nasonia (estimates of heritability, input of new mutations, and the identification of four Quantitative Trait Loci, or QTL). We have also begun to explore what genes are expressed during oviposition. In this proposal, we will build on this work to explore the genetic basis of sex ratio variation and control in Nasonia, using three complementary approaches. First, we will first follow-up our recent QTL study using a Restriction Site Associated DNA sequencing ("RAD-seq") approach and a repeat of the cross between High and Low sex ratio lines drawn from the same natural population. RAD-seq can generate thousands of markers across a genome enabling finer-scale QTL mapping projects. We will also use the data we generate to test for clutch size variation QTL, testing for loci pleiotropically influencing both sex ratio and clutch size. Second, we will follow-up our recent gene expression work to explore changes in gene expression associated with exposure to different LMC environments and different combinations of LMC cues. Back in 2004, Shuker & West experimentally showed that female Nasonia vitripennis responded differentially to "host" versus "social" LMC cues. We will follow a similar protocol, assaying the transcriptomes of the focal females using RNA-seq on the Illumina platform. Our aim is to see whether we can link patterns of gene expression to subtle environmental differences which we know have a big effect on the sex ratio phenotype. Third, we will test whether or not epigenetic modifications of DNA (specifically DNA methylation) are associated with the regulation of sex ratio behaviour. The extent to which epigenetic control of gene expression influences behaviour is currently the focus of much interest, both in humans and other vertebrates, but also increasingly in insects. First, we will look for patterns of differential methylation associated with either mating (as females switch from mate-searching to host-searching) and/or interactions with LMC cues whilst ovipositing. Second, we will disrupt DNA methylation and look for changes in sex allocation. If DNA methylation helps regulate gene networks associated with sex ratio behaviour, then we will see patterns of differential methylation across the treatments in the first experiment and changes in sex allocation across the treatments in the second. Taken together, these approaches will address both the genetic architecture of sex ratio variation and also the genes and gene pathways associated with sex allocation, and whether or not the regulation of those pathways involves DNA methylation. They will provide complementary sets of candidate genes, enabling the functional genomic/molecular evolution studies required to fully realise the genotype-phenotype link.

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  • Funder: UKRI Project Code: BB/K01109X/1
    Funder Contribution: 179,781 GBP

    This project will build on the successes of our two projects in phase 1 of the Bioprocessing Research Industry Club (BRIC1) to develop a system for the growth-associated production of commercially important protein products in a commercially-important production organism - the yeast Pichia pastoris. Proteins, particularly antibodies, are now playing a major role in the treatment of human disease. They are usually produced using animal cells in culture, a procedure that is both costly and time-consuming. An attractive alternative is to engineer a yeast cell to produce human proteins of therapeutic value. Pichia pastoris is often used for this purpose since it may be grown at high cell densities and has an efficient secretion system to release the protein product from the cells. Current processes induce protein production by repeatedly adding methanol to the yeast cultures. Our studies in BRIC1 demonstrated that this is exactly the wrong way to go about this since the cells are repeatedly stressed and produced badly folded proteins that have low biological activity and are not secreted out of the cells. What is required is a continuous process for protein production and recovery and this is what our BRIC2 project aims to achieve. The product proteins to be studied will be guided by our contacts within the BRIC member companies and include a number of proteins used in human therapies. Growth-associated production will enable continuous processes and thus increase commercial productivity. Computer models developed in BRIC1 will be improved, extended, and used to control the novel process. Moreover, the fast protein separation methods that we also developed in BRIC1, will permit the continuous retrieval of product, thus obviating the major barrier to the commercial adoption of continuous systems - the mismatch between continuous production and batchwise downstream processing.

    more_vert
  • Funder: UKRI Project Code: ES/J019402/1
    Funder Contribution: 393,777 GBP

    The research will examine the contribution of labour law reform to poverty alleviation in low and middle-income countries. Since the early 1990s, the World Bank and other international financial institutions have argued that labour laws in developing countries should be made more flexible, with a view to promoting a more 'business friendly' environment in those countries. In some cases, deregulatory labour law reforms have been inititated as a condition of countries receiving financial aid from the World Bank. Recent research suggests that the World Bank's approach understates the role that protective labour laws can play in stimulating economic growth by encouraging investment in human capital and technological upgrading by firms. In addition, labour law institutions such as collective bargaining and social insurance can play a direct role in addressing poverty by redistributing wealth and protecting the least well off in society against workplace hazards and social risks associated with unemployment, sickness and old age. At the same time, this emerging body of evidence suggests that, in order to be effective, labour law rules must be appropriate for developing country contexts. Labour laws which are transplanted from industrialised countries may be inappropriate for emerging and developing labour markets in which only a small part of the labour force has access to regular, waged employment, or where private sector enterprises have limited capacity to comply with labour standards or to adapt to regulatory requirements by increasing their investment in new skills and technologies. Labour laws which do not bed down in a given environment may have the counter-productive effect of increasing informality and casualisation of employment. Thus it is important to have an understanding of the preconditions for the effectiveness of labour laws in practice in developing and emerging markets. The present project proposes to develop a new analytical framework for studying the nature of the 'fit' between labour law institutions and the economic and political context of low and middle income countries. The research will take the form of a series of case studies, based on paired comparisons of countries at roughly equivalent stages of development, but with different institutional, economic and political characteristics: Burkina Faso and Cambodia (which have different experiences of the role of financial conditionality in labour law reform); Chile and South Africa (where the political cycle has taken different forms in the recent past); and India and China (which offer contrasting cases of relative stasis in labour law versus recent reform of labour law institutions, taking place, in both cases, alongside rapid economic growth). The experiences of these countries will be studied using a mix of quantitative and qualitative research techniques, which will allow for a more systematic assessment of the nature of the labour law reform process in the different contexts being studied. The end result of the project will be an analytical template for the evaluation of labour law rules which can be used more widely to assess their contribution to poverty alleviation in low and middle income countries. The template will be developed by the research team in collaboration with officials from the ILO and with the active involvement of users of the research in government, the social partners, global NGOs, and civil society organisations in the case study countries. The project will also make a fundamental contribution to understanding the role that formal, quantitative measures and more qualitative indicators of law and development can play in evaluating policy and reform initiatives in relation to poverty alleviation.

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  • Funder: UKRI Project Code: EP/J010790/1
    Funder Contribution: 613,852 GBP

    String theory is believed to be a theory capable of describing all the known forces of nature, and provides a solution to the venerable problem of finding a theory of gravity consistent with quantum mechanics. To a first approximation, the world we observe corresponds to a vacuum of this theory. String theory admits many of these vacuum states and the class that is most likely to describe the observed world are the so-called `heterotic vacua'. Analysing these vacua requires the application of sophisticated tools drawn from mathematics, particularly from algebraic geometry. If history is any guide, the synthesis of these mathematical tools with observations drawn from physics will lead not only to significant progress in physics, but also important advances in mathematics. An example of such a major insight in mathematics, that arose from string theory, is mirror symmetry. This is the observation that within in a restricted class of string vacua, these arise in `mirror pairs'. This has the consequence that certain mathematical quantities, which are both important and otherwise mysterious, can be calculated in a straightforward manner. The class of heterotic vacua, of interest here, are a wider class of vacua, and an important question is to what extent mirror symmetry generalises and how it acts on this wider class. In a more precise description, the space of heterotic vacua is the parameter space of pairs (X,V) where X is a Calabi-Yau manifold and V is a stable holomorphic vector bundle on X. This space is a major object of study in algebra and geometry. String theory tells us that it is subject to quantum corrections. To understand the nature of these corrections is the key research problem in this proposal and any advance in our understanding will have a important impact in both mathematics and physics. By now it is widely understood that string theory and geometry are intimately related with much to be learned from each other, yet this relationship is relatively unexplored in the heterotic string. This fact, together with recent developments that indicate that longstanding problems have recently become tractable, means that the time is right to revisit the geometry of heterotic vacua.

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  • Funder: UKRI Project Code: ST/K502467/1
    Funder Contribution: 69,046 GBP

    Doctoral Training Partnerships: a range of postgraduate training is funded by the Research Councils. For information on current funding routes, see the common terminology at https://www.ukri.org/apply-for-funding/how-we-fund-studentships/. Training grants may be to one organisation or to a consortia of research organisations. This portal will show the lead organisation only.

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  • Funder: UKRI Project Code: MR/K00042X/1
    Funder Contribution: 362,813 GBP

    Tuberculosis is a global health problem, further compounded due to the rise of multi-drug resistance. The causative bacterium, Mycobacterium tuberculosis has a waxy, protective cell wall which is rich in lipids. One such 'building block' of the cell wall is a group of fatty acids termed mycolic acids. While we know how mycolic acids are made, not much is known about how they are transported to the outside of the cell. This study aims to decipher mycolic acid transport processes by using an array of molecular tools that will identify genes responsible for mycolic acid transport. As mycolic acids are essential for the survival of M. tuberculosis, genes identified in this study have potential to be targeted for drug development. Additionally, as mycolic acids are also required for virulence, these studies will, indirectly, also have implications for our understanding of how M. tuberculosis causes disease.

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  • Funder: UKRI Project Code: MC_PC_13044
    Funder Contribution: 1,720,920 GBP

    The aim of this study to maximise the value of the brain tissue samples available to the research community in the four MRC-funded brain banks by the systematic analysis and integration of data from genomic studies on cases currently available for research in the banks. . All MRC brain banks have ethics approval to function as tissue banks and to collect, store and release tissue samples and data from consented donors. Consent/authorisation for genetic research is recorded and will be used to identify cases for inclusion in this study. Governance mechanisms include local NHS governance, Human Tissue Authority licences and Healthcare Improvement Scotland accreditation, along with MRC policies on research governance. This study will involve the investigation of normal brains from a wide age range and brains from well-characterised disease cohorts in the MRC brain banks. We aim to genetically characterise 1500 representative brains with Alzheimer disease, dementia with Lewy bodies /Parkinson disease, vascular dementia, frontotemporal dementia/motor neurone disease, Creutzfeldt-Jakob disease and controls. The data generated will greatly enrich the clinical and neuropathological data currently associated with these samples. This work will therefore provide major added value to the exiting brain banks, opening up totally new opportunities for mechanistic and translational research in neurodegeneration and brain aging.

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