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University of York

Country: United Kingdom

University of York

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2,370 Projects, page 1 of 474
  • Funder: UKRI Project Code: EP/X027724/1
    Funder Contribution: 1,718,020 GBP

    In Nature the production of hydrogen and methane fuel molecules from readily available starting materials such as water and carbon dioxide is achieved selectively, efficiently and rapidly by electrocatalytic redox-metalloenzymes containing non-precious transition metal active sites. The outstanding recent scientific advances made in molecular biology have made the development of biofuel technologies based on these enzymes a reality, but such applications require a complementary toolkit of physical chemistry methods that can dissect how DNA sequence and protein structure relates to function. Classic bio-electrochemistry methods developed in the 1980s have been a powerful way to probe the active site reactivity of such enzymes, but they have been unable to map the electron transfer processes which underpin the catalysis. Therefore, we have been limited to a narrowly active-site focussed view of enzyme mechanism. This project will transform the state of the art in bio-electrochemistry to deliver a powerful new technique that can "see" the electron-transfer processes of the highly evolved and essential electron-transfer reaction centres in redox-enzymes, and deconvolute their role in electrocatalysis. This will be achieved by deploying advanced computational methods to integrate intelligent experimental design into electrochemistry to develop a methodology that lets us separate and accurately model the electron transfer processes of an enzyme bound to substrate, and chemical biology methods to develop linker molecules for light-activated electrografting of proteins and enzymes onto electrodes. We will showcase the power of this new electrochemical enzymology toolkit by conducting previously impossible hypothesis-led investigations and enzyme-discovery projects into i) cellulose-degrading LPMOs that play a crucial role in biorefinery enzyme cocktails and ii) hydrogenases, Ni+Fe or Fe-only metalloenzymes that are as rapid and efficient at hydrogen-catalysis as platinum.

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  • Funder: UKRI Project Code: BB/G024537/1
    Funder Contribution: 112,878 GBP

    The function of many of the large macromolecules that control biological processes can be affected by the binding of small molecules. This is how most medicines work and much of the early stage research in the pharmaceutical industry focuses on identifying and optimising small molecules to be tested as drugs. Over the past ten years, there has also been an increase in what is known as chemical biology research, where the action of such small molecules is used as a tool in fundamental research to understand how biological processes work. However, it is extremely difficult to find a small molecule with exactly the right shape and properties to bind strongly and specifically to a particular macromolecule. One new technique that has been developed recently is the method of fragment-based discovery. Instead of having to find the complete molecule that fits the binding site, this approach begins by identifying smaller pieces of molecule that bind. If the way in which these small fragments can be understood, then the chemist can design changes that merge or grow these fragments into the larger compound with the correct properties.

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  • Funder: UKRI Project Code: 1642919

    Background. Cytoskeletal crosslinkers have been recently placed at the forefront of mechanotransduction. They act as sensors of mechanical strain by triggering a novel inducible autophagy mechanism when they unfold. IGFN1 is a novel muscle-specific protein conserved in mammals and a strong candidate for a mechanotransduction sensor in skeletal muscle. Objectives. The role of IGFN1 will be evaluated by: 1) Generating an Igfn1 loss of function allele in single adult muscles by CRISPR/CAS mediated genome editing. Using a highly efficient electroporation method, loss of function mutations will be generated in hindlimb muscles of adult mice in vivo; 2) Measuring the loss of function effect on muscle structure and function by histology, immunofluorescence and electron microscopy; and 3) Measuring the elastic properties of purified IGFN1 by atomic force microscopy. Cytoskeletal sensors must extend and contract in order to maintain the sarcomeric integrity during muscle contraction and relaxation. The force vs. extension curves obtained will inform about the maximum length of unfolded IGFN1, which can be related to the physical dimensions of the Z-disc, and the domain composition in this crosslinker protein. Novelties. Genome editing of adult muscle in vivo is a novel approach for mechanistic studies. Successful genome editing of EDL muscle will be evaluated at genomic level. If IGFN1 is required for normal physiological activity, elimination of functional alleles in the majority of myonuclei will result in recognizable myopathic changes. These will be assessed at the single fibre level. Timeliness. The scope of chaperone-assisted selective autophagy in muscle mechanotransduction is not established. This mechanism has only been partially elucidated in smooth muscle cells, but not in skeletal or heart muscle. This project will provide mechanistic insights into the role of IGFN1 as a structural stabilizer and client of chaperone-assisted autophagy using state-of-the-art genome editing and single-molecule biophysical tools.

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  • Funder: UKRI Project Code: NE/L007266/1
    Funder Contribution: 133,971 GBP

    What drives the abundance and distribution of animal species in space and time? This central question in ecology and conservation has so far been approached mainly by investigating the impact of predator-prey relationships and competition for limited resources such as food. However, it is becoming increasingly clear that animals may also have substantial effects on each other by acting as critical sources of information, for example when they communicate the presence of a predator or the location of food. The potential importance of information exchange between species is evident from the widespread occurrence of mixed-species groups in nature, in taxa ranging from spiders and fish to birds and mammals. Yet, currently almost nothing is known about how the advantage of living next to valuable informants affects patterns in social attraction between species. Our study addresses this question from an integrated theoretical and empirical angle. We will build a general model to predict how information benefits shape the composition of mixed-species groups in nature. Our model will take into account the key costs and benefits from group life: (i) the information benefits from joining many eyes, ears and noses, (ii) the benefit of being close to others that may be eaten instead of you when predators attack, and (iii) the costs from increased competition over limited resources. To test our model in the real world, we focus on the mixed-species groups of herbivores dominating the African savannas in a field study. The many eyes, ears and noses in these herds are known to result in all-important information benefits when alarm signals are emitted. To determine how patterns in social attraction between species in this system depends on their value as informants, we use predator simulations and playback experiments to determine (i) the information contained in the alarm signals from each species in the community and (ii) to what extent this information is transferred between species. We will also obtain measures of the vulnerability of each herbivore species to the various predators in the community as well as costs from food competition when diets overlap. On this basis, we will be able to use social network analysis to test the role of communication (relative to other costs and benefits) as a driver of group formation between species. The savannah herbivore study will thus allow us to address fundamental questions in biology by (i) revealing which species within the community group together and why, and (ii) establishing the nature of coexistence between species: are multispecies groups mutually beneficial or do they rather form when one species parasitizes on the information produced by another? The project will provide novel insights into the basic links between species in the natural environment by integrating communication benefits into classical food-web-based models of ecosystem structure. By establishing new fundamental principles that shape the social associations between species, the study will bring a deeper understanding of ecosystem dynamics that can be critical for identifying conservation priorities. Our conceptual framework will allow conservationists to assess when declines in key species are likely to have repercussions throughout the ecosystem by affecting the survival of others, and when these indirect effects are likely to become a conservation concern for endangered species.

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  • Funder: UKRI Project Code: 2752057

    Enteroviruses (e.g. Poliovirus, Rhinovirus, Coxsackievirus) comprise a diverse group of human and animal pathogens, which together are estimated to cause over one billion infections annually. Once inside the host cell, their positive-sense, single-stranded RNA genomes are directly translated to produce the viral polyprotein. A key event in the infection cycle is the recruitment of host ribosomes to initiate translation. This occurs via an internal ribosome entry site (IRES) in the 5' untranslated region of the genome. The enterovirus type 1 IRES is ~450 nt in length and organized into five structured domains, which interact with trans-acting protein factors (ITAFs) leading to recruitment of 43S complexes. However, our understanding of this network of interactions has been hampered by the lack of any high-resolution three-dimensional structures. Furthermore, a new gene has recently been discovered in some enteroviruses, located upstream of the main polyprotein (Lulla et al., Nat Microbiol, 2019). This exploits an alternate AUG codon located within domain VI of the IRES itself, but the mechanistic basis for start-site selection is not understood. You will study the structural and mechanistic basis of enterovirus initiation at a variety of model IRESs. This will involve the reconstitution of initiation in vitro, purification of initiation complexes, sample optimization, cryo-EM data collection and processing. You will also study protein RNA-interactions between ITAFs and IRES domains using a variety of biophysical and biochemical tools. You will explore key findings in virus-infected cells, in collaboration with the Lulla lab (University of Cambridge). You will join a vibrant, diverse and highly supportive training environment with the combined expertise of three supervisors - ribosome structural biology and protein-RNA interactions (Hill and Plevin labs) and Enterovirus molecular biology (Lulla lab). You will also benefit from access to state-of the art cryo-EM infrastructure at YSBL, and the molecular interactions laboratory at the Biology Technology Facility. Candidates from under-represented groups are particularly encouraged to apply.

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