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  • Journal article
    Guerrero P, Perez-Carrasco R, 2024,

    Choice of friction coefficient deeply affects tissue behaviour in stochastic epithelial vertex models.

    , Philos Trans R Soc Lond B Biol Sci, Vol: 379

    To understand the mechanisms that coordinate the formation of biological tissues, the use of numerical implementations is necessary. The complexity of such models involves many assumptions and parameter choices that result in unpredictable consequences, obstructing the comparison with experimental data. Here, we focus on vertex models, a family of spatial models used extensively to simulate the dynamics of epithelial tissues. Usually, in the literature, the choice of the friction coefficient is not addressed using quasi-static deformation arguments that generally do not apply to realistic scenarios. In this manuscript, we discuss the role that the choice of friction coefficient has on the relaxation times and consequently in the conditions of cell cycle progression and division. We explore the effects that these changes have on the morphology, growth rate and topological transitions of the tissue dynamics. These results provide a deeper understanding of the role that an accurate mechanical description plays in the use of vertex models as inference tools. This article is part of a discussion meeting issue 'Causes and consequences of stochastic processes in development and disease'.

  • Journal article
    Kabasakal BV, Cotton CAR, Murray JW, 2024,

    Dynamic lid domain of Chloroflexus aurantiacus Malonyl-CoA reductase controls the reaction.

    , Biochimie, Vol: 219, Pages: 12-20, ISSN: 0300-9084

    Malonyl-Coenzyme A Reductase (MCR) in Chloroflexus aurantiacus, a characteristic enzyme of the 3-hydroxypropionate (3-HP) cycle, catalyses the reduction of malonyl-CoA to 3-HP. MCR is a bi-functional enzyme; in the first step, malonyl-CoA is reduced to the free intermediate malonate semialdehyde by the C-terminal region of MCR, and this is further reduced to 3-HP by the N-terminal region of MCR. Here we present the crystal structures of both N-terminal and C-terminal regions of the MCR from C. aurantiacus. A catalytic mechanism is suggested by ligand and substrate bound structures, and structural and kinetic studies of MCR variants. Both MCR structures reveal one catalytic, and one non-catalytic SDR (short chain dehydrogenase/reductase) domain. C-terminal MCR has a lid domain which undergoes a conformational change and controls the reaction. In the proposed mechanism of the C-terminal MCR, the conversion of malonyl-CoA to malonate semialdehyde is based on the reduction of malonyl-CoA by NADPH, followed by the decomposition of the hemithioacetal to produce malonate semialdehyde and coenzyme A. Conserved arginines, Arg734 and Arg773 are proposed to play key roles in the mechanism and conserved Ser719, and Tyr737 are other essential residues forming an oxyanion hole for the substrate intermediates.

  • Journal article
    Mwima R, Hui T-YJ, Kayondo JK, Burt Aet al., 2024,

    The population genetics of partial diapause, with applications to the aestivating malaria mosquito Anopheles coluzzii.

    , Mol Ecol Resour

    Diapause, a form of dormancy to delay or halt the reproductive development during unfavourable seasons, has evolved in many insect species. One example is aestivation, an adult-stage diapause enhancing malaria vectors' survival during the dry season (DS) and their re-establishment in the next rainy season (RS). This work develops a novel genetic approach to estimate the number or proportion of individuals undergoing diapause, as well as the breeding sizes of the two seasons, using signals from temporal allele frequency dynamics. Our modelling shows the magnitude of drift is dampened at early RS when previously aestivating individuals reappear. Aestivation severely biases the temporal effective population size ( N e $$ {N}_e $$ ), leading to overestimation of the DS breeding size by 1 / 1 - α 2 $$ 1/{\left(1-\alpha \right)}^2 $$ across 1 year, where α $$ \alpha $$ is the aestivating proportion. We find sampling breeding individuals in three consecutive seasons starting from an RS is sufficient for parameter estimation, and perform extensive simulations to verify our derivations. This method does not require sampling individuals in the dormant state, the biggest challenge in most studies. We illustrate the method by applying it to a published data set for Anopheles coluzzii mosquitoes from Thierola, Mali. Our method and the expected evolutionary implications are applicable to any species in which a fraction of the population diapauses for more than one generation, and are difficult or impossible to sample during that stage.

  • Journal article
    Perkins R, Barron L, Glauser G, Whitehead M, Woodward G, Goulson Det al., 2024,

    Down-the-drain pathways for fipronil and imidacloprid applied as spot-on parasiticides to dogs: Estimating aquatic pollution.

    , Sci Total Environ, Vol: 917

    Fipronil and imidacloprid have been widely detected in UK surface waters in recent years, often at concentrations that ecotoxicological studies have shown can harm aquatic life. Down-the-drain (DTD) passage of pet flea and tick treatments are being implicated as an important source, with many of the UK's 22 million cats and dogs receiving routine, year-round preventative doses containing these parasiticides. The UK Water Industry's 3rd Chemical Investigation Programme (UKWIR CIP3) has confirmed wastewater as a major entry pathway for these chemicals into surface waters, but the routes by which they enter the wastewater system remain unclear. We addressed this knowledge gap by conducting the first quantification of DTD emissions from 98 dogs treated with spot-on ectoparasiticides containing fipronil or imidacloprid, through bathing, bed washing and washing of owners' hands. Both chemicals were detected in 100 % of washoff samples, with bathing accounting for the largest emissions per event (up to 16.8 % of applied imidacloprid and 24.5 % of applied fipronil). Modelled to account for the frequency of emitting activities, owner handwashing was identified as the largest source of DTD emissions from the population overall, with handwash emissions occurring for at least 28 days following product application and an estimated 4.9 % of imidacloprid and 3.1 % of fipronil applied in dog spot-ons passing down-the-drain via this route. The normalised daily per capita emissions for all routes combined were 8.7 μg/person/day for imidacloprid and 2.1 μg/person/day for fipronil, equivalent to 20-40 % of the daily per capita load in wastewater, as estimated from UKWIR CIP3 data. Within the current international regulatory framework adhered to by the UK, the environmental exposure of veterinary medicines intended for use in small companion animals is assumed to be low, and DTD pathways are not considered. We recommend a systematic rev

  • Journal article
    Reda O, Monde K, Sugata K, Rahman A, Sakhor W, Rajib SA, Sithi SN, Tan BJY, Niimura K, Motozono C, Maeda K, Ono M, Takeuchi H, Satou Yet al., 2024,

    HIV-Tocky system to visualize proviral expression dynamics.

    , Commun Biol, Vol: 7

    Determinants of HIV-1 latency establishment are yet to be elucidated. HIV reservoir comprises a rare fraction of infected cells that can survive host and virus-mediated killing. In vitro reporter models so far offered a feasible means to inspect this population, but with limited capabilities to dissect provirus silencing dynamics. Here, we describe a new HIV reporter model, HIV-Timer of cell kinetics and activity (HIV-Tocky) with dual fluorescence spontaneous shifting to reveal provirus silencing and reactivation dynamics. This unique feature allows, for the first time, identifying two latent populations: a directly latent, and a recently silenced subset, with the latter having integration features suggestive of stable latency. Our proposed model can help address the heterogeneous nature of HIV reservoirs and offers new possibilities for evaluating eradication strategies.

  • Journal article
    Ogwang R, Murugu L, Nailain I, Nyamako L, Kai O, Mwai K, Murungi L, Idro R, Bejon P, Tuju J, Kinyanjui SM, Osier FHAet al., 2024,

    Bi-isotype immunoglobulins enhance antibody-mediated neutrophil activity against Plasmodium falciparum parasites

    , Frontiers in Immunology-Vaccines and Molecular Therapeutics
  • Journal article
    van Haaren C, Byrne B, Kazarian SG, 2024,

    Study of Monoclonal Antibody Aggregation at the Air-Liquid Interface under Flow by ATR-FTIR Spectroscopic Imaging.

    , Langmuir, Vol: 40, Pages: 5858-5868

    Throughout bioprocessing, transportation, and storage, therapeutic monoclonal antibodies (mAbs) experience stress conditions that may cause protein unfolding and/or chemical modifications. Such structural changes may lead to the formation of aggregates, which reduce mAb potency and may cause harmful immunogenic responses in patients. Therefore, aggregates need to be detected and removed or ideally prevented from forming. Air-liquid interfaces, which arise during various stages of bioprocessing, are one of the stress factors causing mAb aggregation. In this study, the behavior of an immunoglobulin G (IgG) at the air-liquid interface was investigated under flow using macro attenuated total reflection Fourier transform infrared (ATR-FTIR) spectroscopic imaging. This chemically specific imaging technique allows observation of adsorption of IgG to the air-liquid interface and detection of associated secondary structural changes. Chemical images revealed that IgG rapidly accumulated around an injected air bubble under flow at 45 °C; however, no such increase was observed at 25 °C. Analysis of the second derivative spectra of IgG at the air-liquid interface revealed changes in the protein secondary structure associated with increased intermolecular β-sheet content, indicative of aggregated IgG. The addition of 0.01% w/v polysorbate 80 (PS80) reduced the amount of IgG at the air-liquid interface in a static setup at 30 °C; however, this protective effect was lost at 45 °C. These results suggest that the presence of air-liquid interfaces under flow may be detrimental to mAb stability at elevated temperatures and demonstrate the power of ATR-FTIR spectroscopic imaging for studying the structural integrity of mAbs under bioprocessing conditions.

  • Journal article
    Smith TP, Clegg T, Ransome E, Martin-Lilley T, Rosindell J, Woodward G, Pawar S, Bell Tet al., 2024,

    High-throughput characterization of bacterial responses to complex mixtures of chemical pollutants.

    , Nat Microbiol

    Our understanding of how microbes respond to micropollutants, such as pesticides, is almost wholly based on single-species responses to individual chemicals. However, in natural environments, microbes experience multiple pollutants simultaneously. Here we perform a matrix of multi-stressor experiments by assaying the growth of model and non-model strains of bacteria in all 255 combinations of 8 chemical stressors (antibiotics, herbicides, fungicides and pesticides). We found that bacterial strains responded in different ways to stressor mixtures, which could not be predicted simply from their phylogenetic relatedness. Increasingly complex chemical mixtures were both more likely to negatively impact bacterial growth in monoculture and more likely to reveal net interactive effects. A mixed co-culture of strains proved more resilient to increasingly complex mixtures and revealed fewer interactions in the growth response. These results show predictability in microbial population responses to chemical stressors and could increase the utility of next-generation eco-toxicological assays.

  • Journal article
    Guder F, Collins ASP, Kurt H, Duggan C, Cotur Y, Coatsworth P, Naik A, Kaisti M, Bozkurt Oet al., 2024,

    Parallel, Continuous Monitoring and Quantification of Programmed Cell Death in Plant Tissue

    , Advanced Science, ISSN: 2198-3844
  • Journal article
    Majumdar A, Upadhyay MK, Giri B, Yadav P, Moulick D, Sarkar S, Thakur BK, Sahu K, Srivastava AK, Buck M, Tibbett M, Jaiswal MK, Roychowdhury Tet al., 2024,

    Sustainable water management in rice cultivation reduces arsenic contamination, increases productivity, microbial molecular response, and profitability.

    , J Hazard Mater, Vol: 466

    Arsenic (As) and silicon (Si) are two structurally competitive natural elements where Si minimises As accumulation in rice plants, and based on this two-year field trial, the study proposes adopting alternating wetting and drying (AWD) irrigation as a sustainable water management strategy allowing greater Si availability. This field-based project is the first report on AWD's impact on As-Si distribution in fluvio-alluvial soils of the entire Ganga valley (24 study sites, six divisions), seasonal variance (pre-monsoon and monsoon), rice plant anatomy and productivity, soil microbial diversity, microbial gene ontology profiling and associated metabolic pathways. Under AWD to flooded and pre-monsoon to monsoon cultivations, respectively, greater Si availability was achieved and As-bioavailability was reduced by 8.7 ± 0.01-9.2 ± 0.02% and 25.7 ± 0.09-26.1 ± 0.01%. In the pre-monsoon and monsoon seasons, the physiological betterment of rice plants led to the high rice grain yield under AWD improved by 8.4 ± 0.07% and 10.0 ± 0.07%, proving the economic profitability. Compared to waterlogging, AWD evidences as an optimal soil condition for supporting soil microbial communities in rice fields, allowing diverse metabolic activities, including As-resistance, and active expression of As-responsive genes and gene products. Greater expressions of gene ontological terms and complex biochemical networking related to As metabolism under AWD proved better cellular, genetic and environmental responsiveness in microbial communities. Finally, by implementing AWD, groundwater usage can be reduced, lowering the cost of pumping and field management and generating an economic profit for farmers. These combined assessments prove the acceptability of AWD for the establishment of multiple sustainable development goals (SDGs).

  • Journal article
    Komenda J, Sobotka R, Nixon PJ, 2024,

    The biogenesis and maintenance of photosystem II: recent advances and current challenges

    , The Plant Cell, ISSN: 1040-4651
  • Journal article
    Perrett S, Chatrchyan V, Buckup T, van Thor JJet al., 2024,

    Application of density matrix Wigner transforms for ultrafast macromolecular and chemical x-ray crystallography.

    , J Chem Phys, Vol: 160

    Time-Resolved Serial Femtosecond Crystallography (TR-SFX) conducted at X-ray Free Electron Lasers (XFELs) has become a powerful tool for capturing macromolecular structural movies of light-initiated processes. As the capabilities of XFELs advance, we anticipate that a new range of coherent control and structural Raman measurements will become achievable. Shorter optical and x-ray pulse durations and increasingly more exotic pulse regimes are becoming available at free electron lasers. Moreover, with high repetition enabled by the superconducting technology of European XFEL (EuXFEL) and Linac Coherent Light Source (LCLS-II) , it will be possible to improve the signal-to-noise ratio of the light-induced differences, allowing for the observation of vibronic motion on the sub-Angstrom level. To predict and assign this coherent motion, which is measurable with a structural technique, new theoretical approaches must be developed. In this paper, we present a theoretical density matrix approach to model the various population and coherent dynamics of a system, which considers molecular system parameters and excitation conditions. We emphasize the use of the Wigner transform of the time-dependent density matrix, which provides a phase space representation that can be directly compared to the experimental positional displacements measured in a TR-SFX experiment. Here, we extend the results from simple models to include more realistic schemes that include large relaxation terms. We explore a variety of pulse schemes using multiple model systems using realistic parameters. An open-source software package is provided to perform the density matrix simulation and Wigner transformations. The open-source software allows us to define any arbitrary level schemes as well as any arbitrary electric field in the interaction Hamiltonian.

  • Journal article
    Jackson MC, Friberg N, Moliner Cachazo L, Clark DR, Mutinova PT, O'Gorman EJ, Kordas RL, Gallo B, Pichler DE, Bespalaya Y, Aksenova OV, Milner A, Brooks SJ, Dunn N, Lee KWK, Ólafsson JS, Gíslason GM, Millan L, Bell T, Dumbrell AJ, Woodward Get al., 2024,

    Regional impacts of warming on biodiversity and biomass in high latitude stream ecosystems across the Northern Hemisphere.

    , Commun Biol, Vol: 7

    Warming can have profound impacts on ecological communities. However, explorations of how differences in biogeography and productivity might reshape the effect of warming have been limited to theoretical or proxy-based approaches: for instance, studies of latitudinal temperature gradients are often conflated with other drivers (e.g., species richness). Here, we overcome these limitations by using local geothermal temperature gradients across multiple high-latitude stream ecosystems. Each suite of streams (6-11 warmed by 1-15°C above ambient) is set within one of five regions (37 streams total); because the heating comes from the bedrock and is not confounded by changes in chemistry, we can isolate the effect of temperature. We found a negative overall relationship between diatom and invertebrate species richness and temperature, but the strength of the relationship varied regionally, declining more strongly in regions with low terrestrial productivity. Total invertebrate biomass increased with temperature in all regions. The latter pattern combined with the former suggests that the increased biomass of tolerant species might compensate for the loss of sensitive species. Our results show that the impact of warming can be dependent on regional conditions, demonstrating that local variation should be included in future climate projections rather than simply assuming universal relationships.

  • Journal article
    Smith HE, Mackenzie AM, Seddon C, Mould R, Kalampouka I, Malakar P, Needham SR, Beis K, Bell JD, Nunn A, Botchway SWet al., 2024,

    The use of NADH anisotropy to investigate mitochondrial cristae alignment.

    , Sci Rep, Vol: 14

    Life may be expressed as the flow of electrons, protons, and other ions, resulting in large potential difference. It is also highly photo-sensitive, as a large proportion of the redox capable molecules it relies on are chromophoric. It is thus suggestive that a key organelle in eukaryotes, the mitochondrion, constantly adapt their morphology as part of the homeostatic process. Studying unstained in vivo nano-scale structure in live cells is technically very challenging. One option is to study a central electron carrier in metabolism, reduced nicotinamide adenine dinucleotide (NADH), which is fluorescent and mostly located within mitochondria. Using one and two-photon absorption (340-360 nm and 730 nm, respectively), fluorescence lifetime imaging and anisotropy spectroscopy of NADH in solution and in live cells, we show that mitochondria do indeed appear to be aligned and exhibit high anisotropy (asymmetric directionality). Aqueous solution of NADH showed an anisotropy of ~ 0.20 compared to fluorescein or coumarin of < 0.1 and 0.04 in water respectively and as expected for small organic molecules. The anisotropy of NADH also increased further to 0.30 in the presence of proteins and 0.42 in glycerol (restricted environment) following two-photon excitation, suggesting more ordered structures. Two-photon NADH fluorescence imaging of Michigan Cancer Foundation-7 (MCF7) also showed strong anisotropy of 0.25 to 0.45. NADH has a quantum yield of fluorescence of 2% compared to more than 40% for photoionisation (electron generation), when exposed to light at 360 nm and below. The consequence of such highly ordered and directional NADH patterns with respect to electron ejection upon ultra-violet (UV) excitation could be very informative-especially in relation to ascertaining the extent of quantum effects in biology, including electron and photonic cascade, communication and modulation of effects such as spin and tunnelling.

  • Journal article
    Sheppard S, Srpan K, Lin W, Lee M, Delconte RB, Owyong M, Carmeliet P, Davis DM, Xavier JB, Hsu KC, Sun JCet al., 2024,

    Fatty acid oxidation fuels natural killer cell responses against infection and cancer.

    , Proc Natl Acad Sci U S A, Vol: 121

    Natural killer (NK) cells are a vital part of the innate immune system capable of rapidly clearing mutated or infected cells from the body and promoting an immune response. Here, we find that NK cells activated by viral infection or tumor challenge increase uptake of fatty acids and their expression of carnitine palmitoyltransferase I (CPT1A), a critical enzyme for long-chain fatty acid oxidation. Using a mouse model with an NK cell-specific deletion of CPT1A, combined with stable 13C isotope tracing, we observe reduced mitochondrial function and fatty acid-derived aspartate production in CPT1A-deficient NK cells. Furthermore, CPT1A-deficient NK cells show reduced proliferation after viral infection and diminished protection against cancer due to impaired actin cytoskeleton rearrangement. Together, our findings highlight that fatty acid oxidation promotes NK cell metabolic resilience, processes that can be optimized in NK cell-based immunotherapies.

  • Journal article
    Bossanyi DG, Matthiesen M, Jayaprakash R, Bhattacharya S, Zaumseil J, Clark Jet al., 2024,

    Singlet fission is incoherent in pristine orthorhombic single crystals of rubrene: no evidence of triplet-pair emission.

    , Faraday Discuss, Vol: 250, Pages: 162-180

    Singlet fission (SF) and its inverse, triplet-triplet annihilation (TTA), are promising strategies for enhancing photovoltaic efficiencies. However, detailed descriptions of the processes of SF/TTA are not fully understood, even in the most well-studied systems. Reports of the photophysics of crystalline rubrene, for example, are often inconsistent. Here we attempt to resolve these inconsistencies using time-resolved photoluminescence and transient absorption spectroscopy of 'pristine' rubrene orthorhombic single crystals. We find the reported time-resolved photoluminescence behaviour that hinted at triplet-pair emission is found only at specific sites on the crystals and likely arises from surface defects. Using transient absorption spectroscopy of the same crystals, we also observe no evidence of instantaneous generation of triplet-pair population with ∼100 fs excitation, independent of excitation wavelength (532 nm, 495 nm) or excitation angle. Our results suggest that SF occurs incoherently on a relatively slow (picosecond) timescale in rubrene single crystals, as expected from the original theoretical calculations. We conclude that the sub-100 fs formation of triplet pairs in crystalline rubrene films is likely to be due to static disorder.

  • Journal article
    Grover M, Gang SS, Troemel ER, Barkoulas Met al., 2024,

    Proteasome inhibition triggers tissue-specific immune responses against different pathogens in C. elegans.

    , PLoS Biol, Vol: 22

    Protein quality control pathways play important roles in resistance against pathogen infection. For example, the conserved transcription factor SKN-1/NRF up-regulates proteostasis capacity after blockade of the proteasome and also promotes resistance against bacterial infection in the nematode Caenorhabditis elegans. SKN-1/NRF has 3 isoforms, and the SKN-1A/NRF1 isoform, in particular, regulates proteasomal gene expression upon proteasome dysfunction as part of a conserved bounce-back response. We report here that, in contrast to the previously reported role of SKN-1 in promoting resistance against bacterial infection, loss-of-function mutants in skn-1a and its activating enzymes ddi-1 and png-1 show constitutive expression of immune response programs against natural eukaryotic pathogens of C. elegans. These programs are the oomycete recognition response (ORR), which promotes resistance against oomycetes that infect through the epidermis, and the intracellular pathogen response (IPR), which promotes resistance against intestine-infecting microsporidia. Consequently, skn-1a mutants show increased resistance to both oomycete and microsporidia infections. We also report that almost all ORR/IPR genes induced in common between these programs are regulated by the proteasome and interestingly, specific ORR/IPR genes can be induced in distinct tissues depending on the exact trigger. Furthermore, we show that increasing proteasome function significantly reduces oomycete-mediated induction of multiple ORR markers. Altogether, our findings demonstrate that proteasome regulation keeps innate immune responses in check in a tissue-specific manner against natural eukaryotic pathogens of the C. elegans epidermis and intestine.

  • Journal article
    Kogenaru V, Isalan M, Kogenaru M, 2024,

    A drug stabilizable GAL80ds for conditional control of gene expression via GAL4-UAS and CRISPR-Cas9 systems in Drosophila

    , Scientific Reports, ISSN: 2045-2322
  • Journal article
    Rizos G, Lawson J, Mitchell S, Shah P, Wen X, Banks-Leite C, Ewers R, Schuller BWet al., 2024,

    Propagating variational model uncertainty for bioacoustic call label smoothing.

    , Patterns (N Y), Vol: 5

    Along with propagating the input toward making a prediction, Bayesian neural networks also propagate uncertainty. This has the potential to guide the training process by rejecting predictions of low confidence, and recent variational Bayesian methods can do so without Monte Carlo sampling of weights. Here, we apply sample-free methods for wildlife call detection on recordings made via passive acoustic monitoring equipment in the animals' natural habitats. We further propose uncertainty-aware label smoothing, where the smoothing probability is dependent on sample-free predictive uncertainty, in order to downweigh data samples that should contribute less to the loss value. We introduce a bioacoustic dataset recorded in Malaysian Borneo, containing overlapping calls from 30 species. On that dataset, our proposed method achieves an absolute percentage improvement of around 1.5 points on area under the receiver operating characteristic (AU-ROC), 13 points in F1, and 19.5 points in expected calibration error (ECE) compared to the point-estimate network baseline averaged across all target classes.

  • Journal article
    Flo V, Joshi J, Sabot M, Sandoval D, Prentice ICet al., 2024,

    Incorporating photosynthetic acclimation improves stomatal optimisation models

    , Plant, Cell and Environment, ISSN: 0140-7791
  • Journal article
    King FJ, Yuen ELH, Bozkurt TO, 2024,

    Border Control: Manipulation of the Host-Pathogen Interface by Perihaustorial Oomycete Effectors.

    , Mol Plant Microbe Interact, ISSN: 0894-0282

    Filamentous plant pathogens, including fungi and oomycetes, cause some of the most devastating plant diseases. These organisms serve as ideal models for understanding the intricate molecular interplay between plants and the invading pathogens. Filamentous pathogens secrete effector proteins via haustoria, specialized structures for infection and nutrient uptake, to suppress the plant immune response and to reprogram plant metabolism. Recent advances in cell biology have provided crucial insights into the biogenesis of the extrahaustorial membrane and the redirection of host endomembrane trafficking toward this interface. Functional studies have shown that an increasing number of oomycete effectors accumulate at the perihaustorial interface to subvert plant focal immune responses, with a particular convergence on targets involved in host endomembrane trafficking. In this review, we summarize the diverse mechanisms of perihaustorial effectors from oomycetes and pinpoint pressing questions regarding their role in manipulating host defense and metabolism at the haustorial interface. [Formula: see text] Copyright © 2024 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license.

  • Journal article
    Gardner S, Jin Y, Fyfe PK, Voisin T, Bellón JS, Pohler E, Piehler J, Moraga I, Bubeck Det al., 2024,

    Structural insights into IL-11-mediated signalling and human IL6ST variant-associated immunodeficiency

    , Nature Communications, Vol: 15, ISSN: 2041-1723

    IL-11 and IL-6 activate signalling via assembly the cell surface receptor gp130; however, it is unclear how signals are transmitted across the membrane to instruct cellular responses. Here we solve the cryoEM structure of the IL-11 receptor recognition complex to discover how differences in gp130-binding interfaces may drive signalling outcomes. We explore how mutations in the IL6ST gene encoding for gp130, which cause severe immune deficiencies in humans, impair signalling without blocking cytokine binding. We use cryoEM to solve structures of both IL-11 and IL-6 complexes with a mutant form of gp130 associated with human disease. Together with molecular dynamics simulations, we show that the disease-associated variant led to an increase in flexibility including motion within the cytokine-binding core and increased distance between extracellular domains.However, these distances are minimized as the transmembrane helix exits the membrane, suggesting a stringency in geometry for signalling and dimmer switch mode of action.

  • Journal article
    Qi L, Bennett E, Isalan M, 2024,

    A directed evolution protocol for engineering minimal transcription factors, based on CIS display.

    , Methods in Molecular Biology, ISSN: 1064-3745
  • Journal article
    Beis K, 2024,

    Structural basis for the modulation of MRP2 activity by phosphorylation and drugs

    , Nature Communications, ISSN: 2041-1723
  • Journal article
    Chukhutsina VU, Hutchison CDM, van Thor JJ, 2024,

    The Carbonyl Group in β2 of the Carotenoid Tunes the Photocycle Kinetics in Orange Carotenoid Protein

    , Journal of Molecular Biology, Vol: 436, Pages: 168463-168463, ISSN: 0022-2836
  • Journal article
    Pawar S, Huxley PJ, Smallwood TRC, Nesbit ML, Chan AHH, Shocket MS, Johnson LR, Kontopoulos D-G, Cator LJet al., 2024,

    Variation in temperature of peak trait performance constrains adaptation of arthropod populations to climatic warming.

    , Nat Ecol Evol, Vol: 8, Pages: 500-510

    The capacity of arthropod populations to adapt to long-term climatic warming is currently uncertain. Here we combine theory and extensive data to show that the rate of their thermal adaptation to climatic warming will be constrained in two fundamental ways. First, the rate of thermal adaptation of an arthropod population is predicted to be limited by changes in the temperatures at which the performance of four key life-history traits can peak, in a specific order of declining importance: juvenile development, adult fecundity, juvenile mortality and adult mortality. Second, directional thermal adaptation is constrained due to differences in the temperature of the peak performance of these four traits, with these differences expected to persist because of energetic allocation and life-history trade-offs. We compile a new global dataset of 61 diverse arthropod species which provides strong empirical evidence to support these predictions, demonstrating that contemporary populations have indeed evolved under these constraints. Our results provide a basis for using relatively feasible trait measurements to predict the adaptive capacity of diverse arthropod populations to geographic temperature gradients, as well as ongoing and future climatic warming.

  • Journal article
    Gumbs R, Scott O, Bates R, Böhm M, Forest F, Gray CL, Hoffmann M, Kane D, Low C, Pearse WD, Pipins S, Tapley B, Turvey ST, Jetz W, Owen NR, Rosindell Jet al., 2024,

    Global conservation status of the jawed vertebrate Tree of Life

    , Nature Communications, Vol: 15, ISSN: 2041-1723

    Human-driven extinction threatens entire lineages across the Tree of Life. Here we assess the conservation status of jawed vertebrate evolutionary history, using three policy-relevant approaches. First, we calculate an index of threat to overall evolutionary history, showing that we expect to lose 86-150 billion years (11-19%) of jawed vertebrate evolutionary history over the next 50-500 years. Second, we rank jawed vertebrate species by their EDGE scores to identify the highest priorities for species-focused conservation of evolutionary history, finding that chondrichthyans, ray-finned fish and testudines rank highest of all jawed vertebrates. Third, we assess the conservation status of jawed vertebrate families. We found that species within monotypic families are more likely to be threatened and more likely to be in decline than other species. We provide a baseline for the status of families at risk of extinction to catalyse conservation action. This work continues a trend of highlighting neglected groups—such as testudines, crocodylians, amphibians and chondrichthyans—as conservation priorities from a phylogenetic perspective.

  • Journal article
    Blackford K, Kasoar M, Burton C, Burke E, Prentice IC, Voulgarakis Aet al., 2024,

    INFERNO-peat v1.0.0: a representation of northern high latitude peat fires in the JULES-INFERNO global fire model

    , Geoscientific Model Development, ISSN: 1991-959X
  • Journal article
    Wang X, Slater A, Lee SC, Harrison N, Pollock NL, Bakker SE, Navarro S, Nieswandt B, Dafforn TR, García Á, Watson SP, Tomlinson MGet al., 2024,

    Purification and characterisation of the platelet-activating GPVI/FcRγ complex in SMALPs.

    , Arch Biochem Biophys, Vol: 754

    The collagen/fibrin(ogen) receptor, glycoprotein VI (GPVI), is a platelet activating receptor and a promising anti-thrombotic drug target. However, while agonist-induced GPVI clustering on platelet membranes has been shown to be essential for its activation, it is unknown if GPVI dimerisation represents a unique conformation for ligand binding. Current GPVI structures all contain only the two immunoglobulin superfamily (IgSF) domains in the GPVI extracellular region, so lacking the mucin-like stalk, transmembrane, cytoplasmic tail of GPVI and its associated Fc receptor γ (FcRγ) homodimer signalling chain, and provide contradictory insights into the mechanisms of GPVI dimerisation. Here, we utilised styrene maleic-acid lipid particles (SMALPs) to extract GPVI in complex with its two associated FcRγ chains from transfected HEK-293T cells, together with the adjacent lipid bilayer, then purified and characterised the GPVI/FcRγ-containing SMALPs, to enable structural insights into the full-length GPVI/FcRγ complex. Using size exclusion chromatography followed by a native polyacrylamide gel electrophoresis (PAGE) method, SMA-PAGE, we revealed multiple sizes of the purified GPVI/FcRγ SMALPs, suggesting the potential existence of GPVI oligomers. Importantly, GPVI/FcRγ SMALPs were functional as they could bind collagen. Mono-dispersed GPVI/FcRγ SMALPs could be observed under negative stain electron microscopy. These results pave the way for the future investigation of GPVI stoichiometry and structure, while also validating SMALPs as a promising tool for the investigation of human membrane protein interactions, stoichiometry and structure.

  • Journal article
    Yoon S, Bae HE, Hariharan P, Nygaard A, Lan B, Woubshete M, Sadaf A, Liu X, Loland CJ, Byrne B, Guan L, Chae PSet al., 2024,

    Rational approach to improve detergent efficacy for membrane protein stabilization

    , Bioconjugate Chemistry, Vol: 35, Pages: 223-231, ISSN: 1043-1802

    Membrane protein structures are essential for the molecular understanding of diverse cellular processes and drug discovery. Detergents are not only widely used to extract membrane proteins from membranes but also utilized to preserve native protein structures in aqueous solution. However, micelles formed by conventional detergents are suboptimal for membrane protein stabilization, necessitating the development of novel amphiphilic molecules with enhanced protein stabilization efficacy. In this study, we prepared two sets of tandem malonate-derived glucoside (TMG) variants, both of which were designed to increase the alkyl chain density in micelle interiors. The alkyl chain density was modulated either by reducing the spacer length (TMG-Ms) or by introducing an additional alkyl chain between the two alkyl chains of the original TMGs (TMG-Ps). When evaluated with a few membrane proteins including a G protein-coupled receptor, TMG-P10,8 was found to be substantially more efficient at extracting membrane proteins and also effective at preserving protein integrity in the long term compared to the previously described TMG-A13. This result reveals that inserting an additional alkyl chain between the two existing alkyl chains is an effective way to optimize detergent properties for membrane protein study. This new biochemical tool and the design principle described have the potential to facilitate membrane protein structure determination.

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