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  • Journal article
    Endres R, Cavanagh H, Mosbach A, Scalliet G, Lind Ret al., 6424,

    Physics-informed deep learning characterizes morphodynamics of Asian soybean rust disease

    , Nature Communications, Vol: 12, Pages: 1-8, ISSN: 2041-1723

    Medicines and agricultural biocides are often discovered using large phenotypic screens across hundreds of compounds, where visible effects of whole organisms are compared to gauge efficacy and possible modes of action. However, such analysis is often limited to human-defined and static features. Here, we introduce a novel framework that can characterize shape changes (morphodynamics) for cell-drug interactions directly from images, and use it to interpret perturbed development of Phakopsora pachyrhizi, the Asian soybean rust crop pathogen. We describe population development over a 2D space of shapes (morphospace) using two models with condition-dependent parameters: a top-down Fokker-Planck model of diffusive development over Waddington-type landscapes, and a bottom-up model of tip growth. We discover a variety of landscapes, describing phenotype transitions during growth, and identify possible perturbations in the tip growth machinery that cause this variation. This demonstrates a widely-applicable integration of unsupervised learning and biophysical modeling.

  • Journal article
    Cheng S, Prentice IC, Huang Y, Jin Y, Guo Y-K, Arcucci Ret al., 2022,

    Data-driven surrogate model with latent data-assimilation: application to wildfire forecasting

    , Journal of Computational Physics, Vol: 464, ISSN: 0021-9991

    The large and catastrophic wildfires have been increasing across the globe in the recent decade, highlighting the importance of simulating and forecasting fire dynamics in near real-time. This is extremely challenging due to the complexities of physical models and geographical features. Running physics-based simulations for large wildfire events in near real-time are computationally expensive, if not infeasible. In this work, we develop and test a novel data-model integration scheme for fire progression forecasting, that combines Reduced-order modelling, recurrent neural networks (Long-Short-Term Memory), data assimilation, and error covariance tuning. The Reduced-order modelling and the machine learning surrogate model ensure the efficiency of the proposed approach while the data assimilation enables the system to adjust the simulation with observations. We applied this algorithm to simulate and forecast three recent large wildfire events in California from 2017 to 2020. The deep-learning-based surrogate model runs around 1000 times faster than the Cellular Automata simulation which is used to generate training data-sets. The daily fire perimeters derived from satellite observation are used as observation data in Latent Assimilation to adjust the fire forecasting in near real-time. An error covariance tuning algorithm is also performed in the reduced space to estimate prior simulation and observation errors. The evolution of the averaged relative root mean square error (R-RMSE) shows that data assimilation and covariance tuning reduce the RMSE by about 50% and considerably improves the forecasting accuracy. As a first attempt at a reduced order wildfire spread forecasting, our exploratory work showed the potential of data-driven machine learning models to speed up fire forecasting for various applications.

  • Journal article
    Khatri BS, Burt A, 2022,

    A theory of resistance to multiplexed gene drive demonstrates the significant role of weakly deleterious natural genetic variation

    , Proceedings of the National Academy of Sciences, Vol: 119, ISSN: 0027-8424

    <jats:p>Evolution of resistance is a major barrier to successful deployment of gene-drive systems to suppress natural populations, which could greatly reduce the burden of many vector-borne diseases. Multiplexed guide RNAs (gRNAs) that require resistance mutations in all target cut sites are a promising antiresistance strategy since, in principle, resistance would only arise in unrealistically large populations. Using stochastic simulations that accurately model evolution at very large population sizes, we explore the probability of resistance due to three important mechanisms: 1) nonhomologous end-joining mutations, 2) single-nucleotide mutants arising de novo, or 3) single-nucleotide polymorphisms preexisting as standing variation. Our results explore the relative importance of these mechanisms and highlight a complexity of the mutation–selection–drift balance between haplotypes with complete resistance and those with an incomplete number of resistant alleles. We find that this leads to a phenomenon where weakly deleterious naturally occurring variants greatly amplify the probability of multisite resistance compared to de novo mutation. This key result provides design criterion for antiresistance multiplexed systems, which, in general, will need a larger number of gRNAs compared to de novo expectations. This theory may have wider application to the evolution of resistance or evolutionary rescue when multiple changes are required before selection can act.</jats:p>

  • Journal article
    Bubeck D, Jin Y, Fyfe PK, Gardner S, Wilmes S, Moraga Iet al., 2022,

    Structural insights into the assembly and activation of the IL-27 signalling complex

    , EMBO Reports, ISSN: 1469-221X

    Interleukin 27 (IL-27) is a heterodimeric cytokine that elicits potent immuno-suppressive responses. Comprised of EBI3 and p28 subunits, IL-27 binds GP130 and IL-27Rα receptor chains to activate the JAK/STAT signalling cascade. However, how these receptors recognize IL-27 and form a complex capable of phosphorylating JAK proteins remains unclear. Here, we used cryo electron microscopy (cryoEM) and AlphaFold2 modelling to solve the structure of the IL-27 receptor recognition complex. Our data show how IL-27 serves as a bridge connecting IL-27Rα (domains 1-2) with GP130 (domains 1-3) to initiate signalling. While both receptors contact the p28 component of the heterodimeric cytokine, EBI3 stabilizes the complex by binding a positively charged surface of IL-27Rα and Domain 1 of GP130. We find that assembly of the IL-27 receptor recognition complex is distinct from both IL-12 and IL-6 cytokine families and provides a mechanistic blueprint for tuning IL-27 pleiotropic actions.

  • Journal article
    Giannos P, Kechagias K, 2022,

    Socio-economic impacts and challenges of the coronavirus pandemic (COVID-19): An updated review

    , Sustainability, ISSN: 2071-1050
  • Journal article
    Dobson B, Barry S, Maes-Prior R, Mijic A, Woodward G, Pearse WDet al., 2022,

    Predicting catchment suitability for biodiversity at national scales

    , WATER RESEARCH, Vol: 221, ISSN: 0043-1354
  • Journal article
    Whyte CE, Singh K, Burton OT, Aloulou M, Kouser L, Veiga RV, Dashwood A, Okkenhaug H, Benadda S, Moudra A, Bricard O, Lienart S, Bielefeld P, Roca CP, Naranjo-Galindo FJ, Lombard-Vadnais F, Junius S, Bending D, Ono M, Hochepied T, Halim TYF, Schlenner S, Lesage S, Dooley J, Liston Aet al., 2022,

    Correction: Context-dependent effects of IL-2 rewire immunity into distinct cellular circuits.

    , J Exp Med, Vol: 219
  • Journal article
    Christensen AK, Piggott MD, van Sebille E, van Reeuwijk M, Pawar Set al., 2022,

    Investigating microscale patchiness of motile microbes under turbulence in a simulated convective mixed layer.

    , PLoS Comput Biol, Vol: 18

    Microbes play a primary role in aquatic ecosystems and biogeochemical cycles. Spatial patchiness is a critical factor underlying these activities, influencing biological productivity, nutrient cycling and dynamics across trophic levels. Incorporating spatial dynamics into microbial models is a long-standing challenge, particularly where small-scale turbulence is involved. Here, we combine a fully 3D direct numerical simulation of convective mixed layer turbulence, with an individual-based microbial model to test the key hypothesis that the coupling of gyrotactic motility and turbulence drives intense microscale patchiness. The fluid model simulates turbulent convection caused by heat loss through the fluid surface, for example during the night, during autumnal or winter cooling or during a cold-air outbreak. We find that under such conditions, turbulence-driven patchiness is depth-structured and requires high motility: Near the fluid surface, intense convective turbulence overpowers motility, homogenising motile and non-motile microbes approximately equally. At greater depth, in conditions analogous to a thermocline, highly motile microbes can be over twice as patch-concentrated as non-motile microbes, and can substantially amplify their swimming velocity by efficiently exploiting fast-moving packets of fluid. Our results substantiate the predictions of earlier studies, and demonstrate that turbulence-driven patchiness is not a ubiquitous consequence of motility but rather a delicate balance of motility and turbulent intensity.

  • Journal article
    Giannos P, 2022,

    Associations of bioavailable serum testosterone with cognitive function in older men: results from the National Health and Nutrition Examination Survey

    , The Journals of Gerontology, Series A: Biological Sciences and Medical Sciences, ISSN: 1079-5006

    Background: Age-associated cognitive decline may be influenced by testosterone status. However, studies evaluating the impact of bioavailable testosterone, the active, free testosterone, on cognitive function are scarce. Our study determined the relationship between calculated bioavailable testosterone and cognitive performance in older men.Methods: We used data from the US National Health and Nutrition Examination Survey (NHANES) between 2013 and 2014. This study consisted of 208 men aged ≥ 60 years. Bioavailable serum testosterone was calculated based on the total serum testosterone, sex hormone-binding globulin, and albumin levels, while cognitive performance was assessed through the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) Word List Learning Test (WLLT), Word List Recall Test (WLRT), and Intrusion Word Count Test (WLLT-IC and WLRT-IC), the Animal Fluency Test (AFT), and the Digit Symbol Substitution Test (DSST). Multiple linear regression analyses were performed upon adjustment for age, ethnicity, socio-economic status, education level, medical history, body mass index, energy, alcohol intake, physical activity levels and sleep duration.Results: A significant positive association between bioavailable testosterone and DSST (β: 0.049, P=0.002) score was detected, with no signs of a plateau effect. No significant associations with CERAD WLLT (P=0.132), WLRT (P=0.643), WLLT-IC (P=0.979), and WLRT-IC (P=0.387), and AFT (P=0.057) were observed. Conclusion: Calculated bioavailable testosterone presented a significant positive association with processing speed, sustained attention and working memory in older men above 60 years of age. Further research is warranted to elucidate the impact of the inevitable age-related decline in testosterone on cognitive function in older men.

  • Journal article
    Hamilton C, Olona A, Leishman S, MacDonald-Ramsahai K, Cockcroft S, Larrouy-Maumus G, Anand Pet al., 2022,

    NLRP3 inflammasome priming and activation are regulated by a phosphatidylinositol-dependent mechanism

    , ImmunoHorizons, ISSN: 2573-7732

    Imbalance in lipid homeostasis is associated with discrepancies in immune signaling and is tightly linked to metabolic disorders. The diverse ways in which lipids impact immune signaling, however, remain ambiguous. The phospholipid phosphatidylinositol (PI), which is implicated in numerous immune disorders, is chiefly defined by its phosphorylation status. By contrast, the significance of the two fatty acid chains attached to the PI remains unknown. Here, by employing a mass-spectrometry-based assay, we demonstrate a role for PI acyl group chains in regulating both the priming and activation steps of the NLRP3 inflammasome in mouse macrophages. In response to NLRP3 stimuli, cells deficient in ABC transporter ABCB1, which effluxes lipid derivatives, revealed defective inflammasome activation. Mechanistically, Abcb1-deficiency shifted the total PI configuration exhibiting a reduced ratio of short-chain to long-chain PI acyl lipids. Consequently, Abcb1-deficiency initiated the rapid degradation of TIRAP, the TLR adaptor protein which binds PI (4,5)-bisphosphate, resulting in defective TLR-dependent signaling, and thus NLRP3 expression. Moreover, this accompanied increased NLRP3 phosphorylation at the Ser291 position and contributed to blunted inflammasome activation. Exogenously supplementing WT cells with linoleic acid, but not arachidonic acid, reconfigured PI acyl chains. Accordingly, linoleic acid supplementation increased TIRAP degradation, elevated NLRP3 phosphorylation, and abrogated inflammasome activation. Furthermore, NLRP3 Ser291 phosphorylation was dependent on prostaglandin E2-induced protein kinase A signaling as pharmacological inhibition of this pathway in linoleic acid-enriched cells dephosphorylated NLRP3. Altogether, our study reveals a novel metabolic-inflammatory circuit which contributes to calibrating immune responses.

  • Journal article
    Vitale M, Leo C, Courty T, Kranjc N, Connolly JB, Morselli G, Bamikole C, Haghighat-Khah RE, Bernardini F, Fuchs Set al., 2022,

    Comprehensive characterization of a transgene insertion in a highly repetitive, centromeric region of Anopheles mosquitoes

    , PATHOGENS AND GLOBAL HEALTH, ISSN: 2047-7724
  • Journal article
    Windbichler N, 2022,

    Gene drive mosquitoes can aid malaria elimination by retarding Plasmodium sporogonic development

    , Science Advances, ISSN: 2375-2548

    Abstract: Gene drives hold promise for the genetic control of malaria vectors. The development of vector population modification strategies hinges on the availability of effector mechanisms impeding parasite development in transgenic mosquitoes. We augmented a midgut gene of the malaria mosquito Anopheles gambiae to secrete two exogenous antimicrobial peptides, Magainin 2 and Melittin. This small genetic modification, capable of efficient non-autonomous gene drive, hampers oocyst development in both Plasmodium falciparum and Plasmodium berghei. It delays the release of infectious sporozoites while it simultaneously reduces the lifespan of homozygous female transgenic mosquitoes. Modeling the spread of this modification using a large-scale agent-based model of malaria epidemiology reveals that it can break the cycle of disease transmission across a range of transmission intensities.

  • Journal article
    Chukhutsina VU, van Thor JJ, 2022,

    Molecular Activation Mechanism and Structural Dynamics of Orange Carotenoid Protein

    , Physchem, Vol: 2, Pages: 235-252

    <jats:p>Like most photosynthetic organisms, cyanobacteria are vulnerable to fluctuations in light intensity, which can damage their photosynthetic machinery. To protect against this, they use a photoprotective mechanism called non-photochemical quenching (NPQ), where excess absorbed photo-energy is dissipated as heat. In cyanobacteria, light activation of Orange Carotenoid Protein (OCP) is the critical first step in the NPQ response. OCP is also the only known photosensitive protein, which uses carotenoid for its activation. We summarize the current knowledge on the light induced reactions of OCP; the different mechanisms of activation that have been proposed; photocycle kinetics and characteristics; and the reported structural intermediates. We discuss the possible interpretations of reported experimental results, and we formulate important open questions and directions for future work, to reveal the molecular and structural basis of photosensing by OCP.</jats:p>

  • Journal article
    Brosh O, Fabian DK, Cogni R, Tolosana I, Day JP, Olivieri F, Merckx M, Akilli N, Szkuta P, Jiggins FMet al., 2022,

    A novel transposable element-mediated mechanism causes antiviral resistance in Drosophila through truncating the Veneno protein.

    , Proc Natl Acad Sci U S A, Vol: 119

    Hosts are continually selected to evolve new defenses against an ever-changing array of pathogens. To understand this process, we examined the genetic basis of resistance to the Drosophila A virus in Drosophila melanogaster. In a natural population, we identified a polymorphic transposable element (TE) insertion that was associated with an ∼19,000-fold reduction in viral titers, allowing flies to largely escape the harmful effects of infection by this virulent pathogen. The insertion occurs in the protein-coding sequence of the gene Veneno, which encodes a Tudor domain protein. By mutating Veneno with CRISPR-Cas9 in flies and expressing it in cultured cells, we show that the ancestral allele of the gene has no effect on viral replication. Instead, the TE insertion is a gain-of-function mutation that creates a gene encoding a novel resistance factor. Viral titers remained reduced when we deleted the TE sequence from the transcript, indicating that resistance results from the TE truncating the Veneno protein. This is a novel mechanism of virus resistance and a new way by which TEs can contribute to adaptation.

  • Journal article
    Viola S, Roseby W, Santabarbara S, Nürnberg D, Assunção R, Dau H, Sellés J, Boussac A, Fantuzzi A, Rutherford Aet al., 2022,

    Impact of energy limitations on function and resilience in long-wavelength photosystem II

    , eLife, ISSN: 2050-084X

    Photosystem II (PSII) uses the energy from red light to split water and reduce quinone, an energy-demanding process based on chlorophyll a (Chl-a) photochemistry. Two types of cyanobacterial PSII can use chlorophyll d (Chl-d) and chlorophyll f (Chl-f) to perform the same reactions using lower energy, far-red light. PSII from Acaryochloris marina has Chl-d replacing all but one of its 35 Chl-a, while PSII from Chroococcidiopsis thermalis, a facultative far-red species, has just 4 Chl-f and 1 Chl-d and 30 Chl-a. From bioenergetic considerations, the far-red PSII were predicted to lose photochemical efficiency and/or resilience to photodamage. Here, we compare enzyme turnover efficiency, forward electron transfer, back-reactions and photodamage in Chl-f-PSII, Chl-d-PSII and Chl-a-PSII. We show that: i) all types of PSII have a comparable efficiency in enzyme turnover; ii) the modified energy gaps on the acceptor side of Chl-d-PSII favour recombination via PD1+Phe- repopulation, leading to increased singlet oxygen production and greater sensitivity to high-light damage compared to Chl-a-PSII and Chl-f-PSII; iii) the acceptor-side energy gaps in Chl-f-PSII are tuned to avoid harmful back reactions, favouring resilience to photodamage over efficiency of light usage. The results are explained by the differences in the redox tuning of the electron transfer cofactors Phe and QA and in the number and layout of the chlorophylls that share the excitation energy with the primary electron donor. PSII has adapted to lower energy in two distinct ways, each appropriate for its specific environment but with different functional penalties.

  • Journal article
    Kaplan M, Oikonomou CM, Wood CR, Chreifi G, Ghosal D, Dobro MJ, Yao Q, Pal RR, Baidya AK, Liu Y, Maggi S, McDowall AW, Ben-Yehuda S, Rosenshine I, Briegel A, Beeby M, Chang Y-W, Shaffer CL, Jensen GJet al., 2022,

    Discovery of a Novel Inner Membrane-Associated Bacterial Structure Related to the Flagellar Type III Secretion System

    , JOURNAL OF BACTERIOLOGY, ISSN: 0021-9193
  • Journal article
    Musasia FK, Nkumama IN, Frank R, Kipkemboi V, Schneider M, Mwai K, Odera DO, Rosenkranz M, Fürle K, Kimani D, Tuju J, Njuguna P, Hamaluba M, Kapulu MC, Wardemann H, CHMI-SIKA Study Team, Osier FHAet al., 2022,

    Phagocytosis of Plasmodium falciparum ring-stage parasites predicts protection against malaria.

    , Nat Commun, Vol: 13

    Ring-infected erythrocytes are the predominant asexual stage in the peripheral circulation but are rarely investigated in the context of acquired immunity against Plasmodium falciparum malaria. Here we compare antibody-dependent phagocytosis of ring-infected parasite cultures in samples from a controlled human malaria infection (CHMI) study (NCT02739763). Protected volunteers did not develop clinical symptoms, maintained parasitaemia below a predefined threshold of 500 parasites/μl and were not treated until the end of the study. Antibody-dependent phagocytosis of both ring-infected and uninfected erythrocytes from parasite cultures was strongly correlated with protection. A surface proteomic analysis revealed the presence of merozoite proteins including erythrocyte binding antigen-175 and -140 on ring-infected and uninfected erythrocytes, providing an additional antibody-mediated protective mechanism for their activity beyond invasion-inhibition. Competition phagocytosis assays support the hypothesis that merozoite antigens are the key mediators of this functional activity. Targeting ring-stage parasites may contribute to the control of parasitaemia and prevention of clinical malaria.

  • Journal article
    Rubin C-J, Enbody ED, Dobreva MP, Abzhanov A, Davis BW, Lamichhaney S, Pettersson M, Sendell-Price AT, Sprehn CG, Valle CA, Vasco K, Wallerman O, Grant BR, Grant PR, Andersson Let al., 2022,

    Rapid adaptive radiation of Darwin's finches depends on ancestral genetic modules

    , SCIENCE ADVANCES, Vol: 8, ISSN: 2375-2548
  • Journal article
    Barker J, Davies J, Goralczyk M, Patel S, O'Connor J, Evans J, Sharp R, Gollock M, Wood FR, Rosindell J, Bartlett C, Garner BJ, Jones D, Quigley D, Wray Bet al., 2022,

    The distribution, ecology and predicted habitat use of the Critically Endangered angelshark (Squatina squatina) in coastal waters of Wales and the central Irish Sea

    , JOURNAL OF FISH BIOLOGY, ISSN: 0022-1112
  • Journal article
    Chaukimath P, Frankel G, Visweswariah SS, 2022,

    The metabolic impact of bacterial infection in the gut

    , FEBS JOURNAL, ISSN: 1742-464X
  • Journal article
    Cheng S, Jin Y, Harrison S, Quilodrán Casas C, Prentice C, Guo Y-K, Arcucci Ret al., 2022,

    Parameter flexible wildfire prediction using machine learning techniques: forward and inverse modelling

    , Remote Sensing, Vol: 14, ISSN: 2072-4292

    Parameter identification for wildfire forecasting models often relies on case-by-case tuning or posterior diagnosis/analysis, which can be computationally expensive due to the complexity of the forward prediction model. In this paper, we introduce an efficient parameter flexible fire prediction algorithm based on machine learning and reduced order modelling techniques. Using a training dataset generated by physics-based fire simulations, the method forecasts burned area at different time steps with a low computational cost. We then address the bottleneck of efficient parameter estimation by developing a novel inverse approach relying on data assimilation techniques (latent assimilation) in the reduced order space. The forward and the inverse modellings are tested on two recent large wildfire events in California. Satellite observations are used to validate the forward prediction approach and identify the model parameters. By combining these forward and inverse approaches, the system manages to integrate real-time observations for parameter adjustment, leading to more accurate future predictions.

  • Journal article
    Zhang K, Li S, Wang Y, Wang Z, Mulvenna N, Yang H, Zhang P, Chen H, Li Y, Wang H, Gao Y, Wigneshweraraj S, Matthews S, Zhang K, Liu Bet al., 2022,

    Bacteriophage protein PEIP is a potent Bacillus subtilis enolase inhibitor.

    , Cell Rep, Vol: 40

    Enolase is a highly conserved enzyme that presents in all organisms capable of glycolysis or fermentation. Its immediate product phosphoenolpyruvate is essential for other important processes like peptidoglycan synthesis and the phosphotransferase system in bacteria. Therefore, enolase inhibitors are of great interest. Here, we report that Gp60, a phage-encoded enolase inhibitor protein (PEIP) of bacteriophage SPO1 for Bacillus subtilis, is an enolase inhibitor. PEIP-expressing bacteria exhibit growth attenuation, thinner cell walls, and safranin color in Gram staining owing to impaired peptidoglycan synthesis. We solve the structure of PEIP-enolase tetramer and show that PEIP disassembles enolase by disrupting the basic dimer unit. The structure reveals that PEIP does not compete for substrate binding but induces a cascade of conformational changes that limit accessibility to the enolase catalytic site. This phage-inspired disassembly of enolase represents an alternative strategy for the development of anti-microbial drugs.

  • Journal article
    Giannos P, 2022,

    Altered mitochondrial microenvironment at the spotlight of musculoskeletal aging and Alzheimer’s disease

    , Scientific Reports, Vol: 12, ISSN: 2045-2322

    Emerging evidence has linked Alzheimer’s disease (AD) onset with musculoskeletal aging via a muscle-brain crosstalk mediated by dysregulation of the mitochondrial microenvironment. This study investigated gene expression profiles from skeletal muscle tissues of older healthy adults to identify potential gene biomarkers whose dysregulated expression and protein interactome were involved in AD. Screening of the literature resulted in 12 relevant microarray datasets (GSE25941, GSE28392, GSE28422, GSE47881, GSE47969, GSE59880) in musculoskeletal aging and (GSE4757, GSE5281, GSE16759, GSE28146, GSE48350, GSE84422) in AD. Retrieved differentially expressed genes (DEGs) were used to construct two unique protein-protein interaction (PPI) networks and clustering gene modules were identified. Overlapping module DEGs in the musculoskeletal aging and AD networks were ranked based on 11 topological algorithms and the five highest-ranked ones were considered as hub genes. The analysis revealed that the dysregulated expression of the mitochondrial microenvironment genes, NDUFAB1, UQCRC1, UQCRFS1, NDUFS3, and MRPL15, overlapped between both musculoskeletal aging and AD networks. Thus, these genes may have a potential role as markers of AD occurrence in musculoskeletal aging. Human studies are warranted to evaluate the functional role and prognostic value of these genes in aging populations with sarcopenia and AD.

  • Journal article
    Whyte CE, Singh K, Burton OT, Aloulou M, Kouser L, Veiga RV, Dashwood A, Okkenhaug H, Benadda S, Moudra A, Bricard O, Lienart S, Bielefeld P, Roca CP, Naranjo-Galindo FJ, Lombard-Vadnais F, Junius S, Bending D, Ono M, Hochepied T, Halim TYF, Schlenner S, Lesage S, Dooley J, Liston Aet al., 2022,

    Context-dependent effects of IL-2 rewire immunity into distinct cellular circuits.

    , J Exp Med, Vol: 219

    Interleukin 2 (IL-2) is a key homeostatic cytokine, with therapeutic applications in both immunogenic and tolerogenic immune modulation. Clinical use has been hampered by pleiotropic functionality and widespread receptor expression, with unexpected adverse events. Here, we developed a novel mouse strain to divert IL-2 production, allowing identification of contextual outcomes. Network analysis identified priority access for Tregs and a competitive fitness cost of IL-2 production among both Tregs and conventional CD4 T cells. CD8 T and NK cells, by contrast, exhibited a preference for autocrine IL-2 production. IL-2 sourced from dendritic cells amplified Tregs, whereas IL-2 produced by B cells induced two context-dependent circuits: dramatic expansion of CD8+ Tregs and ILC2 cells, the latter driving a downstream, IL-5-mediated, eosinophilic circuit. The source-specific effects demonstrate the contextual influence of IL-2 function and potentially explain adverse effects observed during clinical trials. Targeted IL-2 production therefore has the potential to amplify or quench particular circuits in the IL-2 network, based on clinical desirability.

  • Journal article
    Jones S, Bell T, Coleman CM, Harris D, Woodward G, Worledge L, Roberts H, McElhinney L, Aegerter J, Ransome E, Savolainen Vet al., 2022,

    Testing bats in rehabilitation for SARS-CoV-2 before release into the wild

    , Conservation Science and Practice, Vol: 4, ISSN: 2578-4854

    Several studies have suggested SARS-CoV-2 originated from a viral ancestor in bats, but whether transmission occurred directly or via an intermediary host to humans remains unknown. Concerns of spillover of SARS-CoV-2 into wild bat populations are hindering bat rehabilitation and conservation efforts in the United Kingdom and elsewhere. Current protocols state that animals cared for by individuals who have tested positive for SARS-CoV-2 cannot be released into the wild and must be isolated to reduce the risk of transmission to wild populations. Here, we propose a reverse transcription-quantitative polymerase chain reaction (RT-qPCR)-based protocol for detection of SARS-CoV-2 in bats, using fecal sampling. Bats from the United Kingdom were tested following suspected exposure to SARS-CoV-2 and tested negative for the virus. With current UK and international legislation, the identification of SARS-CoV-2 infection in wild animals is becoming increasingly important, and protocols such as the one developed here will help improve understanding and mitigation of SARS-CoV-2 in the future.

  • Journal article
    Mullish BH, McDonald JAK, Marchesi JR, 2022,

    Mechanisms of efficacy of intestinal microbiota transplant: do not forget the metabolites

    , The Lancet Gastroenterology & Hepatology, Vol: 7, Pages: 594-594, ISSN: 2468-1253
  • Journal article
    Yunus IS, Anfelt J, Sporre E, Miao R, Hudson EP, Jones PRet al., 2022,

    Synthetic metabolic pathways for conversion of CO2 into secreted short-to medium-chain hydrocarbons using cyanobacteria

    , METABOLIC ENGINEERING, Vol: 72, Pages: 14-23, ISSN: 1096-7176
  • Journal article
    Rurangwa ML, Niyigaba P, Tobias JA, Whittaker RJet al., 2022,

    Functional and phylogenetic diversity of an agricultural matrix avifauna: The role of habitat heterogeneity in Afrotropical farmland

    , Ecology and Evolution, Vol: 12, ISSN: 2045-7758

    Varied strategies to alleviate the loss of farmland biodiversity have been tested, yet there is still insufficient evidence supporting their effectiveness, especially when considering phylogenetic and functional diversity alongside traditional taxonomic diversity metrics. This conservation challenge is accentuated in the Afrotropics by the rapid agricultural expansion and intensification for the production of cash crops and by a comparative lack of research. In this study, we assessed how farming practices influence avian phylogenetic and functional diversity. We conducted point-count surveys to assess avian diversity in monocultures of tea and mixed crop farming systems surrounding the Nyungwe rainforest in south-west Rwanda, allowing us to investigate the drivers of avian diversity at farm level. Species composition was found to be moderately different between farm types, with mixed crop farms supporting higher phylogenetic diversity than tea plantations. There were no significant seasonal differences in species composition, functional or phylogenetic diversity. Overall, functional diversity did not differ between farm types, but the dispersion of trophic-related traits was significantly higher in mixed crop farms. Both functional and phylogenetic diversity were influenced by floristic diversity, vegetation height, tree number, and elevation to varying degrees. Our results also (i) highlight the role of farmland heterogeneity (e.g., crop species composition, height, and tree cover extent) in encouraging avian functional and phylogenetic diversity in the Afrotropics and (ii) indicate that the generally negative biodiversity impacts of monoculture agriculture can be partially alleviated by extensive agroforestry with an emphasis on indigenous tree species.

  • Journal article
    Marghoub A, Williams CJA, Leite JV, Kirby AC, Kever L, Porro LB, Barrett PM, Bertazzo S, Abzhanov A, Vickaryous M, Herrel A, Evans SE, Moazen Met al., 2022,

    Unravelling the structural variation of lizard osteoderms

    , ACTA BIOMATERIALIA, Vol: 146, Pages: 306-316, ISSN: 1742-7061
  • Journal article
    Cao H, Mathur A, Robertson C, Antonopoulos A, Henderson S, Girard L-P, Wong JH, Davie A, Wright S, Brewin J, Rees DC, Dell A, Haslam SM, Vickers MAet al., 2022,

    Measurement of erythrocyte membrane mannoses to assess splenic function

    , British Journal of Haematology, Vol: 198, Pages: 155-164, ISSN: 0007-1048

    Red blood cells (RBCs) lose plasma membrane in the spleen as they age, but the cells and molecules involved are yet to be identified. Sickle cell disease and infection by Plasmodium falciparum cause oxidative stress that induces aggregates of cross-linked proteins with N-linked high-mannose glycans (HMGs). These glycans can be recognised by mannose-binding lectins, including the mannose receptor (CD206), expressed on macrophages and specialised phagocytic endothelial cells in the spleen to mediate the extravascular haemolysis characteristic of these diseases. We postulated this system might also mediate removal of molecules and membrane in healthy individuals. Surface expression of HMGs on RBCs from patients who had previously undergone splenectomy was therefore assessed: high levels were indeed observable as large membrane aggregates. Glycomic analysis by mass spectrometry identified a mixture of Man5-9GlcNAc2 structures. HMG levels correlated well with manual pit counts (r = 0.75–0.85). To assess further whether HMGs might act as a splenic reticuloendothelial function test, we measured levels on RBCs from patients with potential functional hyposplenism, some of whom exhibited high levels that may indicate risk of complications.

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