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  • Journal article
    Basu S, Shukron O, Hall D, Parutto P, Ponjavic A, Shah D, Boucher W, Lando D, Zhang W, Reynolds N, Sober LH, Jartseva A, Ragheb R, Ma X, Cramard J, Floyd R, Balmer J, Drury TA, Carr AR, Needham L-M, Aubert A, Communie G, Gor K, Steindel M, Morey L, Blanco E, Bartke T, Di Croce L, Berger I, Schaffitzel C, Lee SF, Stevens TJ, Klenerman D, Hendrich BD, Holcman D, Laue EDet al., 2023,

    Live-cell three-dimensional single-molecule tracking reveals modulation of enhancer dynamics by NuRD.

    , Nat Struct Mol Biol, Vol: 30, Pages: 1628-1639

    To understand how the nucleosome remodeling and deacetylase (NuRD) complex regulates enhancers and enhancer-promoter interactions, we have developed an approach to segment and extract key biophysical parameters from live-cell three-dimensional single-molecule trajectories. Unexpectedly, this has revealed that NuRD binds to chromatin for minutes, decompacts chromatin structure and increases enhancer dynamics. We also uncovered a rare fast-diffusing state of enhancers and found that NuRD restricts the time spent in this state. Hi-C and Cut&Run experiments revealed that NuRD modulates enhancer-promoter interactions in active chromatin, allowing them to contact each other over longer distances. Furthermore, NuRD leads to a marked redistribution of CTCF and, in particular, cohesin. We propose that NuRD promotes a decondensed chromatin environment, where enhancers and promoters can contact each other over longer distances, and where the resetting of enhancer-promoter interactions brought about by the fast decondensed chromatin motions is reduced, leading to more stable, long-lived enhancer-promoter relationships.
  • Journal article
    Bailey AJ, Ukegbu CV, Giorgalli M, Besson TRB, Christophides GK, Vlachou Det al., 2023,

    Intracellular Plasmodium aquaporin 2 is important for sporozoite production in the mosquito vector and malaria transmission.

    , Proc Natl Acad Sci U S A, Vol: 120

    Malaria remains a devastating disease and, with current measures failing to control its transmission, there is a need for novel interventions. A family of proteins that have long been pursued as potential intervention targets are aquaporins, which are channels facilitating the movement of water and other solutes across membranes. We identify an aquaporin in malaria parasites and demonstrate that it is important for completion of Plasmodium development in the mosquito vector. Disruption of AQP2 in the human parasite Plasmodium falciparum and the rodent parasite Plasmodium berghei blocks sporozoite production inside oocysts established on mosquito midguts, greatly limiting parasite infection of salivary glands and transmission to a new host. In vivo epitope tagging of AQP2 in P. berghei, combined with immunofluorescence assays, reveals that the protein is localized in vesicle-like organelles found in the cytoplasm of gametocytes, ookinetes, and sporozoites. The number of these organelles varies between individual parasites and lifecycle stages suggesting that they are likely part of a dynamic endomembrane system. Phylogenetic analysis confirms that AQP2 is unique to malaria and closely related parasites and most closely resembles intracellular aquaporins. Structure prediction analyses identify several unusual features, including a large accessory extracellular loop and an arginine-to-phenylalanine substitution in the selectivity filter principally determining pore function, a unique feature among known aquaporins. This in conjunction with the importance of AQP2 for malaria transmission suggests that AQP2 may be a fruitful target of antimalarial interventions.
  • Journal article
    Lewis-Brown E, Jennings N, Mills M, Ewers Ret al., 2023,

    Comparison of carbon management and emissions of universities that did and did not adopt voluntary carbon offsets

    , Climate Policy, Pages: 1-17, ISSN: 1469-3062

    The urgent need to reduce greenhouse gas emissions, remove carbon from the atmosphere and stabilize natural carbon sinks has led to the development of many carbon management measures, increasingly including voluntary carbon offsets (VCOs). We studied carbon management in universities, institutions with large carbon footprints and considerable influence in climate science and policy fora. However, concerns that VCOs may deter adopters (including universities) from adopting other carbon reduction measures and limit emissions reductions, for example, through moral hazard, have been raised but understudied. We compared the carbon management characteristics (priorities, policies, practices and emissions) of universities that did and did not adopt VCOs. We found adopters measured carbon emissions for longer, and had set targets to reach net zero earlier than had non-adopters. Adopters of VCOs also undertook more carbon management practices in both 2010 and 2020 than non-adopters. We also found that both adopters and non-adopters significantly increased their carbon management practices over the decade studied, but with no difference between groups. Gross CO2 emissions were reduced significantly over time by adopters of VCOs but not by non-adopters, whereas carbon intensity and percentage annual emissions reductions did not relate to adoption status. Consequently, our study showed no indication of mitigation deterrence due to adoption of VCOs at the universities studied. Rather, greater emissions reductions correlated with earlier net zero target dates, and a higher number of policies and carbon management practices. However, our study was constrained to universities that were affiliated with a national environmental network, so research beyond these organizations, and with individuals, would be useful. The survey was voluntary, exposing the study to potential self-selection bias so the findings may not be generalized beyond the study group. Finally, we found the carbon ac
  • Journal article
    Sammon D, Krueger A, Busse-Wicher M, Morgan RM, Haslam S, Schumann B, Briggs D, Hohenester Eet al., 2023,

    Molecular mechanism of decision-making in glycosaminoglycan biosynthesis

    , Nature Communications, Vol: 14, ISSN: 2041-1723

    Two major glycosaminoglycan types, heparan sulfate (HS) and chondroitin sulfate (CS), control many aspects of development and physiology in a type-specific manner. HS and CS are attached to core proteins via a common linker tetrasaccharide, but differ in their polymer backbones. How core proteins are specifically modified with HS or CS has been an enduring mystery. By reconstituting glycosaminoglycan biosynthesis in vitro, we establish that the CS-initiating N-acetylgalactosaminyltransferase CSGALNACT2 modifies all glycopeptide substrates equally, whereas the HS-initiating N-acetylglucosaminyltransferase EXTL3 is selective. Structure-function analysis reveals that acidic residues in the glycopeptide substrate and a basic exosite in EXTL3 are critical for specifying HS biosynthesis. Linker phosphorylation by the xylose kinase FAM20B accelerates linker synthesis and initiation of both HS and CS, but has no effect on the subsequent polymerisation of the backbone. Our results demonstrate that modification with CS occurs by default and must be overridden by EXTL3 to produce HS.
  • Journal article
    Liang G, Reed SC, Stark JM, Waring BGet al., 2023,

    Unraveling mechanisms underlying effects of wetting-drying cycles on soil respiration in a dryland

    , BIOGEOCHEMISTRY, ISSN: 0168-2563
  • Journal article
    El Omari K, Duman R, Mykhaylyk V, Orr CM, Latimer-Smith M, Winter G, Grama V, Qu F, Bountra K, Kwong HS, Romano M, Reis RI, Vogeley L, Vecchia L, Owen CD, Wittmann S, Renner M, Senda M, Matsugaki N, Kawano Y, Bowden TA, Moraes I, Grimes JM, Mancini EJ, Walsh MA, Guzzo CR, Owens RJ, Jones EY, Brown DG, Stuart DI, Beis K, Wagner Aet al., 2023,

    Experimental phasing opportunities for macromolecular crystallography at very long wavelengths.

    , Commun Chem, Vol: 6

    Despite recent advances in cryo-electron microscopy and artificial intelligence-based model predictions, a significant fraction of structure determinations by macromolecular crystallography still requires experimental phasing, usually by means of single-wavelength anomalous diffraction (SAD) techniques. Most synchrotron beamlines provide highly brilliant beams of X-rays of between 0.7 and 2 Å wavelength. Use of longer wavelengths to access the absorption edges of biologically important lighter atoms such as calcium, potassium, chlorine, sulfur and phosphorus for native-SAD phasing is attractive but technically highly challenging. The long-wavelength beamline I23 at Diamond Light Source overcomes these limitations and extends the accessible wavelength range to λ = 5.9 Å. Here we report 22 macromolecular structures solved in this extended wavelength range, using anomalous scattering from a range of elements which demonstrate the routine feasibility of lighter atom phasing. We suggest that, in light of its advantages, long-wavelength crystallography is a compelling option for experimental phasing.
  • Journal article
    Blackhurst L, Gilestro G, 2023,

    Ethoscopy and ethoscope-lab: a framework for behavioural analysis to lower entrance barrier and aid reproducibility behavioural analysis to lower entrance barrier and aidreproducibility

    , Bioinformatics Advances, Vol: 3, ISSN: 2635-0041

    High-throughput analysis of behaviour is a pivotal instrument in modern neuroscience, allowing researchers to combine modern genetics breakthrough to unbiased, objective, reproducible experimental approaches. To this extent, we recently created an open-source hardware platform (ethoscope (Geissmann et al., 2017)) that allows for inexpensive, accessible, high-throughput analysis of behaviour in Drosophila or other animal models. Here we equip ethoscopes with a Python framework for data analysis, ethoscopy, designed to be a user-friendly yet powerful platform, meeting the requirements of researchers with limited coding expertise as well as experienced data scientists. Ethoscopy is best consumed in a prebakedJupyter-based docker container, ethoscope-lab, to improve accessibility and to encourage the use of notebooks as anatural platform to share post-publication data analysis. Ethoscopy is a Python package available on GitHub and PyPi. Ethoscope-lab is a docker container available on DockerHub. A landing page aggregating all the code and documentation is available at https://lab.gilest.ro/ethoscopy.
  • Journal article
    Costa TRD, Patkowski JB, Mace K, Christie PJ, Waksman Get al., 2023,

    Structural and functional diversity of type IV secretion systems

    , Nature Reviews Microbiology, ISSN: 1740-1526

    Considerable progress has been made in recent years in the structural and molecular biology of type IV secretion systems in Gram-negative bacteria. The latest advances have substantially improved our understanding of the mechanisms underlying the recruitment and delivery of DNA and protein substrates to the extracellular environment or target cells. In this Review, we aim to summarize these exciting structural and molecular biology findings and to discuss their functional implications for substrate recognition, recruitment and translocation, as well as the biogenesis of extracellular pili. We also describe adaptations necessary for deploying a breadth of processes, such as bacterial survival, host–pathogen interactions and biotic and abiotic adhesion. We highlight the functional and structural diversity that allows this extremely versatile secretion superfamily to function under different environmental conditions and in different bacterial species. Additionally, we emphasize the importance of further understanding the mechanism of type IV secretion, which will support us in combating antimicrobial resistance and treating type IV secretion system-related infections.
  • Journal article
    O'Gorman EJ, Zhao L, Kordas RL, Dudgeon S, Woodward Get al., 2023,

    Warming indirectly simplifies food webs through effects on apex predators

    , NATURE ECOLOGY & EVOLUTION, ISSN: 2397-334X
  • Journal article
    Williams J, Pettorelli N, Hartmann A, Quinn R, Plaisance L, OMahoney M, Meyer C, Fabricius K, Knowlton N, Ransome Eet al., 2023,

    Decline of a distinct coral reef holobiont community under ocean acidification

    , Microbiome, ISSN: 2049-2618

    Background: Microbes play vital roles across coral reefs both in the environment and inside and upon macrobes (holobionts), where they support critical functions such as nutrition and immune system modulation. These roles highlight the potential ecosystem-level importance of microbes, yet most knowledge of microbial functions on reefs is derived from a small set of holobionts such as corals and sponges. Declining seawater pH - an important global coral reef stressor - can cause ecosystem-level change on coral reefs, providing an opportunity to study the role of microbes at this scale. We use an in situ experimental approach to test the hypothesis that under such ocean acidification (OA) known shifts among macrobe trophic and functional groups may drive a general ecosystem-level response extending across macrobes and microbes, leading to reduced distinctness between the benthic holobiont community microbiome and the environmental microbiome. Results: We test this hypothesis using genetic and chemical data from benthic coral reef community holobionts sampled across a pH gradient from CO2 seeps in Papua New Guinea. We find support for our hypothesis: under OA the microbiome and metabolome of the benthic holobiont community become less compositionally distinct from the sediment microbiome and metabolome, suggesting that benthic macrobe communities are colonized by environmental microbes to a higher degree under OA conditions. We also find a simplification and homogenisation of the benthic photosynthetic community, and an increased abundance of fleshy macroalgae, consistent with previously observed reef microbialisation. Conclusions: We demonstrate a novel structural shift in coral reefs involving macrobes and microbes: that the microbiome of the benthic holobiont community becomes less distinct from the sediment microbiome under OA. Our findings provide evidence that microbialisation and the disruption of macrobe trophic networks are interwoven general responses to envi
  • Journal article
    Kikuchi C, Antonopoulos A, Wang S, Maemura T, Karamanska R, Lee C, Thompson AJ, Dell A, Kawaoka Y, Haslam SM, Paulson JCet al., 2023,

    Glyco-engineered MDCK cells display preferred receptors of H3N2 influenza absent in eggs used for vaccines

    , Nature Communications, Vol: 14, ISSN: 2041-1723

    Evolution of human H3N2 influenza viruses driven by immune selection has narrowed the receptor specificity of the hemagglutinin (HA) to a restricted subset of human-type (Neu5Acα2-6 Gal) glycan receptors that have extended poly-LacNAc (Galβ1-4GlcNAc) repeats. This altered specificity has presented challenges for hemagglutination assays, growth in laboratory hosts, and vaccine production in eggs. To assess the impact of extended glycan receptors on virus binding, infection, and growth, we have engineered N-glycan extended (NExt) cell lines by overexpressing β3-Ν-acetylglucosaminyltransferase 2 in MDCK, SIAT, and hCK cell lines. Of these, SIAT-NExt cells exhibit markedly increased binding of H3 HAs and susceptibility to infection by recent H3N2 virus strains, but without impacting final virus titers. Glycome analysis of these cell lines and allantoic and amniotic egg membranes provide insights into the importance of extended glycan receptors for growth of recent H3N2 viruses and relevance to their production for cell- and egg-based vaccines.
  • Journal article
    Jønsson R, Björling A, Midtgaard SR, Jensen GV, Skar-Gislinge N, Arleth L, Matthews S, Krogfelt KA, Jenssen Het al., 2023,

    Aggregative adherence fimbriae form compact structures as seen by SAXS.

    , Sci Rep, Vol: 13

    Bacterial colonization is mediated by fimbriae, which are thin hair-like appendages dispersed from the bacterial surface. The aggregative adherence fimbriae from enteroaggregative E. coli are secreted through the outer membrane and consist of polymerized minor and major pilin subunits. Currently, the understanding of the structural morphology and the role of the minor pilin subunit in the polymerized fimbriae are limited. In this study we use small-angle X-ray scattering to reveal the structural morphology of purified fimbriae in solution. We show that the aggregative fimbriae are compact arrangements of subunit proteins Agg5A + Agg3B which are assembled pairwise on a flexible string rather than extended in relatively straight filaments. Absence of the minor subunit leads to less compact fimbriae, but did not affect the length. The study provides novel insights into the structural morphology and assembly of the aggregative adherence fimbriae. Our study suggests that the minor subunit is not located at the tip of the fimbriae as previously speculated but has a higher importance for the assembled fimbriae by affecting the global structure.
  • Journal article
    Bentham AR, De la Concepcion JC, Benjumea JV, Kourelis J, Jones S, Mendel M, Stubbs J, Stevenson CEM, Maidment JHR, Youles M, Zdrzałek R, Kamoun S, Banfield MJet al., 2023,

    Allelic compatibility in plant immune receptors facilitates engineering of new effector recognition specificities

    , The Plant Cell, Vol: 35, Pages: 3809-3827, ISSN: 1040-4651

    Engineering the plant immune system offers genetic solutions to mitigate crop diseases caused by diverse agriculturally significant pathogens and pests. Modification of intracellular plant immune receptors of the nucleotide-binding leucine-rich repeat (NLR) receptor superfamily for expanded recognition of pathogen virulence proteins (effectors) is a promising approach for engineering disease resistance. However, engineering can cause NLR autoactivation, resulting in constitutive defense responses that are deleterious to the plant. This may be due to plant NLRs associating in highly complex signaling networks that coevolve together, and changes through breeding or genetic modification can generate incompatible combinations, resulting in autoimmune phenotypes. The sensor and helper NLRs of the rice (Oryza sativa) NLR pair Pik have coevolved, and mismatching between noncoevolved alleles triggers constitutive activation and cell death. This limits the extent to which protein modifications can be used to engineer pathogen recognition and enhance disease resistance mediated by these NLRs. Here, we dissected incompatibility determinants in the Pik pair in Nicotiana benthamiana and found that heavy metal-associated (HMA) domains integrated in Pik-1 not only evolved to bind pathogen effectors but also likely coevolved with other NLR domains to maintain immune homeostasis. This explains why changes in integrated domains can lead to autoactivation. We then used this knowledge to facilitate engineering of new effector recognition specificities, overcoming initial autoimmune penalties. We show that by mismatching alleles of the rice sensor and helper NLRs Pik-1 and Pik-2, we can enable the integration of synthetic domains with novel and enhanced recognition specificities. Taken together, our results reveal a strategy for engineering NLRs, which has the potential to allow an expanded set of integrations and therefore new disease resistance specificities in plants.
  • Journal article
    de Ceglia R, Ledonne A, Litvin DG, Lind BL, Carriero G, Latagliata EC, Bindocci E, Di Castro MA, Savtchouk I, Vitali I, Ranjak A, Congiu M, Canonica T, Wisden W, Harris K, Mameli M, Mercuri N, Telley L, Volterra Aet al., 2023,

    Specialized astrocytes mediate glutamatergic gliotransmission in the CNS.

    , Nature, Vol: 622, Pages: 120-129

    Multimodal astrocyte-neuron communications govern brain circuitry assembly and function1. For example, through rapid glutamate release, astrocytes can control excitability, plasticity and synchronous activity2,3 of synaptic networks, while also contributing to their dysregulation in neuropsychiatric conditions4-7. For astrocytes to communicate through fast focal glutamate release, they should possess an apparatus for Ca2+-dependent exocytosis similar to neurons8-10. However, the existence of this mechanism has been questioned11-13 owing to inconsistent data14-17 and a lack of direct supporting evidence. Here we revisited the astrocyte glutamate exocytosis hypothesis by considering the emerging molecular heterogeneity of astrocytes18-21 and using molecular, bioinformatic and imaging approaches, together with cell-specific genetic tools that interfere with glutamate exocytosis in vivo. By analysing existing single-cell RNA-sequencing databases and our patch-seq data, we identified nine molecularly distinct clusters of hippocampal astrocytes, among which we found a notable subpopulation that selectively expressed synaptic-like glutamate-release machinery and localized to discrete hippocampal sites. Using GluSnFR-based glutamate imaging22 in situ and in vivo, we identified a corresponding astrocyte subgroup that responds reliably to astrocyte-selective stimulations with subsecond glutamate release events at spatially precise hotspots, which were suppressed by astrocyte-targeted deletion of vesicular glutamate transporter 1 (VGLUT1). Furthermore, deletion of this transporter or its isoform VGLUT2 revealed specific contributions of glutamatergic astrocytes in cortico-hippocampal and nigrostriatal circuits during normal behaviour and pathological processes. By uncovering this atypical subpopulation of specialized astrocytes in the adult brain, we provide insights into the complex roles of astrocytes in central nervous system (CNS) physiology and diseases, and ide
  • Journal article
    Devenish AJM, Schmitter P, Jellason NP, Esmail N, Abdi NM, Adanu SK, Adolph B, Al-Zubi M, Amali AA, Barron J, Chapman ASA, Chausson AM, Chibesa M, Davies J, Dugan E, Edwards GI, Egeru A, Gebrehiwot T, Griffiths GH, Haile A, Hunga HG, Igbine L, Jarju OM, Keya F, Khalifa M, Ledoux WA, Lejissa LT, Loupa P, Lwanga J, Mapedza ED, Marchant R, McLoud T, Mukuyu P, Musah LM, Mwanza M, Mwitwa J, Neina D, Newbold T, Njogo S, Robinson EJZ, Singini W, Umar BB, Wesonga F, Willcock S, Yang J, Tobias JAet al., 2023,

    One hundred priority questions for the development of sustainable food systems in Sub-Saharan Africa

    , Land, Vol: 12, ISSN: 2073-445X

    Sub-Saharan Africa is facing an expected doubling of human population and tripling of food demand over the next quarter century, posing a range of severe environmental, political, and socio-economic challenges. In some cases, key Sustainable Development Goals (SDGs) are in direct conflict, raising difficult policy and funding decisions, particularly in relation to trade-offs between food production, social inequality, and ecosystem health. In this study, we used a horizon-scanning approach to identify 100 practical or research-focused questions that, if answered, would have the greatest positive impact on addressing these trade-offs and ensuring future productivity and resilience of food-production systems across sub-Saharan Africa. Through direct canvassing of opinions, we obtained 1339 questions from 331 experts based in 55 countries. We then used online voting and participatory workshops to produce a final list of 100 questions divided into 12 thematic sections spanning topics from gender inequality to technological adoption and climate change. Using data on the background of respondents, we show that perspectives and priorities can vary, but they are largely consistent across different professional and geographical contexts. We hope these questions provide a template for establishing new research directions and prioritising funding decisions in sub-Saharan Africa.
  • Journal article
    Murray J, Smith AP, Simpson M, Elizondo KM, Aitkenhead-Peterson JA, Waring Bet al., 2023,

    Climate, as well as branch-level processes, drive canopy soil abundance and chemistry

    , GEODERMA, Vol: 438, ISSN: 0016-7061
  • Journal article
    Savolainen V, 2023,

    Environmental DNA helps reveal reef shark distribution across a remote archipelago

    , Ecological Indicators, Vol: 154, Pages: 1-10, ISSN: 1470-160X

    Environmental DNA (eDNA) methods are being increasingly used in proof-of-concept studies to detect shark species, many populations of which are experiencing severe declines. These methods are widely seen as the future of biodiversity monitoring, but they have yet to become established as routine monitoring techniques for elasmobranch species. Here, we developed species-specific quantitative PCR assays for the detection of grey reef shark (Carcharhinus amblyrhynchos) and silvertip shark (Carcharhinus albimarginatus). We assessed whether species-specific eDNA methods could infer the distribution of the two species around the atolls of the Chagos Archipelago, which, despite being surrounded by a large marine protected area, experience contrasting levels of illegal fishing leading to heterogeneity in shark population densities. We found that eDNA detections were significantly reduced and sporadic around the northern atolls, which are under high pressure from illegal fishing. By contrast eDNA detections of both species were ubiquitous and consistent around the highly protected atoll Diego Garcia. We postulate that current levels of illegal, unreported and unregulated (IUU) fishing is having a significant impact on the shark community in the northern atolls and suppressing local reef shark populations. In the northern atolls we also employed visual and acoustic telemetry techniques to reveal the distribution of reef sharks. We found that despite eDNA samples being taken directly after visual surveys, detection results did not correlate, suggesting a need for further optimisation of eDNA methods for detecting sharks. However, both species were detected by eDNA in sites where they were not observed, highlighting that the scale of the sampling environment must be considered when inferring eDNA results and showing that eDNA methods can be used to fill gaps in data from more established monitoring techniques. We conclude that eDNA methods should be used in combination with oth
  • Journal article
    Adachi H, Sakai T, Kourelis J, Pai H, Gonzalez Hernandez JL, Utsumi Y, Seki M, Maqbool A, Kamoun Set al., 2023,

    Jurassic NLR: conserved and dynamic evolutionary features of the atypically ancient immune receptor ZAR1

    , The Plant Cell, Vol: 35, Pages: 3662-3685, ISSN: 1040-4651

    Plant nucleotide-binding leucine-rich repeat (NLR) immune receptors generally exhibit hallmarks of rapid evolution, even at the intraspecific level. We used iterative sequence similarity searches coupled with phylogenetic analyses to reconstruct the evolutionary history of HOPZ-ACTIVATED RESISTANCE1 (ZAR1), an atypically conserved NLR that traces its origin to early flowering plant lineages ∼220 to 150 million yrs ago (Jurassic period). We discovered 120 ZAR1 orthologs in 88 species, including the monocot Colocasia esculenta, the magnoliid Cinnamomum micranthum, and most eudicots, notably the Ranunculales species Aquilegia coerulea, which is outside the core eudicots. Ortholog sequence analyses revealed highly conserved features of ZAR1, including regions for pathogen effector recognition and cell death activation. We functionally reconstructed the cell death activity of ZAR1 and its partner receptor-like cytoplasmic kinase (RLCK) from distantly related plant species, experimentally validating the hypothesis that ZAR1 evolved to partner with RLCKs early in its evolution. In addition, ZAR1 acquired novel molecular features. In cassava (Manihot esculenta) and cotton (Gossypium spp.), ZAR1 carries a C-terminal thioredoxin-like domain, and in several taxa, ZAR1 duplicated into 2 paralog families, which underwent distinct evolutionary paths. ZAR1 stands out among angiosperm NLR genes for having experienced relatively limited duplication and expansion throughout its deep evolutionary history. Nonetheless, ZAR1 also gave rise to noncanonical NLRs with integrated domains and degenerated molecular features.
  • Journal article
    Tossell K, Yu X, Giannos P, Anuncibay Soto B, Nollet M, Yustos R, Miracca G, Vicente M, Miao A, Hsieh B, Ma Y, Vysstoski A, Constandinou T, Franks N, Wisden Wet al., 2023,

    Somatostatin neurons in prefrontal cortex initiate sleep preparatory behavior and sleep via the preoptic and lateral hypothalamus

    , Nature Neuroscience, Vol: 26, Pages: 1805-1819, ISSN: 1097-6256

    The prefrontal cortex (PFC) enables mammals to respond to situations, including internal states, with appropriate actions. One such internal state could be ‘tiredness’. Here, using activity tagging in the mouse PFC, we identified particularly excitable, fast-spiking, somatostatin-expressing, γ-aminobutyric acid (GABA) (PFCSst-GABA) cells that responded to sleep deprivation. These cells projected to the lateral preoptic (LPO) hypothalamus and the lateral hypothalamus (LH). Stimulating PFCSst-GABA terminals in the LPO hypothalamus caused sleep-preparatory behavior (nesting, elevated theta power and elevated temperature), and stimulating PFCSst-GABA terminals in the LH mimicked recovery sleep (non-rapid eye-movement sleep with higher delta power and lower body temperature). PFCSst-GABA terminals had enhanced activity during nesting and sleep, inducing inhibitory postsynaptic currents on diverse cells in the LPO hypothalamus and the LH. The PFC also might feature in deciding sleep location in the absence of excessive fatigue. These findings suggest that the PFC instructs the hypothalamus to ensure that optimal sleep takes place in a suitable place.
  • Journal article
    Haas O, Prentice IC, Harrison SP, 2023,

    The response of wildfire regimes to Last Glacial Maximum carbon dioxide and climate

    , Biogeosciences, Vol: 20, Pages: 3981-3995, ISSN: 1726-4170

    Climate and fuel availability jointly control the incidence of wildfires. The effects of atmospheric CO2 on plant growth influence fuel availability independently of climate, but the relative importance of each in driving largescale changes in wildfire regimes cannot easily be quantified from observations alone. Here, we use previously developed empirical models to simulate the global spatial pattern of burnt area, fire size, and fire intensity for modern and Last Glacial Maximum (LGM; ∼21 000 ka) conditions using both realistic changes in climate and CO2 and sensitivity experiments to separate their effects. Three different LGM scenarios are used to represent the range of modelled LGM climates.We show large, modelled reductions in burnt area at the LGM compared to the recent period, consistent with the sedimentary charcoal record. This reduction was predominantly driven by the effect of low CO2 on vegetation productivity. The amplitude of the reduction under low-CO2 conditions was similar regardless of the LGM climate scenario and was not observed in any LGM scenario when only climate effects were considered, with one LGM climate scenario showing increased burning under these conditions. Fire intensity showed a similar sensitivity to CO2 across different climates but was also sensitive to changes in vapour pressure deficit (VPD). Modelled fire size was reduced under LGM CO2 in many regions but increased under LGM climates because of changes in wind strength, dry days (DDs), and diurnal temperature range (DTR). This increase was offset under the coldest LGM climate in the northern latitudes because of a large reduction in VPD. These results emphasize the fact that the relative magnitudes of changes in different climate variables influence the wildfire regime and that different aspects of climate change can have opposing effects. The importance of CO2 effects imply that future projections of wildfire must take rising CO2 into account.
  • Journal article
    Wiggins BG, Wang Y-F, Burke A, Grunberg N, Vlachaki Walker JM, Dore M, Chahrour C, Pennycook BR, Sanchez-Garrido J, Vernia S, Barr AR, Frankel G, Birdsey GM, Randi AM, Schiering Cet al., 2023,

    Endothelial sensing of AHR ligands regulates intestinal homeostasis

    , Nature, Vol: 621, Pages: 821-829, ISSN: 0028-0836

    Endothelial cells (ECs) line the blood and lymphatic vasculature, and act as an essential physical barrier, control nutrient transport, facilitate tissue immunosurveillance, and coordinate angiogenesis/ lymphangiogenesis1,2. In the intestine, dietary and microbial cues are particularly important in the regulation of organ homeostasis. However, whether enteric ECs actively sense and integrate such signals is currently unknown. Here, we show that the aryl hydrocarbon receptor (AHR) acts as a critical node for EC-sensing of dietary metabolites in adult mice and human primary ECs. We first established a comprehensive single-cell endothelial atlas of the mouse small intestine, uncovering the cellular complexity and functional heterogeneity of blood and lymphatic ECs. Analyses of AHR mediated responses at single-cell resolution identified tissue-protective transcriptional signatures and regulatory networks promoting cellular quiescence and vascular normalcy at steady state. Endothelial AHR-deficiency in adult mice resulted in dysregulated inflammatory responses, and the initiation of proliferative pathways. Furthermore, endothelial sensing of dietary AHR ligands was required for optimal protection against enteric infection. In human ECs, AHR signalling promoted quiescence and restrained activation by inflammatory mediators. Together, our data provide a comprehensive dissection of the impact of environmental sensing across the spectrum of enteric endothelia, demonstrating that endothelial AHR signalling integrates dietary cues to maintain tissue homeostasis by promoting EC quiescence and vascular normalcy.
  • Journal article
    Cáceres C, Bourtzis K, Gouvi G, Vreysen MJB, Bimbilé Somda NS, Hejníčková M, Marec F, Meza JSet al., 2023,

    Development of a novel genetic sexing strain of Ceratitis capitata based on an X-autosome translocation.

    , Sci Rep, Vol: 13

    Genetic sexing strains (GSS), such as the Ceratitis capitata (medfly) VIENNA 8 strain, facilitate male-only releases and improve the efficiency and cost-effectiveness of sterile insect technique (SIT) applications. Laboratory domestication may reduce their genetic diversity and mating behaviour and hence, refreshment with wild genetic material is frequently needed. As wild males do not carry the T(Y;A) translocation, and wild females do not easily conform to artificial oviposition, the genetic refreshment of this GSS is a challenging and time-consuming process. In the present study, we report the development of a novel medfly GSS, which is based on a viable homozygous T(XX;AA) translocation using the same selectable markers, the white pupae and temperature-sensitive lethal genes. This allows the en masse cross of T(XX;AA) females with wild males, and the backcrossing of F1 males with the T(XX;AA) females thus facilitating the re-establishment of the GSS as well as its genetic refreshment. The rearing efficiency and mating competitiveness of the novel GSS are similar to those of the T(Y;A)-based VIENNA 8 GSS. However, its advantage to easily allow the genetic refreshment is of great importance as it can ensure the mass production of high-quality males and enhanced efficacy of operational SIT programs.
  • Journal article
    Boussac A, Sugiura M, Nakamura M, Nagao R, Noguchi T, Viola S, Rutherford AW, Sellés Jet al., 2023,

    Absorption changes in Photosystem II in the Soret band region upon the formation of the chlorophyll cation radical [PD1PD2].

    , Photosynth Res

    Flash-induced absorption changes in the Soret region arising from the [PD1PD2]+ state, the chlorophyll cation radical formed upon light excitation of Photosystem II (PSII), were measured in Mn-depleted PSII cores at pH 8.6. Under these conditions, TyrD is i) reduced before the first flash, and ii) oxidized before subsequent flashes. In wild-type PSII, when TyrD● is present, an additional signal in the [PD1PD2]+-minus-[PD1PD2] difference spectrum was observed when compared to the first flash when TyrD is not oxidized. The additional feature was "W-shaped" with troughs at 434 nm and 446 nm. This feature was absent when TyrD was reduced, but was present (i) when TyrD was physically absent (and replaced by phenylalanine) or (ii) when its H-bonding histidine (D2-His189) was physically absent (replaced by a Leucine). Thus, the simple difference spectrum without the double trough feature at 434 nm and 446 nm, seemed to require the native structural environment around the reduced TyrD and its H bonding partners to be present. We found no evidence of involvement of PD1, ChlD1, PheD1, PheD2, TyrZ, and the Cytb559 heme in the W-shaped difference spectrum. However, the use of a mutant of the PD2 axial His ligand, the D2-His197Ala, shows that the PD2 environment seems involved in the formation of "W-shaped" signal.
  • Journal article
    Drury F, Grover M, Hintze M, Saunders J, Fasseas MK, Constantinou C, Barkoulas Met al., 2023,

    A PAX6-regulated receptor tyrosine kinase pairs with a pseudokinase to activate immune defense upon oomycete recognition in Caenorhabditis elegans.

    , Proc Natl Acad Sci U S A, Vol: 120

    Oomycetes were recently discovered as natural pathogens of Caenorhabditis elegans, and pathogen recognition alone was shown to be sufficient to activate a protective transcriptional program characterized by the expression of multiple chitinase-like (chil) genes. However, the molecular mechanisms underlying oomycete recognition in animals remain fully unknown. We performed here a forward genetic screen to uncover regulators of chil gene induction and found several independent loss-of-function alleles of old-1 and flor-1, which encode receptor tyrosine kinases belonging to the C. elegans-specific KIN-16 family. We report that OLD-1 and FLOR-1 are both necessary for mounting the immune response and act in the epidermis. FLOR-1 is a pseudokinase that acts downstream of the active kinase OLD-1 and regulates OLD-1 levels at the plasma membrane. Interestingly, the old-1 locus is adjacent to the chil genes in the C. elegans genome, thereby revealing a genetic cluster important for oomycete resistance. Furthermore, we demonstrate that old-1 expression at the anterior side of the epidermis is regulated by the VAB-3/PAX6 transcription factor, well known for its role in visual system development in other animals. Taken together, our study reveals both conserved and species-specific factors shaping the activation and spatial characteristics of the immune response to oomycete recognition.
  • Journal article
    Frankel G, David S, Low WW, Seddon C, Wong JLC, Beis Ket al., 2023,

    Plasmids pick a bacterial partner before committing to conjugation

    , NUCLEIC ACIDS RESEARCH, Vol: 51, Pages: 8925-8933, ISSN: 0305-1048
  • Journal article
    Ukegbu CV, Gomes AR, Giorgalli M, Campos M, Bailey AJ, Besson TRB, Billker O, Vlachou D, Christophides GKet al., 2023,

    Identification of genes required for<i> Plasmodium</i> gametocyte-to-sporozoite development in the mosquito vector

    , CELL HOST & MICROBE, Vol: 31, Pages: 1539-+, ISSN: 1931-3128
  • Journal article
    Sasidharan S, Davis DM, Dunlop IE, 2023,

    Bioinspired Materials for Immunoengineering of T Cells and Natural Killer Cells

    , ADVANCED FUNCTIONAL MATERIALS, ISSN: 1616-301X
  • Journal article
    Lagou V, Jiang L, Ulrich A, Zudina L, González KSG, Balkhiyarova Z, Faggian A, Maina JG, Chen S, Todorov PV, Sharapov S, David A, Marullo L, Mägi R, Rujan R-M, Ahlqvist E, Thorleifsson G, Gao Η, Εvangelou Ε, Benyamin B, Scott RA, Isaacs A, Zhao JH, Willems SM, Johnson T, Gieger C, Grallert H, Meisinger C, Müller-Nurasyid M, Strawbridge RJ, Goel A, Rybin D, Albrecht E, Jackson AU, Stringham HM, Corrêa IR, Farber-Eger E, Steinthorsdottir V, Uitterlinden AG, Munroe PB, Brown MJ, Schmidberger J, Holmen O, Thorand B, Hveem K, Wilsgaard T, Mohlke KL, Wang Z, GWA-PA Consortium, Shmeliov A, den Hoed M, Loos RJF, Kratzer W, Haenle M, Koenig W, Boehm BO, Tan TM, Tomas A, Salem V, Barroso I, Tuomilehto J, Boehnke M, Florez JC, Hamsten A, Watkins H, Njølstad I, Wichmann H-E, Caulfield MJ, Khaw K-T, van Duijn CM, Hofman A, Wareham NJ, Langenberg C, Whitfield JB, Martin NG, Montgomery G, Scapoli C, Tzoulaki I, Elliott P, Thorsteinsdottir U, Stefansson K, Brittain EL, McCarthy MI, Froguel P, Sexton PM, Wootten D, Groop L, Dupuis J, Meigs JB, Deganutti G, Demirkan A, Pers TH, Reynolds CA, Aulchenko YS, Kaakinen MA, Jones B, Prokopenko I, Meta-Analysis of Glucose and Insulin-Related Traits Consortium MAGICet al., 2023,

    GWAS of random glucose in 476,326 individuals provide insights into diabetes pathophysiology, complications and treatment stratification

    , Nature Genetics, Vol: 55, Pages: 1448-1461, ISSN: 1061-4036

    Conventional measurements of fasting and postprandial blood glucose levels investigated in genome-wide association studies (GWAS) cannot capture the effects of DNA variability on 'around the clock' glucoregulatory processes. Here we show that GWAS meta-analysis of glucose measurements under nonstandardized conditions (random glucose (RG)) in 476,326 individuals of diverse ancestries and without diabetes enables locus discovery and innovative pathophysiological observations. We discovered 120 RG loci represented by 150 distinct signals, including 13 with sex-dimorphic effects, two cross-ancestry and seven rare frequency signals. Of these, 44 loci are new for glycemic traits. Regulatory, glycosylation and metagenomic annotations highlight ileum and colon tissues, indicating an underappreciated role of the gastrointestinal tract in controlling blood glucose. Functional follow-up and molecular dynamics simulations of lower frequency coding variants in glucagon-like peptide-1 receptor (GLP1R), a type 2 diabetes treatment target, reveal that optimal selection of GLP-1R agonist therapy will benefit from tailored genetic stratification. We also provide evidence from Mendelian randomization that lung function is modulated by blood glucose and that pulmonary dysfunction is a diabetes complication. Our investigation yields new insights into the biology of glucose regulation, diabetes complications and pathways for treatment stratification.
  • Journal article
    de Ceglia R, Ledonne A, Litvin DG, Lind BL, Carriero G, Latagliata EC, Bindocci E, Di Castro MA, Savtchouk I, Vitali I, Ranjak A, Congiu M, Canonica T, Wisden W, Harris K, Mameli M, Mercuri N, Telley L, Volterra Aet al., 2023,

    Specialized astrocytes mediate glutamatergic gliotransmission in the CNS

    , NATURE, ISSN: 0028-0836
  • Journal article
    Boyle KB, Ellison CJ, Elliott PR, Schuschnig M, Grimes K, Dionne MS, Sasakawa C, Munro S, Martens S, Randow Fet al., 2023,

    TECPR1 conjugates LC3 to damaged endomembranes upon detection of sphingomyelin exposure

    , EMBO JOURNAL, Vol: 42, ISSN: 0261-4189

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