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  • Journal article
    Schuster M, Eisele S, Armas-Egas L, Kessenbrock T, Kourelis J, Kaiser M, van der Hoorn RALet al., 2024,

    Enhanced late blight resistance by engineering an EpiC2B-insensitive immune protease

    , Plant Biotechnology Journal, Vol: 22, Pages: 284-286, ISSN: 1467-7644

    Papain-like immune proteases (PLCPs) are promising engineering targets for crop protection, given their significant roles in plant immunity for key crops such as tomato, maize and citrus (Misas-Villamil et al., 2016). The wide range of pathogen-secreted PLCP inhibitors highlights the importance of these proteases in defending against various pathogens. Depletion of the apoplastic immune PLCP Phytophthora-inhibited protease 1 (Pip1) from tomato, for instance, causes hyper-susceptibility to bacterial, fungal and oomycete tomato pathogens (Ilyas et al., 2015). Immunity by Pip1 in wild-type tomato is, however, suboptimal since Pip1 is suppressed during infection by diverse pathogen-secreted inhibitors, such as the cystatin-like EpiC2B from the oomycete late blight pathogen Phytophthora infestans (Tian et al., 2007). Here, we tested whether we could increase Pip1-based immunity against late blight by engineering Pip1 into an EpiC2B-insensitive protease. To guide Pip1 mutagenesis, we generated a structural model of the EpiC2B-Pip1 complex using AlphaFold-Multimer (Evans et al., 2022). This structural model represents a classic interaction between the tripartite wedge of cystatin (EpiC2B) in the substrate binding groove of papain (Pip1). This model indicated that engineering Pip1 to prevent inhibition without affecting Pip1 substrate specificity is possible because the interaction surface of Pip1 with EpiC2B is larger than the substrate binding groove (Figure 1a).

  • Journal article
    Cantwell-Jones A, Tylianakis J, Larson K, Gill Ret al., 2024,

    Using individual-based trait frequency distributions to forecast plant-pollinator network responses to environmental change

    , Ecology Letters, Vol: 27, ISSN: 1461-023X

    Determining how and why organisms interact is fundamental to understanding ecosystem responses to future environmental change. To assess the impact on plant-pollinator interactions, recent studies have examined how the effects of environmental change on individual interactions accumulate to generate species-level responses. Here, we review recent developments in using plant-pollinator networks of interacting individuals along with their functional traits, where individuals are nested within species nodes. We highlight how these individual-level, trait-based networks connect intraspecific trait variation (as frequency distributions of multiple traits) with dynamic responses within plant-pollinator communities. This approach can better explain interaction plasticity, and changes to interaction probabilities and network structure over spatiotemporal or other environmental gradients. We argue that only through appreciating such trait-based interaction plasticity can we accurately forecast the potential vulnerability of interactions to future environmental change. We follow this with general guidance on how future studies can collect and analyse high-resolution interaction and trait data, with the hope of improving predictions of future plant-pollinator network responses for targeted and effective conservation.

  • Report
    Waring BG, 2024,

    The potential for enhanced soil carbon sequestration to mitigate climate change

    This briefing note assesses the potential for soil carbon sequestration to mitigate climate change, summarising the basic science and providing an overview of best practices for measuring and modifying soil carbon stocks. We also set out recommendations for policy makers, examining UK land use policies as a case study.

  • Journal article
    Li S, Waring B, Powers J, Medvigy Det al., 2024,

    Tropical dry forest response to nutrient fertilization: a model validation and sensitivity analysis

    , Biogeosciences, Vol: 21, Pages: 455-471, ISSN: 1726-4170

    Soil nutrients, especially nitrogen (N) and phosphorus (P), regulate plant growth and hence influence carbon fluxes between the land surface and atmosphere. However, how forests adjust biomass partitioning to leaves, wood, and fine roots in response to N and/or P fertilization remains puzzling. Recent work in tropical forests suggests that trees increase fine root production under P fertilization, but it is unclear whether mechanistic models can reproduce this dynamic. In order to better understand mechanisms governing nutrient effects on plant allocation and improve models, we used the nutrient-enabled ED2 model to simulate a fertilization experiment being conducted in a secondary tropical dry forest in Costa Rica. We evaluated how different allocation parameterizations affected model performance. These parameterizations prescribed a linear relationship between relative allocation to fine roots and soil P concentrations. The slope of the linear relationship was allowed to be positive, negative, or zero. Some parameterizations realistically simulated leaf, wood, and fine root production, and these parameterizations all assumed a positive relationship between relative allocation to fine roots and soil P concentration. Model simulations of a 30-year timeframe indicated strong sensitivity to parameterization and fertilization treatment. Without P fertilization, the simulated aboveground biomass (AGB) accumulation was insensitive to the parameterization. With P fertilization, the model was highly sensitive to the parameterization and the greatest AGB accumulation occurred when relative allocation to fine roots was independent of soil P. Our study demonstrates the need for simultaneous measurements of leaf, wood, and fine root production in nutrient fertilization experiments and for longer-term experiments. Models that do not accurately represent allocation to fine roots may be highly biased in their simulations of AGB, especially on multi-decadal timescales.

  • Journal article
    Wan Y, Myall AC, Boonyasiri A, Bolt F, Ledda A, Mookerjee S, Weiße AY, Getino M, Turton JF, Abbas H, Prakapaite R, Sabnis A, Abdolrasouli A, Malpartida-Cardenas K, Miglietta L, Donaldson H, Gilchrist M, Hopkins KL, Ellington MJ, Otter JA, Larrouy-Maumus G, Edwards AM, Rodriguez-Manzano J, Didelot X, Barahona M, Holmes AH, Jauneikaite E, Davies Fet al., 2024,

    Integrated analysis of patient networks and plasmid genomes reveals a regional, multi-species outbreak of carbapenemase-producing Enterobacterales carrying both blaIMP and mcr-9 genes.

    , J Infect Dis

    BACKGROUND: Carbapenemase-producing Enterobacterales (CPE) are challenging in healthcare, with resistance to multiple classes of antibiotics. This study describes the emergence of IMP-encoding CPE amongst diverse Enterobacterales species between 2016 and 2019 across a London regional network. METHODS: We performed a network analysis of patient pathways, using electronic health records, to identify contacts between IMP-encoding CPE positive patients. Genomes of IMP-encoding CPE isolates were overlayed with patient contacts to imply potential transmission events. RESULTS: Genomic analysis of 84 Enterobacterales isolates revealed diverse species (predominantly Klebsiella spp, Enterobacter spp, E. coli); 86% (72/84) harboured an IncHI2 plasmid carrying blaIMP and colistin resistance gene mcr-9 (68/72). Phylogenetic analysis of IncHI2 plasmids identified three lineages showing significant association with patient contacts and movements between four hospital sites and across medical specialities, which was missed on initial investigations. CONCLUSIONS: Combined, our patient network and plasmid analyses demonstrate an interspecies, plasmid-mediated outbreak of blaIMPCPE, which remained unidentified during standard investigations. With DNA sequencing and multi-modal data incorporation, the outbreak investigation approach proposed here provides a framework for real-time identification of key factors causing pathogen spread. Plasmid-level outbreak analysis reveals that resistance spread may be wider than suspected, allowing more interventions to stop transmission within hospital networks.

  • Journal article
    Worboys JD, Davis DM, 2024,

    Do inhibitory receptors need to be proximal to stimulatory receptors to function?

    , Genes Immun
  • Journal article
    Hersperger F, Meyring T, Weber P, Chhatbar C, Monaco G, Dionne MS, Paeschke K, Prinz M, Groß O, Classen A-K, Kierdorf Ket al., 2024,

    DNA damage signaling in Drosophila macrophages modulates systemic cytokine levels in response to oxidative stress

    , eLife, Vol: 12

    <jats:p>Environmental factors, infection, or injury can cause oxidative stress in diverse tissues and loss of tissue homeostasis. Effective stress response cascades, conserved from invertebrates to mammals, ensure reestablishment of homeostasis and tissue repair. Hemocytes, the <jats:italic>Drosophila</jats:italic> blood-like cells, rapidly respond to oxidative stress by immune activation. However, the precise signals how they sense oxidative stress and integrate these signals to modulate and balance the response to oxidative stress in the adult fly are ill-defined. Furthermore, hemocyte diversification was not explored yet on oxidative stress. Here, we employed high-throughput single nuclei RNA-sequencing to explore hemocytes and other cell types, such as fat body, during oxidative stress in the adult fly. We identified distinct cellular responder states in plasmatocytes, the <jats:italic>Drosophila</jats:italic> macrophages, associated with immune response and metabolic activation upon oxidative stress. We further define oxidative stress-induced DNA damage signaling as a key sensor and a rate-limiting step in immune-activated plasmatocytes controlling JNK-mediated release of the pro-inflammatory cytokine <jats:italic>unpaired-3</jats:italic>. We subsequently tested the role of this specific immune activated cell stage during oxidative stress and found that inhibition of DNA damage signaling in plasmatocytes, as well as JNK or upd3 overactivation, result in a higher susceptibility to oxidative stress. Our findings uncover that a balanced composition and response of hemocyte subclusters is essential for the survival of adult <jats:italic>Drosophila</jats:italic> on oxidative stress by regulating systemic cytokine levels and cross-talk to other organs, such as the fat body, to control energy mobilization.</jats:p>

  • Journal article
    Meccariello A, 2024,

    Gene drive and genetic sex conversion in theglobal agricultural pest Ceratitis capitata

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

    Homing-based gene drives are recently proposed interventions promising the area-wide, species-specific genetic control of harmful insect populations. Here we characterise a first set of gene drives in a tephritid agricultural pest species, the Mediterranean fruit fly Ceratitis capitata (medfly). Our results show that the medfly is highly amenable to homing-based gene drive strategies. By targeting the medfly transformer gene, we also demonstrate how CRISPR-Cas9 gene drive can be coupled to sex conversion, whereby genetic females are transformed into fertile and harmless XX males. Given this unique malleability of sex determination, we modelled gene drive interventions that couple sex conversion and female sterility and found that such approaches could be effective and tolerant of resistant allele selection in the target population. Our results open the door for developing gene drive strains for the population suppression of the medfly and related tephritid pests by co-targeting female reproduction and shifting the reproductive sex ratio towards males. They demonstrate the untapped potential for gene drives to tackle agricultural pests in an environmentally friendly and economical way.

  • Journal article
    Savolainen V, Bailey NW, Diamond L, Swift-Gallant A, Gavrilets S, Raymond M, Verweij KJHet al., 2024,

    A broader cultural view is necessary to study the evolution of sexual orientation

    , Nature Ecology and Evolution, Vol: 8, Pages: 181-183, ISSN: 2397-334X

    The causation of sexual orientation is likely to be complex and influenced by multiple factors1. We advocate incorporating a broader cultural view into evolutionary andgenetic studies to account for differences in how sexual orientation is experienced, expressed, and understood in both human and non-human animals.

  • Journal article
    Zhang X, Gao F, Ye F, Zhang B, Cronin N, Buck Met al., 2024,

    Structural basis of s54 displacement and promoter escape in bacterial transcription

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

    Gene transcription is a fundamental cellular process carried out by RNA polymerase (RNAP). Transcription initiation is highly regulated and in bacteria, transcription initiation is mediated by sigma (σ) factors. σ recruits RNAP to the promoter DNA region, located upstream oftranscription start site (TSS), and facilitates open complex formation, where double stranded DNA is opened up into a transcription bubble and template strand DNA is positioned inside RNAP for initial RNA synthesis. During initial transcription, RNAP remains bound to sigma andupstream DNA, presumably with an enlarging transcription bubble. The release of RNAP fromupstream DNA is required for promoter escape and processive transcription elongation. Bacteria sigma factors can be broadly separated into two classes with the majority belonging to the σ70 class, represented by the σ70 that regulates housekeeping genes. σ54 forms a class on its own and regulates stress response genes. Extensive studies on σ70 have revealed the molecularmechanisms of σ70 dependent process while how σ54 transitions from initial transcription to elongation is currently unknown. Here we present a series of cryo electron microscopy structures of the RNAP-σ54 initial transcribing complexes with progressively longer RNA, which reveal structural changes that lead to promoter escape. Our data show that initially, the transcription bubble enlarges, DNA strands scrunch, reducing the interactions between σ54 and DNA strands in the transcription bubble. RNA extension and further DNA scrunching help to release RNAP from σ54 and upstream DNA, enabling the transition to elongation.

  • Journal article
    Grob A, Enrico Bena C, Di Blasi R, Pessina D, Sood M, Yunyue Z, Bosia C, Isalan M, Ceroni Fet al., 2024,

    Mammalian cell growth characterisation by a non-invasive plate reader assay

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

    Automated and non-invasive mammalian cell analysis is currently lagging behind due to a lack of methods suitable for a variety of cell lines and applications. Here, we report the development of a high throughput non-invasive method for tracking mammalian cell growth and performance based on plate reader measurements. We show the method to be suitable for both suspension and adhesion cell lines, and we demonstrate it can be adopted when cells are grown under different environmental conditions. We establish that the method is suitable to inform on effective drug treatments to be used depending on the cell line considered, and that it can support characterisation of engineered mammalian cells over time. This work provides the scientific community with an innovative approach to mammalian cell screening, also contributing to the current efforts towards high throughput and automated mammalian cell engineering.

  • Journal article
    Sugiura M, Kimura M, Shimamoto N, Nakamura M, Koyama K, Selles J, Boussac A, Rutherford Aet al., 2024,

    Tuning of the ChlD1 and ChlD2 properties in photosystem II by site-directed mutagenesis of neighbouring amino acids

    , BBA: Bioenergetics, Vol: 1865, ISSN: 0005-2728

    Photosystem II is the water/plastoquinone photo-oxidoreductase of photosynthesis. The photochemistry and catalysis occur in a quasi-symmetrical heterodimer, D1D2, that evolved from a homodimeric ancestor. Here, we studied site-directed mutants in PSII from the thermophilic cyanobacterium Thermosynechoccocus elongatus, focusing on the primary electron donor chlorophyll a in D1, ChlD1, and on its symmetrical counterpart in D2, ChlD2, which does not play a direct photochemical role. The main conserved amino acid specific to ChlD1 is D1/T179, which H-bonds the water ligand to its Mg2+, while its counterpart near ChlD2 is the non-H-bonding D2/I178. The symmetrical-swapped mutants, D1/T179I and D2/I178T, and a second ChlD2 mutant, D2/I178H, were studied. The D1 mutations affected the 686 nm absorption attributed to ChlD1, while the D2 mutations affected a 663 nm feature, tentatively attributed to ChlD2. The mutations had little effect on enzyme activity and forward electron transfer, reflecting the robustness of the overall enzyme function. In contrast, the mutations significantly affected photodamage and protective mechanisms, reflecting the importance of redox tuning in these processes. In D1/T179I, the radical pair recombination triplet on ChlD1 was shared onto a pheophytin, presumably PheD1 and the detection of 3PheD1 supports the proposed mechanism for the anomalously short lifetime of 3ChlD1; e.g. electron transfer quenching by QA− of 3PheD1 after triplet transfer from 3ChlD1. In D2/I178T, a charge separation could occur between ChlD2 and PheD2, a reaction that is thought to occur in ancestral precursors of PSII. These mutants help understand the evolution of asymmetry in PSII.

  • Book chapter
    Prentice IC, Cowling SA, 2024,

    Dynamic Global Vegetation Models

    , Encyclopedia of Biodiversity, Third Edition: Volume 1-7, ISBN: 9780323984348

    Dynamic global vegetation models encapsulate our knowledge of plant and ecosystem function. They have many potential applications but not all of these are well developed, and large differences among model predictions are a concern. Fields of application include analysis of land–atmosphere biophysical interactions, carbon and water cycling, climate impacts on vegetation structure, fire, atmospheric trace gas composition, Quaternary vegetation and environmental changes, and ecosystem structure and function through Earth history. There is scope to improve models using a wider range of information from plant functional ecology, ecophysiology, environmental remote sensing, and atmospheric measurement, Quaternary paleoecology, and paleobotany.

  • Book chapter
    McArthur HCW, Bajur AT, Spillane KM, 2024,

    Quantifying force-mediated antigen extraction in the B cell immune synapse using DNA-based tension sensors

    , Methods in Cell Biology

    B cells exert pulling forces against antigen-presenting cells (APCs) to extract antigens for internalization. The application of tugging forces on B cell receptor (BCR)-antigen bonds promotes discrimination of antigen affinities and sensing of APC physical properties. Here, we describe a protocol for preparing antigen-functionalized DNA tension sensors for quantifying force-mediated antigen extraction in the B cell immune synapse. We describe how to attach the sensors to planar lipid bilayers, quantify their surface density, use them to stimulate B cell activation, and analyze the efficiency of antigen extraction in fixed cells by fluorescence microscopy and image analysis. These techniques should be broadly applicable to studies of force-mediated transfer of molecules in cell-cell contacts.

  • Journal article
    Seddon C, Frankel G, Beis K, 2024,

    Structure of the outer membrane porin OmpW from the pervasive pathogen Klebsiella pneumoniae

    , Acta Crystallographica Section F: Structural Biology and Crystallization Communications Online, Vol: 80, Pages: 22-27, ISSN: 1744-3091

    Conjugation is the process by which plasmids, including those that carry antibiotic-resistance genes, are mobilized from one bacterium (the donor) to another (the recipient). The conjugation efficiency of IncF-like plasmids relies on the formation of mating-pair stabilization via intimate interactions between outer membrane proteins on the donor (a plasmid-encoded TraN isoform) and recipient bacteria. Conjugation of the R100-1 plasmid into Escherichia coli and Klebsiella pneumoniae (KP) recipients relies on pairing between the plasmid-encoded TraNα in the donor and OmpW in the recipient. Here, the crystal structure of K. pneumoniae OmpW (OmpWKP) is reported at 3.2 Å resolution. OmpWKP forms an eight-stranded β-barrel flanked by extracellular loops. The structures of E. coli OmpW (OmpWEC) and OmpWKP show high conservation despite sequence variability in the extracellular loops.

  • Journal article
    Beltrán L, Torsilieri H, Patkowski JB, Yang JE, Casanova J, Costa TRD, Wright ER, Egelman EHet al., 2024,

    The mating pilus of E. coli pED208 acts as a conduit for ssDNA during horizontal gene transfer

    , mBio, Vol: 15, ISSN: 2150-7511

    Bacteria are constantly exchanging DNA, which constitutes horizontal gene transfer. While some of these occurs by a non-specific process called natural transformation, some occurs by a specific mating between a donor and a recipient cell. In specific conjugation, the mating pilus is extended from the donor cell to make contact with the recipient cell, but whether DNA is actually transferred through this pilus or by another mechanism involving the type IV secretion system complex without the pilus has been an open question. Using Escherichia coli, we show that DNA can be transferred through this pilus between a donor and a recipient cell that has not established a tight mating junction, providing a new picture for the role of this pilus.

  • Journal article
    Ren Y, Wang H, Harrison SP, Prentice IC, Atkin OK, Smith NG, Mengoli G, Stefanski A, Reich PBet al., 2024,

    Reduced global plant respiration due to the acclimation of leaf dark respiration coupled to photosynthesis

    , New Phytologist, Vol: 241, Pages: 578-591, ISSN: 0028-646X

    Leaf dark respiration (Rd) acclimates to environmental changes. However, the magnitude, controls and time scales of acclimation remain unclear and are inconsistently treated in ecosystem models. We hypothesized that Rd and Rubisco carboxylation capacity (Vcmax) at 25°C (Rd,25, Vcmax,25) are coordinated so that Rd,25 variations support Vcmax,25 at a level allowing full light use, with Vcmax,25 reflecting daytime conditions (for photosynthesis), and Rd,25/Vcmax,25 reflecting night-time conditions (for starch degradation and sucrose export). We tested this hypothesis temporally using a 5-yr warming experiment, and spatially using an extensive field-measurement data set. We compared the results to three published alternatives: Rd,25 declines linearly with daily average prior temperature; Rd at average prior night temperatures tends towards a constant value; and Rd,25/Vcmax,25 is constant. Our hypothesis accounted for more variation in observed Rd,25 over time (R2 = 0.74) and space (R2 = 0.68) than the alternatives. Night-time temperature dominated the seasonal time-course of Rd, with an apparent response time scale of c. 2 wk. Vcmax dominated the spatial patterns. Our acclimation hypothesis results in a smaller increase in global Rd in response to rising CO2 and warming than is projected by the two of three alternative hypotheses, and by current models.

  • Journal article
    Di Pilato V, Codda G, Niccolai C, Willison E, Wong JLC, Coppo E, Frankel G, Marchese A, Rossolini GMet al., 2024,

    Functional features of KPC-109, a novel 270-loop KPC-3 mutant mediating resistance to avibactam-based β-lactamase inhibitor combinations and cefiderocol.

    , Int J Antimicrob Agents, Vol: 63

    OBJECTIVES: To investigate a ceftazidime/avibactam (CZA)-resistant Klebsiella pneumoniae (NE368), isolated from a patient exposed to CZA, expressing a novel K. pneumoniae carbapenemase (KPC)-3 variant (KPC-109). METHODS: Antimicrobial susceptibility testing was performed by reference broth microdilution. Whole-genome sequencing (WGS) analysis of NE368 was performed combining a short- and long-reads approach (Illumina and Oxford Nanopore Technologies). Functional characterization of KPC-109 was performed to investigate the impact of KPC-109 production on the β-lactam resistance phenotype of various Escherichia coli and Klebsiella pneumoniae strains, including derivatives of K. pneumoniae with OmpK35 and OmpK36 porin alterations. Horizontal transfer of the KPC-109-encoding plasmid was investigated by conjugation and transformation experiments. RESULTS: K. pneumoniae NE368 was isolated from a patient after repeated CZA exposure, and showed resistance to CZA, fluoroquinolones, piperacillin/tazobactam, expanded-spectrum cephalosporins, amikacin, carbapenems and cefiderocol. WGS revealed the presence of a large chimeric plasmid of original structure (pKPN-NE368), encoding a novel 270-loop mutated KPC-3 variant (KPC-109; ins_270_KYNKDD). KPC-109 production mediated resistance/decreased susceptibility to avibactam-based combinations (with ceftazidime, cefepime and aztreonam) and cefiderocol, with a trade-off on carbapenem resistance. However, in the presence of porin alterations commonly encountered in high-risk clonal lineages of K. pneumoniae, KPC-109 was also able to confer clinical-level resistance to carbapenems. Resistance of NE368 to cefiderocol was likely contributed by KPC-109 production acting in concert with a mutated EnvZ sensor kinase. The KPC-109-encoding plasmid did not appear to be conjugative. CONCLUSIONS: These findings expand current knowledge about the diversity of emerging KPC enzyme variants with 270-loop alterations that can be encountered in the

  • Journal article
    Panstruga R, Spanu P, 2024,

    Transfer RNA and ribosomal RNA fragments - emerging players in plant-microbe interactions.

    , New Phytol, Vol: 241, Pages: 567-577

    According to current textbooks, the principal task of transfer and ribosomal RNAs (tRNAs and rRNAs, respectively) is synthesizing proteins. During the last decade, additional cellular roles for precisely processed tRNA and rRNAs fragments have become evident in all kingdoms of life. These RNA fragments were originally overlooked in transcriptome datasets or regarded as unspecific degradation products. Upon closer inspection, they were found to engage in a variety of cellular processes, in particular the modulation of translation and the regulation of gene expression by sequence complementarity- and Argonaute protein-dependent gene silencing. More recently, the presence of tRNA and rRNA fragments has also been recognized in the context of plant-microbe interactions, both on the plant and the microbial side. While most of these fragments are likely to affect endogenous processes, there is increasing evidence for their transfer across kingdoms in the course of such interactions; these processes may involve mutual exchange in association with extracellular vesicles. Here, we summarize the state-of-the-art understanding of tRNA and rRNA fragment's roles in the context of plant-microbe interactions, their potential biogenesis, presumed delivery routes, and presumptive modes of action.

  • Journal article
    Tissot FS, Gonzalez-Anton S, Lo Celso C, 2024,

    Intravital Microscopy to Study the Effect of Matrix Metalloproteinase Inhibition on Acute Myeloid Leukemia Cell Migration in the Bone Marrow.

    , Methods Mol Biol, Vol: 2747, Pages: 211-227

    Hematopoiesis is the process through which all mature blood cells are formed and takes place in the bone marrow (BM). Acute myeloid leukemia (AML) is a blood cancer of the myeloid lineage. AML progression causes drastic remodeling of the BM microenvironment, making it no longer supportive of healthy hematopoiesis and leading to clinical cytopenia in patients. Understanding the mechanisms by which AML cells shape the BM to their benefit would lead to the development of new therapeutic strategies. While the role of extracellular matrix (ECM) in solid cancer has been extensively studied during decades, its role in the BM and in leukemia progression has only begun to be acknowledged. In this context, intravital microscopy (IVM) gives the unique insight of direct in vivo observation of AML cell behavior in their environment during disease progression and/or upon drug treatments. Here we describe our protocol for visualizing and analyzing MLL-AF9 AML cell dynamics upon systemic inhibition of matrix metalloproteinases (MMP), combining confocal and two-photon microscopy and focusing on cell migration.

  • Journal article
    Ono M, 2024,

    Unraveling T-cell dynamics using fluorescent timer: Insights from the Tocky system

    , Biophysics and Physicobiology
  • Journal article
    Herzog MK-M, Cazzaniga M, Peters A, Shayya N, Beldi L, Hapfelmeier S, Heimesaat MMM, Bereswill S, Frankel G, Gahan CGM, Hardt W-Det al., 2023,

    Mouse models for bacterial enteropathogen infections: insights into the role of colonization resistance

    , GUT MICROBES, Vol: 15, ISSN: 1949-0976
  • Journal article
    Rosindell J, Manson K, Gumbs R, Pearse WD, Steel Met al., 2023,

    Phylogenetic Biodiversity Metrics Should Account for Both Accumulation and Attrition of Evolutionary Heritage.

    , Syst Biol

    Phylogenetic metrics are essential tools used in the study of ecology, evolution and conservation. Phylogenetic diversity (PD) in particular is one of the most prominent measures of biodiversity, and is based on the idea that biological features accumulate along the edges of phylogenetic trees that are summed. We argue that PD and many other phylogenetic biodiversity metrics fail to capture an essential process that we term attrition. Attrition is the gradual loss of features through causes other than extinction. Here we introduce 'EvoHeritage', a generalisation of PD that is founded on the joint processes of accumulation and attrition of features. We argue that whilst PD measures evolutionary history, EvoHeritage is required to capture a more pertinent subset of evolutionary history including only components that have survived attrition. We show that EvoHeritage is not the same as PD on a tree with scaled edges; instead, accumulation and attrition interact in a more complex non-monophyletic way that cannot be captured by edge lengths alone. This leads us to speculate that the one dimensional edge lengths of classic trees may be insufficiently flexible to capture the nuances of evolutionary processes. We derive a measure of EvoHeritage and show that it elegantly reproduces species richness and PD at opposite ends of a continuum based on the intensity of attrition. We demonstrate the utility of EvoHeritage in ecology as a predictor of community productivity compared with species richness and PD. We also show how EvoHeritage can quantify living fossils and resolve their associated controversy. We suggest how the existing calculus of PD-based metrics and other phylogenetic biodiversity metrics can and should be recast in terms of EvoHeritage accumulation and attrition.

  • Journal article
    González-Ferreras AM, Barquín J, Blyth PSA, Hawksley J, Kinsella H, Lauridsen R, Morris OF, Peñas FJ, Thomas GE, Woodward G, Zhao L, O'Gorman EJet al., 2023,

    Chronic exposure to environmental temperature attenuates the thermal sensitivity of salmonids.

    , Nat Commun, Vol: 14

    Metabolism, the biological processing of energy and materials, scales predictably with temperature and body size. Temperature effects on metabolism are normally studied via acute exposures, which overlooks the capacity for organisms to moderate their metabolism following chronic exposure to warming. Here, we conduct respirometry assays in situ and after transplanting salmonid fish among different streams to disentangle the effects of chronic and acute thermal exposure. We find a clear temperature dependence of metabolism for the transplants, but not the in-situ assays, indicating that chronic exposure to warming can attenuate salmonid thermal sensitivity. A bioenergetic model accurately captures the presence of fish in warmer streams when accounting for chronic exposure, whereas it incorrectly predicts their local extinction with warming when incorporating the acute temperature dependence of metabolism. This highlights the need to incorporate the potential for thermal acclimation or adaptation when forecasting the consequences of global warming on ecosystems.

  • Book chapter
    Shocket M, Caldwell J, Huxley P, Lippi C, Windram F, Keyel Aet al., 2023,

    Modelling the effects of climate and climate change on transmission of vector-borne disease

    , Planetary health approaches to understand and control vector-borne diseases, Editors: Fornace, Conn, Mureb, Chaves, Logan, Publisher: BRILL, Pages: 253-318, ISBN: 9789004688650

    Mathematical and statistical models are critical tools for both understanding how climate can influence patterns of vector-borne disease transmission, and predicting how climate change might affect these patterns in the future. This chapter focuses primarily on quantitative approaches for modelling the effects of climate on mosquito-borne disease (MBD), although we also briefly consider tick-borne disease. We initially describe how the biological mechanisms that contribute to transmission of vector-borne disease can respond to changes in climate and other environmental factors. Importantly, transmission of MBD responds nonlinearly over gradients of both temperature and rainfall. When building or interpreting models for the effects of climate on MBD dynamics, it is important to consider that the effects of temperature and rainfall on disease may be positive, negative, or both depending on circumstance. This context-dependence can limit the transferability of models beyond the setting in which they were fit. Next, we provide an overview of important concepts and approaches for modelling vector-borne diseases using mechanistic and statistical models. This includes the most commonly used modelling methods, techniques for model evaluation and validation, and climate re-analysis products used as model predictors. The best choices of methods for model construction and evaluation depend on the goals of the model and the structure of the underlying data, including their spatial and temporal scales. Then, we explore three case studies of MBD in more detail and use them to illustrate representative modelling approaches across a gradient of spatiotemporal scales: (1) local time series models of dengue fever in San Juan, Puerto Rico; (2) regional models of West Nile virus in the United States; and (3) continental and global models for how climate change may impact future transmission risk for malaria and dengue fever. Finally, we note some key challenges, knowledge gaps, and res

  • Journal article
    Gardner S, Darrow MC, Lukoyanova N, Thalassinos K, Saibil HRet al., 2023,

    Structural basis of substrate progression through the bacterial chaperonin cycle.

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

    The bacterial chaperonin GroEL-GroES promotes protein folding through ATP-regulated cycles of substrate protein binding, encapsulation, and release. Here, we have used cryoEM to determine structures of GroEL, GroEL-ADP·BeF3, and GroEL-ADP·AlF3-GroES all complexed with the model substrate Rubisco. Our structures provide a series of snapshots that show how the conformation and interactions of non-native Rubisco change as it proceeds through the GroEL-GroES reaction cycle. We observe specific charged and hydrophobic GroEL residues forming strong initial contacts with non-native Rubisco. Binding of ATP or ADP·BeF3 to GroEL-Rubisco results in the formation of an intermediate GroEL complex displaying striking asymmetry in the ATP/ADP·BeF3-bound ring. In this ring, four GroEL subunits bind Rubisco and the other three are in the GroES-accepting conformation, suggesting how GroEL can recruit GroES without releasing bound substrate. Our cryoEM structures of stalled GroEL-ADP·AlF3-Rubisco-GroES complexes show Rubisco folding intermediates interacting with GroEL-GroES via different sets of residues.

  • Journal article
    Moriel DG, Piccioli D, Raso MM, Pizza Met al., 2023,

    The overlooked bacterial pandemic.

    , Semin Immunopathol

    The COVID-19 pandemic had a significant economic and health impact worldwide. It also reinforced the misperception that only viruses can pose a threat to human existence, overlooking that bacteria (e.g., plague and cholera) have severely haunted and shaped the course of human civilization. While the world is preparing for the next viral pandemic, it is again overlooking a silent one: antimicrobial resistance (AMR). This review proposes to show the impact of bacterial infections on civilization to remind the pandemic potential. The work will also discuss a few examples of how bacteria can mutate risking global spread and devastating outcomes, the effect on the global burden, and the prophylactic and therapeutic measures. Indeed, AMR is dramatically increasing and if the trend is not reversed, it has the potential to quickly turn into the most important health problem worldwide.

  • Journal article
    Ghani L, Kim S, Ehsan M, Lan B, Poulsen IH, Dev C, Katsube S, Byrne B, Guan L, Loland CJ, Liu X, Im W, Chae PSet al., 2023,

    Melamine-cored glucosides for membrane protein solubilization and stabilization: importance of water-mediated intermolecular hydrogen bonding in detergent performance

    , Chemical Science, Vol: 14, Pages: 13014-13024, ISSN: 2041-6520

    Membrane proteins play essential roles in a number of biological processes, and their structures are important in elucidating such processes at the molecular level and also for rational drug design and development. Membrane protein structure determination is notoriously challenging compared to that of soluble proteins, due largely to the inherent instability of their structures in non-lipid environments. Micelles formed by conventional detergents have been widely used for membrane protein manipulation, but they are suboptimal for long-term stability of membrane proteins, making downstream characterization difficult. Hence, there is an unmet need for the development of new amphipathic agents with enhanced efficacy for membrane protein stabilization. In this study, we designed and synthesized a set of glucoside amphiphiles with a melamine core, denoted melamine-cored glucosides (MGs). When evaluated with four membrane proteins (two transporters and two G protein-coupled receptors), MG-C11 conferred notably enhanced stability compared to the commonly used detergents, DDM and LMNG. These promising findings are mainly attributed to a unique feature of the MGs, i.e., the ability to form dynamic water-mediated hydrogen-bond networks between detergent molecules, as supported by molecular dynamics simulations. Thus, MG-C11 is the first example of a non-peptide amphiphile capable of forming intermolecular hydrogen bonds within a protein-detergent complex environment. Detergent micelles formed via a hydrogen-bond network could represent the next generation of highly effective membrane-mimetic systems useful for membrane protein structural studies.

  • Journal article
    Scopa C, Barnada SM, Cicardi ME, Singer M, Trotti D, Trizzino Met al., 2023,

    JUN upregulation drives aberrant transposable element mobilization, associated innate immune response, and impaired neurogenesis in Alzheimer’s disease

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

    Adult neurogenic decline, inflammation, and neurodegeneration are phenotypic hallmarks of Alzheimer’s disease (AD). Mobilization of transposable elements (TEs) in heterochromatic regions was recently reported in AD, but the underlying mechanisms are still underappreciated. Combining functional genomics with the differentiation of familial and sporadic AD patient derived-iPSCs into hippocampal progenitors, CA3 neurons, and cerebral organoids, we found that the upregulation of the AP-1 subunit, c-Jun, triggers decondensation of genomic regions containing TEs. This leads to the cytoplasmic accumulation of HERVK-derived RNA-DNA hybrids, the activation of the cGAS-STING cascade, and increased levels of cleaved caspase-3, suggesting the initiation of programmed cell death in AD progenitors and neurons. Notably, inhibiting c-Jun effectively blocks all these downstream molecular processes and rescues neuronal death and the impaired neurogenesis phenotype in AD progenitors. Our findings open new avenues for identifying therapeutic strategies and biomarkers to counteract disease progression and diagnose AD in the early, pre-symptomatic stages.

  • Journal article
    Eberhart-Hertel LJ, Rodrigues LF, Krietsch J, Hertel AG, Cruz-López M, Vázquez-Rojas KA, González-Medina E, Schroeder J, Küpper Cet al., 2023,

    Egg size variation in the context of polyandry: a case study using long-term field data from snowy plovers.

    , Evolution, Vol: 77, Pages: 2590-2605

    Gamete size variation between the sexes is central to the concept of sex roles, however, to what extent gamete size variation within the sexes relates to sex role variation remains unclear. Comparative and theoretical studies suggest that, when clutch size is invariable, polyandry is linked to a reduction of egg size, while increased female-female competition for mates favors early breeding when females cannot monopolize multiple males. To understand whether and how breeding phenology, egg size, and mating behavior are related at the individual level, we studied the reproductive histories of 424 snowy plover females observed in the wild over a 15-year period. Egg size, but not polyandry, were highly repeatable for individual females. Consistent with theoretical predictions, we found that polyandrous females were the earliest breeders and that early clutches contained smaller eggs than clutches initiated later. Neither egg size nor mating behavior showed clear signs of an age-related deterioration, on the contrary, prior experience acquired either through age or local recruitment enabled females to nest early. Taken together, these results suggest that gamete size variation is not linked to mating behavior at the individual level, and, consequently, the adaptive potential of such variation appears to be limited.

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