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Journal articlePatin EC, Nenclares P, Chan Wah Hak C, et al., 2024,
Sculpting the tumour microenvironment by combining radiotherapy and ATR inhibition for curative-intent adjuvant immunotherapy.
, Nat Commun, Vol: 15The combination of radiotherapy/chemoradiotherapy and immune checkpoint blockade can result in poor outcomes in patients with locally advanced head and neck squamous cell carcinoma (HNSCC). Here, we show that combining ATR inhibition (ATRi) with radiotherapy (RT) increases the frequency of activated NKG2A+PD-1+ T cells in animal models of HNSCC. Compared with the ATRi/RT treatment regimen alone, the addition of simultaneous NKG2A and PD-L1 blockade to ATRi/RT, in the adjuvant, post-radiotherapy setting induces a robust antitumour response driven by higher infiltration and activation of cytotoxic T cells in the tumour microenvironment. The efficacy of this combination relies on CD40/CD40L costimulation and infiltration of activated, proliferating memory CD8+ and CD4+ T cells with persistent or new T cell receptor (TCR) signalling, respectively. We also observe increased richness in the TCR repertoire and emergence of numerous and large TCR clonotypes that cluster based on antigen specificity in response to NKG2A/PD-L1/ATRi/RT. Collectively, our data point towards potential combination approaches for the treatment of HNSCC.
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Journal articleSellés J, Alric J, Rutherford AW, et al., 2024,
In vivo ElectroChromic Shift measurements of photosynthetic activity in far-red absorbing cyanobacteria.
, Biochim Biophys Acta Bioenerg, Vol: 1865Some cyanobacteria can do photosynthesis using not only visible but also far-red light that is unused by most other oxygenic photoautotrophs because of its lower energy content. These species have a modified photosynthetic apparatus containing red-shifted pigments. The incorporation of red-shifted pigments decreases the photochemical efficiency of photosystem I and, especially, photosystem II, and it might affect the distribution of excitation energy between the two photosystems with possible consequences on the activity of the entire electron transport chain. To investigate the in vivo effects on photosynthetic activity of these pigment changes, we present here the adaptation of a spectroscopic method, based on a physical phenomenon called ElectroChromic Shift (ECS), to the far-red absorbing cyanobacteria Acaryochloris marina and Chroococcidiopsis thermalis PCC7203. ECS measures the electric field component of the trans-thylakoid proton motive force generated by photosynthetic electron transfer. We show that ECS can be used in these cyanobacteria to investigate in vivo the stoichiometry of photosystem I and photosystem II and their absorption cross-section, as well as the overall efficiency of light energy conversion into electron transport. Our results indicate that both species use visible and far-red light with similar efficiency, despite significant differences in their light absorption characteristics. ECS thus represents a new non-invasive tool to study the performance of naturally occurring far-red photosynthesis.
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Journal articleWayman JP, Sadler JP, Martin TE, et al., 2024,
Unravelling the complexities of biotic homogenization and heterogenization in the British avifauna.
, J Anim EcolBiotic homogenization is a process whereby species assemblages become more similar through time. The standard way of identifying the process of biotic homogenization is to look for decreases in spatial beta-diversity. However, using a single assemblage-level metric to assess homogenization can mask important changes in the occupancy patterns of individual species. Here, we analysed changes in the spatial beta-diversity patterns (i.e. biotic heterogenization or homogenization) of British bird assemblages within 30 km × 30 km regions between two periods (1988-1991 and 2008-2011). We partitioned the change in spatial beta-diversity into extirpation and colonization-resultant change (i.e. change in spatial beta-diversity within each region resulting from both extirpation and colonization). We used measures of abiotic change in combination with Bayesian modelling to disentangle the drivers of biotic heterogenization and homogenization. We detected both heterogenization and homogenization across the two time periods and three measures of diversity (taxonomic, phylogenetic, and functional). In addition, both extirpation and colonization contributed to the observed changes, with heterogenization mainly driven by extirpation and homogenization by colonization. These assemblage-level changes were primarily due to shifting occupancy patterns of generalist species. Compared to habitat generalists, habitat specialists had significantly (i) higher average contributions to colonization-resultant change (indicating heterogenization within a region due to colonization) and (ii) lower average contributions to extirpation-resultant change (indicating homogenization from extirpation). Generalists showed the opposite pattern. Increased extirpation-resultant homogenization within regions was associated with increased urban land cover and decreased habitat diversity, precipitation, and temperature. Changes in extirpation-resultant heterogenization and col
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Journal articleEwers RM, 2024,
An audacious approach to conservation.
, Trends Ecol EvolNew digital and sensor technology provides a huge opportunity to revolutionise conservation, but we lack a plan for deploying the technologies effectively. I argue that environmental research should be concentrated at a small number of 'super-sites' and that the concentrated knowledge from super-sites should be used to develop holistic ecosystem models. These, in turn, should be morphed into digital twin ecosystems by live connecting them with automated environmental monitoring programmes. Data-driven simulations can then help select pathways to achieve locally determined conservation goals, and digital twins could revise and adapt those decisions in real-time. This technology-heavy vision for 'smart conservation' provides a map toward a future defined by more flexible, more responsive, and more efficient management of natural environments.
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Journal articleRogers J, Bajur AT, Salaita K, et al., 2024,
Mechanical control of antigen detection and discrimination by T and B cell receptors.
, Biophys J, Vol: 123, Pages: 2234-2255The adaptive immune response is orchestrated by just two cell types, T cells and B cells. Both cells possess the remarkable ability to recognize virtually any antigen through their respective antigen receptors-the T cell receptor (TCR) and B cell receptor (BCR). Despite extensive investigations into the biochemical signaling events triggered by antigen recognition in these cells, our ability to predict or control the outcome of T and B cell activation remains elusive. This challenge is compounded by the sensitivity of T and B cells to the biophysical properties of antigens and the cells presenting them-a phenomenon we are just beginning to understand. Recent insights underscore the central role of mechanical forces in this process, governing the conformation, signaling activity, and spatial organization of TCRs and BCRs within the cell membrane, ultimately eliciting distinct cellular responses. Traditionally, T cells and B cells have been studied independently, with researchers working in parallel to decipher the mechanisms of activation. While these investigations have unveiled many overlaps in how these cell types sense and respond to antigens, notable differences exist. To fully grasp their biology and harness it for therapeutic purposes, these distinctions must be considered. This review compares and contrasts the TCR and BCR, placing emphasis on the role of mechanical force in regulating the activity of both receptors to shape cellular and humoral adaptive immune responses.
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Journal articleIliopoulou M, Bajur AT, McArthur HCW, et al., 2024,
Extracellular matrix rigidity modulates physical properties of subcapsular sinus macrophage-B cell immune synapses.
, Biophys J, Vol: 123, Pages: 2282-2300Subcapsular sinus macrophages (SSMs) play a key role in immune defense by forming immunological barriers that control the transport of antigens from lymph into lymph node follicles. SSMs participate in antibody responses by presenting antigens directly to naive B cells and by supplying antigens to follicular dendritic cells to propagate germinal center reactions. Despite the prominent roles that SSMs play during immune responses, little is known about their cell biology because they are technically challenging to isolate and study in vitro. Here, we used multicolor fluorescence microscopy to identify lymph node-derived SSMs in culture. We focused on the role of SSMs as antigen-presenting cells, and found that their actin cytoskeleton regulates the spatial organization and mobility of multivalent antigens (immune complexes [ICs]) displayed on the cell surface. Moreover, we determined that SSMs are mechanosensitive cells that respond to changes in extracellular matrix rigidity by altering the architecture of the actin cytoskeleton, leading to changes in cell morphology, membrane topography, and IC mobility. Changes to extracellular matrix rigidity also modulate actin remodeling by both SSMs and B cells when they form an immune synapse. This alters synapse duration but not IC internalization nor NF-κB activation in the B cell. Taken together, our data reveal that the mechanical microenvironment may influence B cell responses by modulating physical characteristics of antigen presentation by SSMs.
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Journal articleConnolly JB, Burt A, Christophides G, et al., 2024,
Publisher Correction: Considerations for first field trials of low-threshold gene drive for malaria vector control
, Malaria Journal, Vol: 23, ISSN: 1475-2875 -
Journal articleBa W, Nollet M, Yin C, et al., 2024,
A REM-active basal ganglia circuit that regulates anxiety
, Current Biology, Vol: 34, Pages: 3301-2214.E4, ISSN: 0960-9822REM sleep has been hypothesized to promote emotional resilience, but any neuronal circuits mediating this have not been identified. We find that in mice, somatostatin (Som)neurons in the entopeduncular nucleus (EP Som )/internal globus pallidus are predominantly active during REM sleep. This unique REM activity is necessary and sufficient formaintaining normal REM sleep. Inhibiting or exciting EPSom neurons reduced or increased REM sleep duration, respectively. Activation of the sole downstream target of EPSom neurons, Vglut2 cells in the lateral habenula (LHb), increased sleep via the ventral tegmental area (VTA). A simple chemogenetic scheme to periodically inhibit the LHb over 4 days selectively removed a significant amount of cumulative REM sleep. Chronic, but not acute, REM reduction correlated with mice becoming anxious and more sensitive to aversive stimuli. Therefore, we suggest that cumulative REM sleep, in part generated by the EP→LHb→VTA circuit identified here, could contribute to stabilizing reactions to habitual aversive stimuli.
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Journal articleKabasakal BV, McFarlane CR, Cotton CAR, et al., 2024,
The crystal structure of Shethna protein II (FeSII) from Azotobacter vinelandii suggests a domain swap.
, Acta Crystallogr D Struct Biol, Vol: 80, Pages: 599-604The Azotobacter vinelandii FeSII protein forms an oxygen-resistant complex with the nitrogenase MoFe and Fe proteins. FeSII is an adrenodoxin-type ferredoxin that forms a dimer in solution. Previously, the crystal structure was solved [Schlesier et al. (2016), J. Am. Chem. Soc. 138, 239-247] with five copies in the asymmetric unit. One copy is a normal adrenodoxin domain that forms a dimer with its crystallographic symmetry mate. The other four copies are in an `open' conformation with a loop flipped out exposing the 2Fe-2S cluster. The open and closed conformations were interpreted as oxidized and reduced, respectively, and the large conformational change in the open configuration allowed binding to nitrogenase. Here, the structure of FeSII was independently solved in the same crystal form. The positioning of the atoms in the unit cell is similar to the earlier report. However, the interpretation of the structure is different. The `open' conformation is interpreted as the product of a crystallization-induced domain swap. The 2Fe-2S cluster is not exposed to solvent, but in the crystal its interacting helix is replaced by the same helix residues from a crystal symmetry mate. The domain swap is complicated, as it is unusual in being in the middle of the protein rather than at a terminus, and it creates arrangements of molecules that can be interpreted in multiple ways. It is also cautioned that crystal structures should be interpreted in terms of the contents of the entire crystal rather than of one asymmetric unit.
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Journal articleHutchison CDM, Perrett S, van Thor JJ, 2024,
XFEL beamline optical instrumentation for ultrafast science
, The Journal of Physical Chemistry B, ISSN: 1520-6106Free electron lasers operating in the soft and hard X-ray regime provide capabilities for ultrafast science in many areas, including X-ray spectroscopy, diffractive imaging, solution and material scattering, and X-ray crystallography. Ultrafast time-resolved applications in the picosecond, femtosecond, and attosecond regimes are often possible using single-shot experimental configurations. Aside from X-ray pump and X-ray probe measurements, all other types of ultrafast experiments require the synchronized operation of pulsed laser excitation for resonant or nonresonant pumping. This Perspective focuses on the opportunities for the optical control of structural dynamics by applying techniques from nonlinear spectroscopy to ultrafast X-ray experiments. This typically requires the synthesis of two or more optical pulses with full control of pulse and interpulse parameters. To this end, full characterization of the femtosecond optical pulses is also highly desirable. It has recently been shown that two-color and two-pulse femtosecond excitation of fluorescent protein crystals allowed a Tannor-Rice coherent control experiment, performed under characterized conditions. Pulse shaping and the ability to synthesize multicolor and multipulse conditions are highly desirable and would enable XFEL facilities to offer capabilities for structural dynamics. This Perspective will give a summary of examples of the types of experiments that could be achieved, and it will additionally summarize the laser, pulse shaping, and characterization that would be recommended as standard equipment for time-resolved XFEL beamlines, with an emphasis on ultrafast time-resolved serial femtosecond crystallography.
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Journal articleChik HYJ, Mannarelli M-E, Dos Remedios N, et al., 2024,
Adult telomere length is positively correlated with survival and lifetime reproductive success in a wild passerine
, Mol Ecol, Vol: 33, ISSN: 0962-1083Explaining variation in individual fitness is a key goal in evolutionary biology. Recently, telomeres, repeating DNA sequences capping chromosome ends, have gained attention as a biomarker for body state, physiological costs, and senescence. Existing research has provided mixed evidence for whether telomere length correlates with fitness, including survival and reproductive output. Moreover, few studies have examined how the rate of change in telomere length correlates with fitness in wild populations. Here, we intensively monitored an insular population of house sparrows, and collected longitudinal telomere and life history data (16 years, 1225 individuals). We tested whether telomere length and its rate of change predict fitness measures, namely survival, lifespan and annual and lifetime reproductive effort and success. Telomere length positively predicted short-term survival, independent of age, but did not predict lifespan, suggesting either a diminishing telomere length-survival correlation with age or other extrinsic factors of mortality. The positive association of telomere length with survival translated into reproductive benefits, as birds with longer telomeres produced more genetic recruits, hatchlings and reared more fledglings over their lifetime. In contrast, there was no association between telomere dynamics and annual reproductive output, suggesting telomere dynamics might not reflect the costs of reproduction in this population, potentially masked by variation in individual quality. The rate of change of telomere length did not correlate with neither lifespan nor lifetime reproductive success. Our results provide further evidence that telomere length correlates with fitness, and contribute to our understanding of the selection on, and evolution of, telomere dynamics.
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Journal articleJaillais Y, Bayer E, Bergmann DC, et al., 2024,
Guidelines for naming and studying plasma membrane domains in plants.
, Nat Plants, Vol: 10, Pages: 1172-1183Biological membranes play a crucial role in actively hosting, modulating and coordinating a wide range of molecular events essential for cellular function. Membranes are organized into diverse domains giving rise to dynamic molecular patchworks. However, the very definition of membrane domains has been the subject of continuous debate. For example, in the plant field, membrane domains are often referred to as nanodomains, nanoclusters, microdomains, lipid rafts, membrane rafts, signalling platforms, foci or liquid-ordered membranes without any clear rationale. In the context of plant-microbe interactions, microdomains have sometimes been used to refer to the large area at the plant-microbe interface. Some of these terms have partially overlapping meanings at best, but they are often used interchangeably in the literature. This situation generates much confusion and limits conceptual progress. There is thus an urgent need for us as a scientific community to resolve these semantic and conceptual controversies by defining an unambiguous nomenclature of membrane domains. In this Review, experts in the field get together to provide explicit definitions of plasma membrane domains in plant systems and experimental guidelines for their study. We propose that plasma membrane domains should not be considered on the basis of their size alone but rather according to the biological system being considered, such as the local membrane environment or the entire cell.
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Journal articleRosenkranz M, Nkumama IN, Ogwang R, et al., 2024,
Full-length MSP1 is a major target of protective immunity after controlled human malaria infection
, Life Science Alliance, Vol: 7, ISSN: 2575-1077The merozoite surface protein 1 (MSP1) is the most abundant protein on the surface of the invasive merozoite stages of Plasmodium falciparum and has long been considered a key target of protective immunity. We used samples from a single controlled human malaria challenge study to test whether the full-length version of MSP1 (MSP1FL) induced antibodies that mediated Fc-IgG functional activity in five independent assays. We found that anti-MSP1FL antibodies induced complement fixation via C1q, monocyte-mediated phagocytosis, neutrophil respiratory burst, and natural killer cell degranulation as well as IFNγ production. Activity in each of these assays was strongly associated with protection. The breadth of MSP1-specific Fc-mediated effector functions was more strongly associated with protection than the individual measures and closely mirrored what we have previously reported using the same assays against merozoites. Our findings suggest that MSP1FL is an important target of functional antibodies that contribute to a protective immune response against malaria.
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Journal articleRebuffet L, Melsen JE, Escalière B, et al., 2024,
High-dimensional single-cell analysis of human natural killer cell heterogeneity.
, Nat Immunol, Vol: 25, Pages: 1474-1488Natural killer (NK) cells are innate lymphoid cells (ILCs) contributing to immune responses to microbes and tumors. Historically, their classification hinged on a limited array of surface protein markers. Here, we used single-cell RNA sequencing (scRNA-seq) and cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) to dissect the heterogeneity of NK cells. We identified three prominent NK cell subsets in healthy human blood: NK1, NK2 and NK3, further differentiated into six distinct subgroups. Our findings delineate the molecular characteristics, key transcription factors, biological functions, metabolic traits and cytokine responses of each subgroup. These data also suggest two separate ontogenetic origins for NK cells, leading to divergent transcriptional trajectories. Furthermore, we analyzed the distribution of NK cell subsets in the lung, tonsils and intraepithelial lymphocytes isolated from healthy individuals and in 22 tumor types. This standardized terminology aims at fostering clarity and consistency in future research, thereby improving cross-study comparisons.
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Journal articleRutter JW, Dekker L, Clare C, et al., 2024,
A bacteriocin expression platform for targeting pathogenic bacterial species.
, Nat Commun, Vol: 15Bacteriocins are antimicrobial peptides that are naturally produced by many bacteria. They hold great potential in the fight against antibiotic resistant bacteria, including ESKAPE pathogens. Engineered live biotherapeutic products (eLBPs) that secrete bacteriocins can be created to deliver targeted bacteriocin production. Here we develop a modular bacteriocin secretion platform that can be used to express and secrete multiple bacteriocins from non-pathogenic Escherichia coli host strains. As a proof of concept we create Enterocin A (EntA) and Enterocin B (EntB) secreting strains that show strong antimicrobial activity against Enterococcus faecalis and Enterococcus faecium in vitro, and characterise this activity in both solid culture and liquid co-culture. We then develop a Lotka-Volterra model that can be used to capture the interactions of these competitor strains. We show that simultaneous exposure to EntA and EntB can delay Enterococcus growth. Our system has the potential to be used as an eLBP to secrete additional bacteriocins for the targeted killing of pathogenic bacteria.
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Journal articleGaboriau T, Tobias JA, Silvestro D, et al., 2024,
Exploring the Macroevolutionary Signature of Asymmetric Inheritance at Speciation.
, Syst BiolPopular comparative phylogenetic models such as Brownian Motion, Ornstein-Ulhenbeck, and their extensions, assume that, at speciation, a trait value is inherited identically by two descendant species. This assumption contrasts with models of speciation at a micro-evolutionary scale where descendants' phenotypic distributions are sub-samples of the ancestral distribution. Different speciation mechanisms can lead to a displacement of the ancestral phenotypic mean among descendants and an asymmetric inheritance of the ancestral phenotypic variance. In contrast, even macro-evolutionary models that account for intraspecific variance assume symmetrically conserved inheritance of ancestral phenotypic distribution at speciation. Here we develop an Asymmetric Brownian Motion model (ABM) that relaxes the assumption of symmetric and conserved inheritance of the ancestral distribution at the time of speciation. The ABM jointly models the evolution of both intra- and inter-specific phenotypic variation. It also infers the mode of phenotypic inheritance at speciation, which can range from a symmetric and conserved inheritance, where descendants inherit the ancestral distribution, to an asymmetric and displaced inheritance, where descendants inherit divergent phenotypic means and variances. To demonstrate this model, we analyze the evolution of beak morphology in Darwin finches, finding evidence of displacement at speciation. The ABM model helps to bridge micro- and macro-evolutionary models of trait evolution by providing a more robust framework for testing the effects of ecological speciation, character displacement, and niche partitioning on trait evolution at the macro-evolutionary scale.
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Journal articleMartins LP, Stouffer DB, Blendinger PG, et al., 2024,
Birds optimize fruit size consumed near their geographic range limits.
, Science, Vol: 385, Pages: 331-336Animals can adjust their diet to maximize energy or nutritional intake. For example, birds often target fruits that match their beak size because those fruits can be consumed more efficiently. We hypothesized that pressure to optimize diet-measured as matching between fruit and beak size-increases under stressful environments, such as those that determine species' range edges. Using fruit-consumption and trait information for 97 frugivorous bird and 831 plant species across six continents, we demonstrate that birds feed more frequently on closely size-matched fruits near their geographic range limits. This pattern was particularly strong for highly frugivorous birds, whereas opportunistic frugivores showed no such tendency. These findings highlight how frugivore interactions might respond to stressful conditions and reveal that trait matching may not predict resource use consistently.
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Journal articleLarrouy-Maumus G, 2024,
Transition metal homeostasis is key to metabolism and drug tolerance of Mycobacterium abscessus
, npj Antimicrobials and Resistance, ISSN: 2731-8745Antimicrobial resistance (AMR) is one of the major challenges humans are facing this century. Understanding the mechanisms behind the rise of AMR is therefore crucial to tackle this global threat. The presence of transition metals is one of the growth-limiting factors for both environmental and pathogenic bacteria, and the mechanisms that bacteria use to adapt to and survive under transition metal toxicity resemble those correlated with the rise of AMR. A deeper understanding of transition metal toxicity and their potential as antimicrobial agents will expand our knowledge of AMR and assist the development of therapeutic strategies. In this study, we investigate the antimicrobial effect of two transition metal ions, namely cobalt (Co2+) and nickel (Ni2+), on the non-tuberculous environmental mycobacterium and the opportunistic human pathogen Mycobacterium abscessus. The minimum inhibitory concentrations of Co2+ and Ni2+ on M. abscessus were first quantified and their impact on the bacterial intracellular metallome was investigated. A multi-omics strategy that combines transcriptomics, bioenergetics, metabolomics and phenotypic assays was designed to further investigate the mechanisms behind the effects of transition metals. We show that transition metals induced growth defect and changes in transcriptome and carbon metabolism in M. abscessus, while the induction of the glyoxylate shunt and the WhiB7 regulon in response to metal stresses could be the key response that led to higher AMR levels. Meanwhile, transition metal treatment alters the bacterial response to clinically relevant antibiotics, and enhance the uptake of clarithromycin into bacterial cells, leading to increased efficacy. This work provides insights into the tolerance mechanisms of M. abscessus to transition metal toxicity and demonstrates the possibility of using transition metals to adjuvate the efficacy of currently using antimicrobials against M. abscessus infections.
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Journal articleGarner BH, Creedy TJ, Allan EL, et al., 2024,
The taxonomic composition and chronology of a museum collection of Coleoptera revealed through large-scale digitisation
, Frontiers in Ecology and Evolution, Vol: 12, ISSN: 2296-701XIntroduction: Historic museum collections hold a wealth of biodiversity data that are essential to our understanding of the rapidly changing natural world. Novel curatorial practices are needed to extract and digitise these data, especially for the innumerable pinned insects whose collecting information is held on small labels.Methods: We piloted semi-automated specimen imaging and digitisation of specimen labels for a collection of ~29,000 pinned insects of ground beetles (Carabidae: Lebiinae) held at the Natural History Museum, London. Raw transcription data were curated against literature sources and non-digital collection records. The primary data were subjected to statistical analyses to infer trends in collection activities and descriptive taxonomy over the past two centuries.Results: This work produced research-ready digitised records for 2,546 species (40% of known species of Lebiinae). Label information was available on geography in 91% of identified specimens, and the time of collection in 39.8% of specimens and could be approximated for nearly all specimens. Label data revealed the great age of this collection (average age 91.4 years) and the peak period of specimen acquisition between 1880 and 1930, with little differences among continents. Specimen acquisition declined greatly after about 1950. Early detected species generally were present in numerous specimens but were missing records from recent decades, while more recently acquired species (after 1950) were represented mostly by singleton specimens only. The slowing collection growth was mirrored by the decreasing rate of species description, which was affected by huge time lags of several decades to formal description after the initial specimen acquisition.Discussion: Historic label information provides a unique resource for assessing the state of biodiversity backwards to pre-industrial times. Many species held in historical collections especially from tropical super-diverse areas may not be discov
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Journal articleWan Y, Myall AC, Boonyasiri A, et 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
, Journal of Infectious Diseases, Vol: 230, Pages: e159-e170, ISSN: 0022-1899BackgroundCarbapenemase-producing Enterobacterales (CPE) are challenging in healthcare, with resistance to multiple classes of antibiotics. This study describes the emergence of imipenemase (IMP)–encoding CPE among diverse Enterobacterales species between 2016 and 2019 across a London regional network.MethodsWe 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 overlaid with patient contacts to imply potential transmission events.ResultsGenomic analysis of 84 Enterobacterales isolates revealed diverse species (predominantly Klebsiella spp, Enterobacter spp, and Escherichia coli); 86% (72 of 84) harbored an IncHI2 plasmid carrying blaIMP and colistin resistance gene mcr-9 (68 of 72). Phylogenetic analysis of IncHI2 plasmids identified 3 lineages showing significant association with patient contacts and movements between 4 hospital sites and across medical specialties, which was missed in initial investigations.ConclusionsCombined, our patient network and plasmid analyses demonstrate an interspecies, plasmid-mediated outbreak of blaIMPCPE, which remained unidentified during standard investigations. With DNA sequencing and multimodal 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.SummaryThis was an investigation, using integrated pathway networks and genomics methods, of the emergence of imipenemase-encoding carbapenemase-producing Enterobacterales among diverse Enterobacterales species between 2016 and 2019 in patients across a London regional hospital network, which was missed on routine investigations.
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Journal articleUkleja M, Kricks L, Torrens G, et al., 2024,
Flotillin-mediated stabilization of unfolded proteins in bacterial membrane microdomains
, Nature Communications, Vol: 15<jats:title>Abstract</jats:title><jats:p>The function of many bacterial processes depends on the formation of functional membrane microdomains (FMMs), which resemble the lipid rafts of eukaryotic cells. However, the mechanism and the biological function of these membrane microdomains remain unclear. Here, we show that FMMs in the pathogen methicillin-resistant <jats:italic>Staphylococcus aureus</jats:italic> (MRSA) are dedicated to confining and stabilizing proteins unfolded due to cellular stress. The FMM scaffold protein flotillin forms a clamp-shaped oligomer that holds unfolded proteins, stabilizing them and favoring their correct folding. This process does not impose a direct energy cost on the cell and is crucial to survival of ATP-depleted bacteria, and thus to pathogenesis. Consequently, FMM disassembling causes the accumulation of unfolded proteins, which compromise MRSA viability during infection and cause penicillin re-sensitization due to PBP2a unfolding. Thus, our results indicate that FMMs mediate ATP-independent stabilization of unfolded proteins, which is essential for bacterial viability during infection.</jats:p>
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Journal articleHowes B, Gonzalez-Suarez M, Banks-Leite C, et al., 2024,
A global latitudinal gradient in the proportion of terrestrial vertebrate forest species
, GLOBAL ECOLOGY AND BIOGEOGRAPHY, Vol: 33, ISSN: 1466-822X -
Journal articleSaranholi BH, Franca FM, Vogler AP, et al., 2024,
Testing and optimizing metabarcoding of iDNA from dung beetles to sample mammals in the hyperdiverse Neotropics
, MOLECULAR ECOLOGY RESOURCES, Vol: 24, ISSN: 1755-098X -
Journal articleChia K-S, Kourelis J, Teulet A, et al., 2024,
The N-terminal domains of NLR immune receptors exhibit structural and functional similarities across divergent plant lineages
, The Plant Cell, Vol: 36, Pages: 2491-2511, ISSN: 1040-4651Nucleotide-binding domain and leucine-rich repeat (NLR) proteins are a prominent class of intracellular immune receptors in plants. However, our understanding of plant NLR structure and function is limited to the evolutionarily young flowering plant clade. Here, we describe an extended spectrum of NLR diversity across divergent plant lineages and demonstrate the structural and functional similarities of N-terminal domains that trigger immune responses. We show that the broadly distributed coiled-coil (CC) and toll/interleukin-1 receptor (TIR) domain families of non-flowering plants retain immune-related functions through trans-lineage activation of cell death in the angiosperm Nicotiana benthamiana. We further examined a CC subfamily specific to non-flowering lineages and uncovered an essential N-terminal MAEPL motif that is functionally comparable to motifs in resistosome-forming CC-NLRs. Consistent with a conserved role in immunity, the ectopic activation of CCMAEPL in the non-flowering liverwort Marchantia polymorpha led to profound growth inhibition, defense gene activation, and signatures of cell death. Moreover, comparative transcriptomic analyses of CCMAEPL activity delineated a common CC-mediated immune program shared across evolutionarily divergent non-flowering and flowering plants. Collectively, our findings highlight the ancestral nature of NLR-mediated immunity during plant evolution that dates its origin to at least ∼500 million years ago.
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Journal articleDunning J, Sanchez-Tojar A, Girndt A, et al., 2024,
Extrapair paternity alongside social reproduction increases male lifetime fitness
, Animal Behaviour, Vol: 213, Pages: 117-123, ISSN: 0003-3472Within breeding years, male birds vary in their reproductive strategy. While some maintain monogamy with a social partner, others also engage with extrapair partners, while others forgo monogamy altogether in favour of exclusively seeking extrapair paternity. Although theory predicts that extrapair paternity is beneficial to males, which sire extrapair offspring without investing in costly parental care, empirical examples from wild populations are sparse. We used 17 years of data from a closed population of house sparrows, Passer domesticus, with a complete genetic pedigree, to test the hypothesis that extrapair paternity increases male lifetime reproductive success. We compared a mixed strategy of within-pair (or social) and extrapair paternity with total genetic monogamy and total extrapair paternity. We demonstrate that males who combine within-pair and extrapair paternity have increased reproductive success against the other two groups. Our results also suggest that males that exclusively seek extrapair paternity have the lowest lifetime fitness. Overall, we provide an empirical demonstration of the theory, showing that where males can sire extrapair offspring alongside within-pair offspring, extrapair paternity is beneficial to male lifetime fitness.
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Journal articleMoreno-Contreras I, Jokimäki J, Kaisanlahti-Jokimäki M-L, et al., 2024,
Disentangling the drivers of urban bird diversity in the non-breeding season: A general synthesis.
, Glob Chang Biol, Vol: 30Current knowledge about the impacts of urbanisation on bird assemblages is based on evidence from studies partly or wholly undertaken in the breeding season. In comparison, the non-breeding season remains little studied, despite the fact that winter conditions at higher latitudes are changing more rapidly than other seasons. During the non-breeding season, cities may attract or retain bird species because they offer milder conditions or better feeding opportunities than surrounding habitats. However, the range of climatic, ecological and anthropogenic mechanisms shaping different facets of urban bird diversity in the non-breeding season are poorly understood. We explored these mechanisms using structural equation modelling to assess how urbanisation affects the taxonomic, phylogenetic and functional diversity of avian assemblages sampled worldwide in the non-breeding season. We found that minimum temperature, elevation, urban area and city age played a critical role in determining taxonomic diversity while a range of factors-including productivity, precipitation, elevation, distance to coasts and rivers, socio-economic (as a proxy of human facilitation) and road density-each contributed to patterns of phylogenetic and functional diversity. The structure and function of urban bird assemblages appear to be predominantly shaped by temperature, productivity and city age, with effects of these factors differing across seasons. Our results underline the importance of considering multiple hypotheses, including seasonal effects, when evaluating the impacts of urbanisation on biodiversity.
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Journal articleEwers RM, Orme CDL, Pearse WD, et al., 2024,
Thresholds for adding degraded tropical forest to the conservation estate.
, Nature, Vol: 631, Pages: 808-813Logged and disturbed forests are often viewed as degraded and depauperate environments compared with primary forest. However, they are dynamic ecosystems1 that provide refugia for large amounts of biodiversity2,3, so we cannot afford to underestimate their conservation value4. Here we present empirically defined thresholds for categorizing the conservation value of logged forests, using one of the most comprehensive assessments of taxon responses to habitat degradation in any tropical forest environment. We analysed the impact of logging intensity on the individual occurrence patterns of 1,681 taxa belonging to 86 taxonomic orders and 126 functional groups in Sabah, Malaysia. Our results demonstrate the existence of two conservation-relevant thresholds. First, lightly logged forests (<29% biomass removal) retain high conservation value and a largely intact functional composition, and are therefore likely to recover their pre-logging values if allowed to undergo natural regeneration. Second, the most extreme impacts occur in heavily degraded forests with more than two-thirds (>68%) of their biomass removed, and these are likely to require more expensive measures to recover their biodiversity value. Overall, our data confirm that primary forests are irreplaceable5, but they also reinforce the message that logged forests retain considerable conservation value that should not be overlooked.
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Journal articleSimpson EG, Fraser I, Woolf H, et al., 2024,
Variation in near-surface soil temperature drives plant assemblage differentiation across aspect.
, Ecol Evol, Vol: 14, ISSN: 2045-7758Quantifying assemblage variation across environmental gradients provides insight into the ecological and evolutionary mechanisms that differentiate assemblages locally within a larger climate regime. We assessed how vascular plant functional composition and diversity varied across microenvironment to identify ecological differences in assemblages in a mountainous fieldsite in northeastern Utah, USA. Then, we looked at how life-history strategies and information about phylogenetic differences affect the relationship between functional metrics and environment. We found less functionally dispersed assemblages that were shorter and more resource-conservative on south-facing slopes where intra-annual soil temperature was hotter and more variable. In contrast, we found more functionally dispersed assemblages, that were taller and more resource-acquisitive on north-facing slopes where intra-annual temperature was cooler and less variable. Herbaceous and woody perennials drove these trends. Additionally, including information about phylogenetic differences in a dispersion metric indicated that phylogeny accounts for traits we did not measure. At this fieldsite, soil temperature acts as an environmental filter across aspect. If soil temperature increases and becomes more variable, intra-annually, the function of north- versus south-facing assemblages may be at risk for contrasting reasons. On south-facing slopes, assemblages may not have the variance in functional diversity needed to respond to more intense, stressful conditions. Conversely, assemblages on north-facing slopes may not have the resource-conservative strategies needed to persist if temperatures become hotter and more variable intra-annually. Given these results, we advocate for the inclusion of aspect differentiation in studies seeking to understand species and assemblage shifts in response to changing climate conditions.
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Journal articleLi Z, Di Vagno L, Chawla H, et al., 2024,
Xylosyltransferase Bump-and-hole Engineering to Chemically Manipulate Proteoglycans in Mammalian Cells.
, bioRxivMammalian cells orchestrate signalling through interaction events on their surfaces. Proteoglycans are an intricate part of these interactions, carrying large glycosaminoglycan polysaccharides that recruit signalling molecules. Despite their importance in development, cancer and neurobiology, a relatively small number of proteoglycans have been identified. In addition to the complexity of glycan extension, biosynthetic redundancy in the first protein glycosylation step by two xylosyltransferase isoenzymes XT1 and XT2 complicates annotation of proteoglycans. Here, we develop a chemical genetic strategy that manipulates the glycan attachment site of cellular proteoglycans. By employing a tactic termed bump- and-hole engineering, we engineer the two isoenzymes XT1 and XT2 to specifically transfer a chemically modified xylose analogue to target proteins. The chemical modification contains a bioorthogonal tag, allowing the ability to visualise and profile target proteins modified by both transferases in mammalian cells. The versatility of our approach allows pinpointing glycosylation sites by tandem mass spectrometry, and exploiting the chemical handle to manufacture proteoglycans with defined GAG chains for cellular applications. Engineered XT enzymes permit a view into proteoglycan biology that is orthogonal to conventional techniques in biochemistry.
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Journal articleTica J, Chen H, LUO S, et al., 2024,
Engineering tunable, low latency spatial computation with dual input quorum sensing promoters
, ACS Synthetic Biology, Vol: 13, Pages: 1750-1761, ISSN: 2161-5063Quorum sensing signals have evolved for population-level signaling in bacterial communities and are versatile tools for engineering cell–cell signaling in synthetic biology projects. Here, we characterize the spatial diffusion of a palette of quorum sensing signals and find that their diffusion in agar can be predicted from their molecular weight with a simple power law. We also engineer novel dual- and multi-input promoters that respond to quorum-sensing diffusive signals for use in engineered genetic systems. We engineer a promoter scaffold that can be adapted for activation and repression by multiple diffusers simultaneously. Lastly, we combine the knowledge on diffusion dynamics with the novel genetic components to build a new generation of spatial, stripe-forming systems with a simplified design, improved robustness, tuneability, and response time.
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