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Journal articleEfron A, Brozzi A, Biolchi A, et al., 2024,
Genetic characterization and estimated 4CMenB vaccine strain coverage of 284 Neisseria meningitidis isolates causing invasive meningococcal disease in Argentina in 2010-2014.
, Hum Vaccin Immunother, Vol: 20Meningococcal (Neisseria meningitidis) serogroup B (MenB) strain antigens are diverse and a limited number of strains can be evaluated using the human serum bactericidal antibody (hSBA) assay. The genetic Meningococcal Antigen Typing System (gMATS) was developed to predict the likelihood of coverage for large numbers of isolates by the 4CMenB vaccine, which includes antigens Neisseria adhesin A (NadA), Neisserial Heparin-Binding Antigen (NHBA), factor H-binding protein (fHbp), and Porin A (PorA). In this study, we characterized by whole-genome analyses 284 invasive MenB isolates collected from 2010 to 2014 by the Argentinian National Laboratories Network (52-61 isolates per year). Strain coverage was estimated by gMATS on all isolates and by hSBA assay on 74 randomly selected isolates, representative of the whole panel. The four most common clonal complexes (CCs), accounting for 81.3% of isolates, were CC-865 (75 isolates, 26.4%), CC-32 (59, 20.8%), CC-35 (59, 20.8%), and CC-41/44 (38, 13.4%). Vaccine antigen genotyping showed diversity. The most prevalent variants/peptides were fHbp variant 2, NHBA peptides 24, 21, and 2, and PorA variable region 2 profiles 16-36 and 14. The nadA gene was present in 66 (23.2%) isolates. Estimated strain coverage by hSBA assay showed 78.4% of isolates were killed by pooled adolescent sera, and 51.4% and 64.9% (based on two different thresholds) were killed by pooled infant sera. Estimated coverage by gMATS (61.3%; prediction interval: 55.5%, 66.7%) was consistent with the infant hSBA assay results. Continued genomic surveillance is needed to evaluate the persistence of major MenB CCs in Argentina.
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Journal articleTong Jia Ming S, Tan Yi Jun K, Carissimo G, 2024,
Pathogenicity and virulence of O’nyong-nyong virus: A less studied <i>Togaviridae</i> with pandemic potential
, Virulence, Vol: 15, ISSN: 2150-5594 -
Journal articleAbitbol V, Martinón-Torres F, Taha M-K, et al., 2024,
4CMenB journey to the 10-year anniversary and beyond.
, Hum Vaccin Immunother, Vol: 20The 4-component meningococcal serogroup B (MenB) vaccine, 4CMenB, the first broadly protective, protein-based MenB vaccine to be licensed, is now registered in more than 50 countries worldwide. Real-world evidence (RWE) from the last decade confirms its effectiveness and impact, with infant immunization programs showing vaccine effectiveness of 71-95% against invasive MenB disease and cross-protection against non-B serogroups, including a 69% decrease in serogroup W cases in 4CMenB-eligible cohorts in England. RWE from different countries also demonstrates the potential for additional moderate protection against gonorrhea in adolescents. The real-world safety profile of 4CMenB is consistent with prelicensure reports. Use of the endogenous complement human serum bactericidal antibody (enc-hSBA) assay against 110 MenB strains may enable assessment of the immunological effectiveness of multicomponent MenB vaccines in clinical trial settings. Equitable access to 4CMenB vaccination is required to better protect all age groups, including older adults, and vulnerable groups through comprehensive immunization policies.
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Journal articleSchroeder J, Dunning J, Chan AHH, et al., 2024,
Not so social in old age: demography as one driver of decreasing sociality.
, Philos Trans R Soc Lond B Biol Sci, Vol: 379Humans become more selective with whom they spend their time, and as a result, the social networks of older humans are smaller than those of younger ones. In non-human animals, processes such as competition and opportunity can result in patterns of declining sociality with age. While there is support for declining sociality with age in mammals, evidence from wild bird populations is lacking. Here, we test whether sociality declines with age in a wild, insular bird population, where we know the exact ages of individuals. Using 6 years of sociality data, we find that as birds aged, their degree and betweenness decreased. The number of same-age birds still alive also decreased with age. Our results suggest that a longitudinal change in sociality with age may be, in part, an emergent effect of natural changes in demography. This highlights the need to investigate the changing costs and benefits of sociality across a lifetime.This article is part of the discussion meeting issue 'Understanding age and society using natural populations'.
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Journal articleEwers RM, Cook J, Daniel OZ, et al., 2024,
New insights to be gained from a Virtual Ecosystem
, Ecological Modelling, Vol: 498, ISSN: 0304-3800The myriad interactions among individual plants, animals, microbes and their abiotic environment generate emergent phenomena that will determine the future of life on Earth. Here, we argue that holistic ecosystem models – incorporating key biological domains and feedbacks between biotic and abiotic processes and capable of predicting emergent phenomena – are required if we are to understand the functioning of complex, terrestrial ecosystems in a rapidly changing planet. We argue that holistic ecosystem models will provide a framework for integrating the many approaches used to study ecosystems, including biodiversity science, population and community ecology, soil science, biogeochemistry, hydrology and climate science. Holistic models will provide new insights into the nature and importance of feedbacks that cut across scales of space and time, and that connect ecosystem domains such as microbes with animals or above with below ground. They will allow us to critically examine the origins and maintenance of ecosystem stability, resilience and sustainability through the lens of systems theory, and provide a much-needed boost for conservation and the management of natural environments. We outline our approach to developing a holistic ecosystem model – the Virtual Ecosystem – and argue that while the construction of such complex models is obviously ambitious, it is both feasible and necessary.
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Journal articleWoubshete M, Chan LI, Diallinas G, et al., 2024,
The dimer of human SVCT1 is key for transport function.
, Biochim Biophys Acta Biomembr, Vol: 1866Humans and other primates lack the ability to synthesize the essential nutrient, Vitamin C, which is derived exclusively from the diet. Crucial for effective vitamin C uptake are the Na+ dependent Vitamin C transporters, SVCT1 and SVCT2, members of the nucleobase ascorbate transporter (NAT) family. SVCT1 and 2 actively transport the reduced form of Vitamin C, ascorbic acid, into key tissues. The recent structure of the mouse SVCT1 revealed the molecular basis of substrate binding and that, like the other structurally characterised members of the NAT family, it exists as a closely associated dimer. SVCT1 is likely to function via the elevator mechanism with the core domain of each protomer able to bind substrate and move through the membrane carrying the substrate across the membrane. Here we explored the function of a range of variants of the human SVCT1, revealing a range of residues involved in substrate selection and binding, and confirming the importance of the C-terminus in membrane localisation. Furthermore, using a dominant negative mutant we show that the dimer is essential for transport function, as previously seen in the fungal homologue, UapA. In addition, we show that a localisation deficient C-terminal truncation of SVCT1 blocks correct localisation of co-expressed, associated wildtype SVCT1. These results clearly show the importance of the dimer in both correct SVCT1 trafficking and transport activity.
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Journal articleMajumdar A, Upadhyay MK, Ojha M, et al., 2024,
A critical review on the organo-metal(loid)s pollution in the environment: Distribution, remediation and risk assessment.
, Sci Total Environ, Vol: 951Toxic metal(loid)s, e.g., mercury, arsenic, lead, and cadmium are known for several environmental disturbances creating toxicity to humans if accumulated in high quantities. Although not discussed critically, the organo-forms of these inorganic metal(loid)s are considered a greater risk to humans than their elemental forms possibly due to physico-chemical modulation triggering redox alterations or by the involvement of biological metabolism. This extensive review describes the chemical and physical causes of organometals and organometal(loid)s distribution in the environment with ecotoxicity assessment and potential remediation strategies. Organo forms of various metal(loid)s, such as mercury (Hg), arsenic (As), lead (Pb), tin (Sn), antimony (Sb), selenium (Se), and cadmium (Cd) have been discussed in the context of their ecotoxicity. In addition, we elaborated on the transformation, speciation and transformation pathways of these toxic metal(loid)s in soil-water-plant-microbial systems. The present review has pointed out the status of toxic organometal(loid)s, which is required to make the scientific community aware of this pressing condition of organometal(loid)s distribution in the environment. The gradual disposal and piling of organometal(loid)s in the environment demand a thorough revision of the past-present status with possible remediation strategies prescribed as reflected in this review.
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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 articleParry C, Turnbull C, Barter L, et al., 2024,
Shedding light on pollination deficits: cueing into plant spectral reflectance signatures to monitor pollination delivery across landscapes
, Journal of Applied Ecology, ISSN: 0021-8901 -
Journal articleCheong B, Tang W, Kostrzewa M, et al., 2024,
Use of stable isotope combined with intact cell lipidomic by routine MALDI mass spectrometry analysis for rapid drug susceptibility assay in mycobacteria.
, Rapid Commun Mass Spectrom, Vol: 38RATIONALE: Rapid, accurate, and easy-to-perform diagnostic assays are required to address the current need for the diagnosis of resistant pathogens. That is particularly the case for mycobacteria, such as the human pathogen Mycobacterium tuberculosis, which requires up to 2 weeks for the determination of the drug susceptibility profile using the conventional broth microdilution method. To address this challenge, we investigated the incorporation of deuterium, the stable isotope of hydrogen, into lipids as a read out of the drug susceptibility profile. METHODS: Deuterium is incorporated into newly synthesized proteins or lipids in place of hydrogen as bacterial cells grow, increasing the mass of the macromolecules, which can then be observed via matrix-assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF MS). As proof-of-concept, we used the non-pathogenic Mycobacterium smegmatis mc2155 strain, which is susceptible to the aminoglycoside antibiotic kanamycin, and M. smegmatis mc2155 containing the empty vector pVV16, which is kanamycin-resistant. Bacteria were incubated in a culture medium containing 50% of deuterium oxide (D2O) and either 1 or 2 times the minimal inhibitory concentration (MIC50) of kanamycin. Lipids were then analyzed using the MBT lipid Xtract matrix combined with routine MALDI mass spectrometry in the positive ion mode to evaluate the changes in the lipid profile. RESULTS: Using this approach, we were able to distinguish susceptible from resistant bacteria in less than 5 h, a process that would take 72 h using the conventional broth microdilution method. CONCLUSIONS: We therefore propose a solution for the rapid determination of drug susceptibility profiles using a phenotypic assay combining D2O stable isotope labelling and lipid analysis by routine MALDI mass spectrometry.
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Journal articleWilliams J, Newbold T, Millard J, et al., 2024,
Important Crop Pollinators Respond Less Negatively to Anthropogenic Land Use Than Other Animals
, Ecology and Evolution, ISSN: 2045-7758Animal-mediated pollination is a key ecosystem service required to some extent by almost three-quarters of the leading human food crops in global food production. Anthropogenic pressures such as habitat loss and land-use intensification are causing shifts in ecological community composition, potentially resulting in declines in pollination services and impacting crop production. Previous research has often overlooked interspecific differences in pollination contribution, yet such differences mean that biodiversity declines will not necessarily negatively impact pollination. Here, we use a novel species-level ecosystem service contribution matrix along with mixed-effects models to explore how groups of terrestrial species who contribute differently to crop pollination respond globally to land-use type, land-use intensity, and availability of natural habitats in the surrounding landscape. We find that the species whose contribution to crop pollination is higher generally respond less negatively (and in some cases positively) to human disturbance of land, compared to species that contribute less or not at all to pollination. This result may be due to these high-contribution species being less sensitive to anthropogenic land conversions, which has led humans to being more reliant on them for crop pollination. However, it also suggests that there is potential for crop pollination to be resilient in the face of anthropogenic land conversions. With such a high proportion of food crops requiring animal-mediated pollination to some extent, understanding how anthropogenic landscapes impact ecological communities and the consequences for pollination is critical for ensuring food security.
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Journal articleThorpe P, Altmann S, Lopez-Cobollo R, et al., 2024,
Multi-omics approaches define novel aphid effector candidates associated with virulence and avirulence phenotypes
, BMC Genomics, ISSN: 1471-2164 -
Journal articleZhang-Zheng H, Deng X, Aguirre-Gutierrez J, et al., 2024,
Why models underestimate West African tropical forest primary productivity
, Nature Communications, ISSN: 2041-1723 -
Journal articleLiu K, Grover M, Trusch F, et al., 2024,
Paired C-type lectin receptors mediate specific recognition of divergent oomycete pathogens in C. elegans
, Cell Reports, ISSN: 2211-1247 -
Journal articleStocker B, Dong N, Perkowski EA, et al., 2024,
Empirical evidence and theoretical understanding ofecosystem carbon and nitrogen cycle interactions
, New Phytologist, ISSN: 0028-646X -
Journal articleSelvaraj M, Toghani A, Pai H, et al., 2024,
Activation of plant immunity through conversion of a helper NLR homodimer into a resistosome
, PLoS Biology, ISSN: 1544-9173Nucleotide-binding domain and leucine-rich repeat (NLR) proteins can engage in complex interactions to detect pathogens and execute a robust immune response via downstream helper NLRs. However, the biochemical mechanisms of helper NLR activation by upstream sensor NLRs remain poorly understood. Here, we show that the coiled-coil helper NLR NRC2 from Nicotiana benthamiana accumulates in vivo as a homodimer that converts into a higher-order oligomer upon activation by its upstream virus disease resistance protein Rx. The cryo-EM structure of NbNRC2 in its resting state revealed intermolecular interactions that mediate homodimer formation and contribute to immune receptor autoinhibition. These dimerization interfaces have diverged between paralogous NRC proteins to insulate critical network nodes and enable redundant immune pathways, possibly to minimise undesired cross-activation and evade pathogen suppression of immunity. Our results expand the molecular mechanisms of NLR activation pointing to transition from homodimers to higher-order oligomeric resistosomes.
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Journal articlePipatpadungsin N, Chao K, Rouse SL, 2024,
Coarse-Grained Simulations of Adeno-Associated Virus and Its Receptor Reveal Influences on Membrane Lipid Organization and Curvature.
, J Phys Chem B, Vol: 128, Pages: 10139-10153Adeno-associated virus (AAV) is a well-known gene delivery tool with a wide range of applications, including as a vector for gene therapies. However, the molecular mechanism of its cell entry remains unknown. Here, we performed coarse-grained molecular dynamics simulations of the AAV serotype 2 (AAV2) capsid and the universal AAV receptor (AAVR) in a model plasma membrane environment. Our simulations show that binding of the AAV2 capsid to the membrane induces membrane curvature, along with the recruitment and clustering of GM3 lipids around the AAV2 capsid. We also found that the AAVR binds to the AAV2 capsid at the VR-I loops using its PKD2 and PKD3 domains, whose binding poses differs from previous structural studies. These first molecular-level insights into AAV2 membrane interactions suggest a complex process during the initial phase of AAV2 capsid internalization.
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Journal articleKundu S, Dos Santos Correia G, Lee Y, et al., 2024,
Secretor status is a modifier of vaginal microbiota-associated preterm birth risk
, Microbial Genomics, ISSN: 2057-5858Mutations in the FUT2 gene that result in a lack of expression of histo-blood group antigens on secreted glycoproteins may shape the vaginal microbiota with consequences for birth outcome. To test this, we analysed the relationship between secretor status, vaginal microbiota and gestational length in an ethnically diverse cohort of 302 pregnant women, including 82 who delivered preterm. Lactobacillus gasseri and Lactobacillus jensenii were found to have distinct co-occurrence patterns with other microbial taxa in non-secretors. Moreover, non-secretors with Lactobacillus spp. depleted, high diversity vaginal microbiota in early pregnancy had significantly shorter gestational length than Lactobacillus spp. dominated non-secretors (mean of 241.54 days (SD=47.14) versus 266.21 (23.61); p-value=0.0251). Similar gestational length was observed between non-secretors with high vaginal diversity and secretors with Lactobacillus spp. dominance (mean of 262.52 days (SD=27.73); p-value=0.0439) or depletion (mean of 266.05 days (SD=20.81); p-value=0.0312). Our data highlight secretor status and blood-group antigen expression as being important mediators of vaginal microbiota-host interactions in the context of preterm birth risk.
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Journal articleHancock PA, North A, Leach AW, et al., 2024,
The potential of gene drives in malaria vector species to control malaria in African environments.
, Nat Commun, Vol: 15Gene drives are a promising means of malaria control with the potential to cause sustained reductions in transmission. In real environments, however, their impacts will depend on local ecological and epidemiological factors. We develop a data-driven model to investigate the impacts of gene drives that causes vector population suppression. We simulate gene drive releases in sixteen ~ 12,000 km2 areas of west Africa that span variation in vector ecology and malaria prevalence, and estimate reductions in vector abundance, malaria prevalence and clinical cases. Average reductions in vector abundance ranged from 71.6-98.4% across areas, while impacts on malaria depended strongly on which vector species were targeted. When other new interventions including RTS,S vaccination and pyrethroid-PBO bednets were in place, at least 60% more clinical cases were averted when gene drives were added, demonstrating the benefits of integrated interventions. Our results show that different strategies for gene drive implementation may be required across different African settings.
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Journal articleKontopoulos D-G, Sentis A, Daufresne M, et al., 2024,
No universal mathematical model for thermal performance curves across traits and taxonomic groups
, Nature Communications, Vol: 15, ISSN: 2041-1723In ectotherms, the performance of physiological, ecological and life-history traits universally increases with temperature to a maximum before decreasing again. Identifying the most appropriate thermal performance model for a specific trait type has broad applications, from metabolic modelling at the cellular level to forecasting the effects of climate change on population, ecosystem and disease transmission dynamics. To date, numerous mathematical models have been designed, but a thorough comparison among them is lacking. In particular, we do not know if certain models consistently outperform others and how factors such as sampling resolution and trait or organismal identity influence model performance. To fill this knowledge gap, we compile 2,739 thermal performance datasets from diverse traits and taxa, to which we fit a comprehensive set of 83 existing mathematical models. We detect remarkable variation in model performance that is not primarily driven by sampling resolution, trait type, or taxonomic information. Our results reveal a surprising lack of well-defined scenarios in which certain models are more appropriate than others. To aid researchers in selecting the appropriate set of models for any given dataset or research objective, we derive a classification of the 83 models based on the average similarity of their fits.
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Journal articleFlintham E, Savolainen V, Otto S, et al., 2024,
The maintenance of genetic polymorphism underlyingsexually antagonistic traits
, Evolution Letters, ISSN: 2056-3744Selection often favours different trait values in males and females, leading to genetic conflicts between the sexes when traits have a shared genetic basis. Such sexual antagonism has beenproposed to maintain genetic polymorphism. However, this notion is based on insights from population genetic models of single loci with fixed fitness effects. It is thus unclear how readily polymorphism emerges from sex-specific selection acting on continuous traits, where fitness effects arisefrom the genotype-phenotype map and the fitness landscape. Here we model the evolution of a continuous trait that has a shared genetic basis but different optima in males and females, considering a wide variety of genetic architectures and fitness landscapes. For autosomal loci, the long-termmaintenance of polymorphism requires strong conflict between males and females that generatesuncharacteristic sex-specific fitness patterns. Instead, more plausible sex-specific fitness landscapestypically generate stabilising selection leading to an evolutionarily stable state that consists of a singlehomozygous genotype. Except for sites tightly linked to the sex determining region, our results indicate that genetic variation due to sexual antagonism should arise only rarely and often be transient,making these signatures challenging to detect in genomic data.
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Journal articleMarshall EKP, Nunes C, Burbaud S, et al., 2024,
Microbial metabolism disrupts cytokine activity to impact host immune response
, Proceedings of the National Academy of Sciences of USA, ISSN: 0027-8424Host-pathogen interactions are shaped by the metabolic status of both the host and pathogen. The host must regulate metabolism to fuel the immune response, whilst the pathogen must extract metabolic resources from the host to enable its own survival. In this study, we focus on the metabolic interactions of Mycobacterium abscessus with Drosophila melanogaster. We identify MAB_1132 as an asparagine transporter required for pathogenicity in M. abscessus. We show that this requirement is specifically associated with damage to the host: flies infected with MAB_1132c knockout bacteria, or with wild-type bacteria grown in asparagine-restricted conditions, are longer lived without showing a significant change in bacterial load. This is associated with a reduction in the host innate immune response, demonstrated by the decreased transcription of antimicrobial peptides, as well as a significant reduction in the ability of the infection to disrupt systemic insulin signalling. Much of the increase in host survival during infection with asparagine-limited M. abscessus can be attributed to alterations in unpaired cytokine signalling. This demonstrates that asparagine transport in M. abscessus prior to infection is not required for replicative fitness in vivo but does significantly influence the interaction with the host immune responses.
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Journal articlePalmer J, Samuelson AE, Gill RJ, et al., 2024,
Foraging distance distributions reveal how honeybee waggle dance recruitment varies with landscape
, Communications Biology, Vol: 7, ISSN: 2399-3642Honeybee (Apis mellifera) colonies use a unique collective foraging system, the waggle dance, to communicate and process the location of resources. Here, we present a means to quantify the effect of recruitment on colony forager allocation across the landscape by simply observing the waggle dance on the dancefloor. We show first, through a theoretical model, that recruitment leaves a characteristic imprint on the distance distribution of foraging sites that a colony visits, which varies according to the proportion of trips driven by individual search. Next, we fit this model to the real-world empirical distance distribution of forage sites visited by 20 honeybee colonies in urban and rural landscapes across South East England, obtained via dance decoding. We show that there is considerable variation in the use of dancing information in colony foraging, particularly in agri-rural landscapes. In our dataset, reliance on dancing increases as arable land gives way to built-up areas, suggesting that dancing may have the greatest impact on colony foraging in the complex and heterogeneous landscapes of forage-rich urban areas. Our model provides a tool to assess the relevance of this extraordinary behaviour across modern anthropogenic landscape types.
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Journal articleDrobnič T, Cohen EJ, Calcraft T, et al., 2024,
Molecular model of a bacterial flagellar motor in situ reveals a "parts-list" of protein adaptations to increase torque.
, bioRxivOne hurdle to understanding how molecular machines work, and how they evolve, is our inability to see their structures in situ. Here we describe a minicell system that enables in situ cryogenic electron microscopy imaging and single particle analysis to investigate the structure of an iconic molecular machine, the bacterial flagellar motor, which spins a helical propeller for propulsion. We determine the structure of the high-torque Campylobacter jejuni motor in situ, including the subnanometre-resolution structure of the periplasmic scaffold, an adaptation essential to high torque. Our structure enables identification of new proteins, and interpretation with molecular models highlights origins of new components, reveals modifications of the conserved motor core, and explain how these structures both template a wider ring of motor proteins, and buttress the motor during swimming reversals. We also acquire insights into universal principles of flagellar torque generation. This approach is broadly applicable to other membrane-residing bacterial molecular machines complexes.
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Journal articleBenjamin S, Jégouzo S, Lieng C, et al., 2024,
A human lectin array for characterizing host-pathogen interactions
, Journal of Biological Chemistry, ISSN: 0021-9258A human lectin array has been developed to probe the interactions of innate immune receptors with pathogenic and commensal micro-organisms. Following the successful introduction of a lectin array containing all of the cow C-type carbohydrate-recognition domains (CRDs), a human array described here contains the C-type CRDs as well as CRDs from other classes of sugar-binding receptors, including galectins, siglecs, R-type CRDs, ficolins, intelectins and chitinase-like lectins. The array is constructed with CRDs modified with single-site biotin tags, ensuring that the sugar-binding sites in CRDs are displayed on a streptavidin-coated surface in a defined orientation and are accessible to the surfaces of microbes. A common approach used for expression and display of CRDs from all of the different structural categories of glycan-binding receptors allows comparisons across lectin families. In addition to previously documented protocols for binding of fluorescently-labeled bacteria, methods have been developed for detecting unlabeled bacteria bound to the array by counter-staining with DNA binding dye. Screening has also been undertaken with viral glycoproteins and bacterial and fungal polysaccharides. The array provides an unbiased screen for sugar ligands that interact with receptors and many show binding not anticipated from earlier studies. For example, some of the galectins bind with high affinity to bacterial glycans that lack lactose or N acetyllactosamine. The results demonstrate the utility of the human lectin array for providing a unique overview of the interactions of multiple classes of glycan-binding proteins in the innate immune system with different types of micro-organisms.
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Journal articleMatthews TJ, Triantis KA, Wayman JP, et al., 2024,
The global loss of avian functional and phylogenetic diversity from anthropogenic extinctions.
, Science, Vol: 386, Pages: 55-60Humans have been driving a global erosion of species richness for millennia, but the consequences of past extinctions for other dimensions of biodiversity-functional and phylogenetic diversity-are poorly understood. In this work, we show that, since the Late Pleistocene, the extinction of 610 bird species has caused a disproportionate loss of the global avian functional space along with ~3 billion years of unique evolutionary history. For island endemics, proportional losses have been even greater. Projected future extinctions of more than 1000 species over the next two centuries will incur further substantial reductions in functional and phylogenetic diversity. These results highlight the severe consequences of the ongoing biodiversity crisis and the urgent need to identify the ecological functions being lost through extinction.
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Journal articleLiu Y, Kim J-W, Feinberg H, et al., 2024,
Interactions that define the arrangement of sugar-binding sites in BDCA-2 and dectin-2 dimers
, Glycobiology, ISSN: 0959-6658The sugar-binding receptors dectin-2 and blood dendritic cell antigen 2 (BDCA-2) bind oligosaccharide ligands through extracellular carbohydrate-recognition domains (CRDs) and initiate intracellular signaling through Fc receptor γ adapters (FcRγ). Dectin-2 stimulates macrophages in response to pathogen binding while BDCA-2 modulates cytokine production in plasmacytoid dendritic cells. The oligomeric states of these receptors and the orientations of their CRDs have been investigated by analysis of a naturally occurring disulfide-bonded variant of BDCA-2 and by replacement of transmembrane domains with N-terminal dimerization domains to create extracellular domain dimers of both dectin-2 and BDCA-2. Analysis of these constructs, as well as previously described crystal structures of the CRDs from these proteins and a novel structure of an extended version of the extracellular domain of dectin-2, showed that there is only limited interaction of the CRDs in the dimers, but interactions can be stabilized by the presence of the neck region. The resulting orientation of sugar-binding sites in the dimers would favor crosslinking of multiple dimers by oligosaccharide ligands, causing clustering of FcRγ to initiate signaling.
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Journal articleBarnada SM, Giner de Gracia A, Morenilla-Palao C, et al., 2024,
ARID1A-BAF coordinates ZIC2 genomic occupancy for epithelial-to-mesenchymal transition in cranial neural crest specification.
, Am J Hum Genet, Vol: 111, Pages: 2232-2252The BAF chromatin remodeler regulates lineage commitment including cranial neural crest cell (CNCC) specification. Variants in BAF subunits cause Coffin-Siris syndrome (CSS), a congenital disorder characterized by coarse craniofacial features and intellectual disability. Approximately 50% of individuals with CSS harbor variants in one of the mutually exclusive BAF subunits, ARID1A/ARID1B. While Arid1a deletion in mouse neural crest causes severe craniofacial phenotypes, little is known about the role of ARID1A in CNCC specification. Using CSS-patient-derived ARID1A+/- induced pluripotent stem cells to model CNCC specification, we discovered that ARID1A-haploinsufficiency impairs epithelial-to-mesenchymal transition (EMT), a process necessary for CNCC delamination and migration from the neural tube. Furthermore, wild-type ARID1A-BAF regulates enhancers associated with EMT genes. ARID1A-BAF binding at these enhancers is impaired in heterozygotes while binding at promoters is unaffected. At the sequence level, these EMT enhancers contain binding motifs for ZIC2, and ZIC2 binding at these sites is ARID1A-dependent. When excluded from EMT enhancers, ZIC2 relocates to neuronal enhancers, triggering aberrant neuronal gene activation. In mice, deletion of Zic2 impairs NCC delamination, while ZIC2 overexpression in chick embryos at post-migratory neural crest stages elicits ectopic delamination from the neural tube. These findings reveal an essential ARID1A-ZIC2 axis essential for EMT and CNCC delamination.
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Journal articleLiu Y, Drickamer K, Taylor ME, 2024,
Preformed mincle dimers stabilized by an interchain disulfide bond in the neck region
, Glycobiology, ISSN: 1460-2423The sugar-binding receptor mincle stimulates macrophages when it encounters surface glycans on pathogens, such as trehalose dimycolate glycolipid in the outer membrane of mycobacteria. Binding of oligosaccharide ligands to the extracellular C-type carbohydrate-recognition domain (CRD) in mincle initiates intracellular signaling through the common Fc receptor γ (FcRγ) adapter molecule associated with mincle. One potential mechanism for initiation of signaling involves clustering of receptors, so it is important to understand the oligomeric state of mincle. Affinity purification of mincle from transfected mammalian cells has been used to show that mincle exists as a pre-formed, disulfide-linked dimer. Deletion of cysteine residues and chemical crosslinking further demonstrate that the dimers of mincle are stabilized by a disulfide bond between cysteine residues in the neck sequence that links the CRD to the membrane. In contrast, cysteine residues in the transmembrane region of mincle are not required for dimer formation or association with FcRγ. A protocol has been developed for efficient production of a disulfide-linked extracellular domain fragment of mincle in a bacterial expression system by appending synthetic dimerization domains to guide dimer formation in the absence of the membrane anchor.
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Journal articleCheaib A, Waring EF, McNellis R, et al., 2024,
Soil nitrogen supply exerts largest influence on leaf nitrogen in environments with the greatest leaf nitrogen demand
, Ecology Letters, ISSN: 1461-023X
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