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Journal articleKing FJ, Yuen ELH, Bozkurt TO, 2024,
Border Control: Manipulation of the Host-Pathogen Interface by Perihaustorial Oomycete Effectors.
, Mol Plant Microbe Interact, ISSN: 0894-0282Filamentous plant pathogens, including fungi and oomycetes, cause some of the most devastating plant diseases. These organisms serve as ideal models for understanding the intricate molecular interplay between plants and the invading pathogens. Filamentous pathogens secrete effector proteins via haustoria, specialized structures for infection and nutrient uptake, to suppress the plant immune response and to reprogram plant metabolism. Recent advances in cell biology have provided crucial insights into the biogenesis of the extrahaustorial membrane and the redirection of host endomembrane trafficking toward this interface. Functional studies have shown that an increasing number of oomycete effectors accumulate at the perihaustorial interface to subvert plant focal immune responses, with a particular convergence on targets involved in host endomembrane trafficking. In this review, we summarize the diverse mechanisms of perihaustorial effectors from oomycetes and pinpoint pressing questions regarding their role in manipulating host defense and metabolism at the haustorial interface. [Formula: see text] Copyright © 2024 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license.
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Journal articleGardner S, Jin Y, Fyfe PK, et al., 2024,
Structural insights into IL-11-mediated signalling and human IL6ST variant-associated immunodeficiency
, Nature Communications, Vol: 15, ISSN: 2041-1723IL-11 and IL-6 activate signalling via assembly the cell surface receptor gp130; however, it is unclear how signals are transmitted across the membrane to instruct cellular responses. Here we solve the cryoEM structure of the IL-11 receptor recognition complex to discover how differences in gp130-binding interfaces may drive signalling outcomes. We explore how mutations in the IL6ST gene encoding for gp130, which cause severe immune deficiencies in humans, impair signalling without blocking cytokine binding. We use cryoEM to solve structures of both IL-11 and IL-6 complexes with a mutant form of gp130 associated with human disease. Together with molecular dynamics simulations, we show that the disease-associated variant led to an increase in flexibility including motion within the cytokine-binding core and increased distance between extracellular domains.However, these distances are minimized as the transmembrane helix exits the membrane, suggesting a stringency in geometry for signalling and dimmer switch mode of action.
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Journal articleQi L, Bennett E, Isalan M, 2024,
A directed evolution protocol for engineering minimal transcription factors, based on CIS display.
, Methods in Molecular Biology, ISSN: 1064-3745 -
Journal articleBeis K, 2024,
Structural basis for the modulation of MRP2 activity by phosphorylation and drugs
, Nature Communications, ISSN: 2041-1723 -
Journal articlePawar S, Huxley PJ, Smallwood TRC, et al., 2024,
Variation in temperature of peak trait performance constrains adaptation of arthropod populations to climatic warming.
, Nat Ecol Evol, Vol: 8, Pages: 500-510The capacity of arthropod populations to adapt to long-term climatic warming is currently uncertain. Here we combine theory and extensive data to show that the rate of their thermal adaptation to climatic warming will be constrained in two fundamental ways. First, the rate of thermal adaptation of an arthropod population is predicted to be limited by changes in the temperatures at which the performance of four key life-history traits can peak, in a specific order of declining importance: juvenile development, adult fecundity, juvenile mortality and adult mortality. Second, directional thermal adaptation is constrained due to differences in the temperature of the peak performance of these four traits, with these differences expected to persist because of energetic allocation and life-history trade-offs. We compile a new global dataset of 61 diverse arthropod species which provides strong empirical evidence to support these predictions, demonstrating that contemporary populations have indeed evolved under these constraints. Our results provide a basis for using relatively feasible trait measurements to predict the adaptive capacity of diverse arthropod populations to geographic temperature gradients, as well as ongoing and future climatic warming.
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Journal articleGrover M, Gang SS, Troemel ER, et al., 2024,
Proteasome inhibition triggers tissue-specific immune responses against different pathogens in C. elegans
, PLoS Biology, Vol: 22, Pages: 1-21, ISSN: 1544-9173Protein quality control pathways play important roles in resistance against pathogen infection. For example, the conserved transcription factor SKN-1/NRF up-regulates proteostasis capacity after blockade of the proteasome and also promotes resistance against bacterial infection in the nematode Caenorhabditis elegans. SKN-1/NRF has 3 isoforms, and the SKN-1A/NRF1 isoform, in particular, regulates proteasomal gene expression upon proteasome dysfunction as part of a conserved bounce-back response. We report here that, in contrast to the previously reported role of SKN-1 in promoting resistance against bacterial infection, loss-of-function mutants in skn-1a and its activating enzymes ddi-1 and png-1 show constitutive expression of immune response programs against natural eukaryotic pathogens of C. elegans. These programs are the oomycete recognition response (ORR), which promotes resistance against oomycetes that infect through the epidermis, and the intracellular pathogen response (IPR), which promotes resistance against intestine-infecting microsporidia. Consequently, skn-1a mutants show increased resistance to both oomycete and microsporidia infections. We also report that almost all ORR/IPR genes induced in common between these programs are regulated by the proteasome and interestingly, specific ORR/IPR genes can be induced in distinct tissues depending on the exact trigger. Furthermore, we show that increasing proteasome function significantly reduces oomycete-mediated induction of multiple ORR markers. Altogether, our findings demonstrate that proteasome regulation keeps innate immune responses in check in a tissue-specific manner against natural eukaryotic pathogens of the C. elegans epidermis and intestine.
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Journal articleChukhutsina VU, Hutchison CDM, van Thor JJ, 2024,
The Carbonyl Group in β2 of the Carotenoid Tunes the Photocycle Kinetics in Orange Carotenoid Protein
, Journal of Molecular Biology, Vol: 436, Pages: 168463-168463, ISSN: 0022-2836 -
Journal articleGumbs R, Scott O, Bates R, et al., 2024,
Global conservation status of the jawed vertebrate Tree of Life
, Nature Communications, Vol: 15, ISSN: 2041-1723Human-driven extinction threatens entire lineages across the Tree of Life. Here we assess the conservation status of jawed vertebrate evolutionary history, using three policy-relevant approaches. First, we calculate an index of threat to overall evolutionary history, showing that we expect to lose 86-150 billion years (11-19%) of jawed vertebrate evolutionary history over the next 50-500 years. Second, we rank jawed vertebrate species by their EDGE scores to identify the highest priorities for species-focused conservation of evolutionary history, finding that chondrichthyans, ray-finned fish and testudines rank highest of all jawed vertebrates. Third, we assess the conservation status of jawed vertebrate families. We found that species within monotypic families are more likely to be threatened and more likely to be in decline than other species. We provide a baseline for the status of families at risk of extinction to catalyse conservation action. This work continues a trend of highlighting neglected groups—such as testudines, crocodylians, amphibians and chondrichthyans—as conservation priorities from a phylogenetic perspective.
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Journal articleBlackford K, Kasoar M, Burton C, et al., 2024,
INFERNO-peat v1.0.0: a representation of northern high latitude peat fires in the JULES-INFERNO global fire model
, Geoscientific Model Development, ISSN: 1991-959X -
Journal articleYoon S, Bae HE, Hariharan P, et al., 2024,
Rational approach to improve detergent efficacy for membrane protein stabilization
, Bioconjugate Chemistry, Vol: 35, Pages: 223-231, ISSN: 1043-1802Membrane protein structures are essential for the molecular understanding of diverse cellular processes and drug discovery. Detergents are not only widely used to extract membrane proteins from membranes but also utilized to preserve native protein structures in aqueous solution. However, micelles formed by conventional detergents are suboptimal for membrane protein stabilization, necessitating the development of novel amphiphilic molecules with enhanced protein stabilization efficacy. In this study, we prepared two sets of tandem malonate-derived glucoside (TMG) variants, both of which were designed to increase the alkyl chain density in micelle interiors. The alkyl chain density was modulated either by reducing the spacer length (TMG-Ms) or by introducing an additional alkyl chain between the two alkyl chains of the original TMGs (TMG-Ps). When evaluated with a few membrane proteins including a G protein-coupled receptor, TMG-P10,8 was found to be substantially more efficient at extracting membrane proteins and also effective at preserving protein integrity in the long term compared to the previously described TMG-A13. This result reveals that inserting an additional alkyl chain between the two existing alkyl chains is an effective way to optimize detergent properties for membrane protein study. This new biochemical tool and the design principle described have the potential to facilitate membrane protein structure determination.
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Journal articleMurphy RA, Pizzato J, Cuthbertson L, et al., 2024,
Antimicrobial peptide glatiramer acetate targets Pseudomonas aeruginosa lipopolysaccharides to breach membranes without altering lipopolysaccharide modification
, npj Antimicrobials and Resistance, Vol: 2, ISSN: 2731-8745Antimicrobial peptides (AMPs) are key components of innate immunity across all domains of life. Natural and synthetic AMPs are receiving renewed attention in efforts to combat the antimicrobial resistance (AMR) crisis and the loss of antibiotic efficacy. The gram-negative pathogen Pseudomonas aeruginosa is one of the most concerning infecting bacteria in AMR, particularly in people with cystic fibrosis (CF) where respiratory infections are difficult to eradicate and associated with increased morbidity and mortality. Cationic AMPs exploit the negatively charged lipopolysaccharides (LPS) on P. aeruginosa to bind and disrupt bacterial membrane(s), causing lethal damage. P. aeruginosa modifies its LPS to evade AMP killing. Free-LPS is also a component of CF sputum and feeds pro-inflammatory cycles. Glatiramer acetate (GA) is a random peptide co-polymer—of glycine, lysine, alanine, tyrosine—used as a drug in treatment of multiple sclerosis (MS); we have previously shown GA to be an AMP which synergises with tobramycin against CF P. aeruginosa, functioning via bacterial membrane disruption. Here, we demonstrate GA’s direct binding and sequestration/neutralisation of P. aeruginosa LPS, in keeping with GA’s ability to disrupt the outer membrane. At CF-relevant LPS concentrations, however, membrane disruption by GA was not strongly inhibited. Furthermore, exposure to GA did not result in increased Lipid A modification of LPS or in increased gene expression of systems involved in AMP sensing and LPS modification. Therefore, despite the electrostatic targeting of LPS by GA as part of its activity, P. aeruginosa does not demonstrate LPS modification in its defence.
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Journal articleOsier FHA, 2024,
Antibody-Dependent Respiratory Burst against Plasmodium falciparum Merozoites in Individuals Living in an Area with Declining Malaria Transmission
, Vaccines, ISSN: 2076-393X -
Thesis dissertationMorrison A, 2024,
Development of Improved Cultivation Methods for Environmental Microorganisms
Cultivation of bacteria remains an essential prerequisite for numerous research and biotechnological applications. Despite their ubiquity, only a minority of environmental bacteria are cultivable using standard techniques. Therefore, a vast microbial ‘dark matter’ awaits exploration for valuable therapeutics or research potential. Despite innovations in enhanced cultivation techniques, limitations remain including throughput, dependencies on environmental factors or abrupt transitions of microorganisms from native to laboratory conditions. This thesis addresses these challenges with the development, optimisation, and experimental assessment of two novel cultivation methodologies. The first methodology allows for the gradual transition and acclimatisation of microorganisms from native environments to culture media using the novel Enhanced Domestication (EDEN) device. Compared to the instantaneous transition, acclimatisation of pond water bacteria to R2A culture media significantly enhanced cultivation diversity, colony yield and greater taxonomic range of isolates including those previously reported to be recalcitrant to cultivation. Moreover, likely novel taxa cultivated with EDEN exhibited antimicrobial activity against methicillin-resistant Staphylococcus aureus. The second methodology involves the development of a cell encapsulation apparatus, termed Bacterial Encapsulation and Containment (BEAD), enabling microinjection and cultivation of bacteria within alginate hydrogel beads using an automated pneumatic pump system. The performance of in situ cultivation with BEAD-encapsulated bacteria were assessed using the newly developed cultivation cassettes growth chambers. The findings propose enhanced cultivation strategies to unlock the biosynthetic potential of uncultured environmental bacteria.
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Journal articleVieira MFM, Hernandez G, Zhong Q, et al., 2024,
The pathogen-encoded signalling receptor Tir exploits host-like intrinsic disorder for infection.
, Commun Biol, Vol: 7The translocated intimin receptor (Tir) is an essential type III secretion system (T3SS) effector of attaching and effacing pathogens contributing to the global foodborne disease burden. Tir acts as a cell-surface receptor in host cells, rewiring intracellular processes by targeting multiple host proteins. We investigated the molecular basis for Tir's binding diversity in signalling, finding that Tir is a disordered protein with host-like binding motifs. Unexpectedly, also are several other T3SS effectors. By an integrative approach, we reveal that Tir dimerises via an antiparallel OB-fold within a highly disordered N-terminal cytosolic domain. Also, it has a long disordered C-terminal cytosolic domain partially structured at host-like motifs that bind lipids. Membrane affinity depends on lipid composition and phosphorylation, highlighting a previously unrecognised host interaction impacting Tir-induced actin polymerisation and cell death. Furthermore, multi-site tyrosine phosphorylation enables Tir to engage host SH2 domains in a multivalent fuzzy complex, consistent with Tir's scaffolding role and binding promiscuity. Our findings provide insights into the intracellular Tir domains, highlighting the ability of T3SS effectors to exploit host-like protein disorder as a strategy for host evasion.
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Journal articleOlechnowicz A, Blatkiewicz M, Jopek K, et al., 2024,
Deregulated transcriptome as a platform for adrenal Huntington’s disease-related pathology
, International Journal of Molecular Sciences, Vol: 25, ISSN: 1422-0067Huntington’s disease (HD) is a neurodegenerative disorder that affects mainly the central nervous system (CNS) by inducing progressive deterioration in both its structure and function. In recent years, there has been growing interest in the impact of HD on peripheral tissue function. Herein, we used the R6/2 mouse model of HD to investigate the influence of the disease on adrenal gland functioning. A transcriptomic analysis conducted using a well-established quantitative method, an Affymetrix array, revealed changes in gene expression in the R6/2 model compared to genetic background controls. For the first time, we identified disruptions in cholesterol and sterol metabolism, blood coagulation, and xenobiotic metabolism in HD adrenal glands. This study showed that the disrupted expression of these genes may contribute to the underlying mechanisms of Huntington’s disease. Our findings may contribute to developing a better understanding of Huntington’s disease progression and aid in the development of novel diagnostic or therapeutic approaches.
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Journal articleNeyret M, Le Provost G, Boesing AL, et al., 2024,
A slow-fast trait continuum at the whole community level in relation to land-use intensification.
, Nat Commun, Vol: 15Organismal functional strategies form a continuum from slow- to fast-growing organisms, in response to common drivers such as resource availability and disturbance. However, whether there is synchronisation of these strategies at the entire community level is unclear. Here, we combine trait data for >2800 above- and belowground taxa from 14 trophic guilds spanning a disturbance and resource availability gradient in German grasslands. The results indicate that most guilds consistently respond to these drivers through both direct and trophically mediated effects, resulting in a 'slow-fast' axis at the level of the entire community. Using 15 indicators of carbon and nutrient fluxes, biomass production and decomposition, we also show that fast trait communities are associated with faster rates of ecosystem functioning. These findings demonstrate that 'slow' and 'fast' strategies can be manifested at the level of whole communities, opening new avenues of ecosystem-level functional classification.
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Journal articleCurrie D, Wong N, Zane I, et al., 2024,
A Potential Prognostic Gene Signature Associated with p53-Dependent NTRK1 Activation and Increased Survival of Neuroblastoma Patients.
, Cancers (Basel), Vol: 16, ISSN: 2072-6694Neuroblastoma is the most common extracranial solid tumour in children, comprising close to 10% of childhood cancer-related deaths. We have demonstrated that activation of NTRK1 by TP53 repression of PTPN6 expression is significantly associated with favourable survival in neuroblastoma. The molecular mechanisms by which this activation elicits cell molecular changes need to be determined. This is critical to identify dependable biomarkers for the early detection and prognosis of tumours, and for the development of personalised treatment. In this investigation we have identified and validated a gene signature for the prognosis of neuroblastoma using genes differentially expressed upon activation of the NTRK1-PTPN6-TP53 module. A random survival forest model was used to construct a gene signature, which was then assessed across validation datasets using Kaplan-Meier analysis and ROC curves. The analysis demonstrated that high BASP1, CD9, DLG2, FNBP1, FRMD3, IL11RA, ISGF10, IQCE, KCNQ3, and TOX2, and low BSG/CD147, CCDC125, GABRB3, GNB2L1/RACK1 HAPLN4, HEBP2, and HSD17B12 expression was significantly associated with favourable patient event-free survival (EFS). The gene signature was associated with favourable tumour histology and NTRK1-PTPN6-TP53 module activation. Importantly, all genes were significantly associated with favourable EFS in an independent manner. Six of the signature genes, BSG/CD147, GNB2L1/RACK1, TXNDC5, FNPB1, B3GAT1, and IGSF10, play a role in cell differentiation. Our findings strongly suggest that the identified gene signature is a potential prognostic biomarker and therapeutic target for neuroblastoma patients and that it is associated with neuroblastoma cell differentiation through the activation of the NTRK1-PTPN6-TP53 module.
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ReportBenton J, Jimenez Zarco J, Banks A, et al., 2024,
Using microbes to remove microplastics from wastewater and sewage sludge
, London, Publisher: Institute for Molecular Science and Engineering, Briefing paper No. 11Microplastics are a widespread form of plastic pollution. There is increasing evidence that they are a threat to human health and the environment. Microplastics in domestic and industrial wastewater become concentrated in sewage sludge during wastewater treatment processes. In 2020, water companies in England produced more than 800,000 tonnes of sewage sludge from urban wastewater. More than 90% of UK sewage sludge is spread on agricultural land as a fertilizer and soil conditioner. This provides a pathway for microplastics to enter the terrestrial environment. There is currently no UK legislation defining safe limits for microplastics in sludge and soils but future regulation is a possibility. There is currently no technology available to remove microplastics from wastewater treatment processes or the resulting sludge. Safe limits for microplastics in treated sewage sludge, soils and water bodies should be identified. This will require a survey of the extent of microplastic pollution throughout the UK, including concentration, identity and characteristics of microplastics in each environmental reservoir, and understanding how microplastics affect different living organisms. Microbes or fungi that break down plastic could be added to existing wastewater treatment process to remove microplastics and prevent their release into the environment. Alternatively, only the active enzymes (rather than the live microorganisms) could be added to the process. Currently, only polyester microplastics (11% of the total microplastic burden) could be treated in this way. Different microorganisms would have to be discovered or developed to tackle other common microplastic polymers such as polypropylene or polyethylene.
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Journal articleMakrydaki E, Donini R, Krueger A, et al., 2024,
Immobilized enzyme cascade for targeted glycosylation
, Nature Chemical Biology, ISSN: 1552-4450Glycosylation is a critical post-translational protein modification that affects folding, half-life and functionality. Glycosylation is a non-templated and heterogeneous process because of the promiscuity of the enzymes involved. We describe a platform for sequential glycosylation reactions for tailored sugar structures (SUGAR-TARGET) that allows bespoke, controlled N-linked glycosylation in vitro enabled by immobilized enzymes produced with a one-step immobilization/purification method. We reconstruct a reaction cascade mimicking a glycosylation pathway where promiscuity naturally exists to humanize a range of proteins derived from different cellular systems, yielding near-homogeneous glycoforms. Immobilized β-1,4-galactosyltransferase is used to enhance the galactosylation profile of three IgGs, yielding 80.2-96.3% terminal galactosylation. Enzyme recycling is demonstrated for a reaction time greater than 80 h. The platform is easy to implement, modular and reusable and can therefore produce homogeneous glycan structures derived from various hosts for functional and clinical evaluation.
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Journal articleWoubshete M, Cioccolo S, Byrne B, 2024,
Advances in membrane mimetic systems for manipulation and analysis of membrane proteins; detergents, polymers, lipids and scaffolds
, ChemPlusChem, ISSN: 2192-6506Extracting membrane proteins from the hydrophobic environment of the biological membrane, in a physiologically relevant and stable state, suitable for downstream analysis remains a challenge. The traditional route to membrane protein extraction has been to use detergents and the last 15 years or so have seen a veritable explosion in the development of novel detergents with improved properties, making them more suitable for individual proteins and specific applications. There have also been significant advances in the development of encapsulation of membrane proteins in lipid based nanodiscs, either directly from the native membrane using polymers allowing effective capture of the protein and protein-associated membrane lipids, or via reconstitution of detergent extracted and purified protein into nanodiscs of defined lipid composition. All of these advances have been successfully applied to the study of membrane proteins via a range of techniques and there have been some spectacular membrane protein structures solved. In addition, the first detailed structural and biophysical analyses of membrane proteins retained within a biological membrane have been reported. Here we summarise and review the recent advances with respect to these new agents and systems for membrane protein extraction, reconstitution and analysis.
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Journal articleDrury JP, Clavel J, Tobias JA, et al., 2024,
Limited ecological opportunity influences the tempo of morphological evolution in birds
, Current Biology, Vol: 34, Pages: 661-669.E4, ISSN: 0960-9822According to classic models of lineage diversification and adaptive radiation, phenotypic evolution should accelerate in the context of ecological opportunity and slow down when niches become saturated.1,2 However, only weak support for these ideas has been found in nature, perhaps because most analyses make the biologically unrealistic assumption that clade members contribute equally to reducing ecological opportunity, even when they occur in different continents or specialize on different habitats and diets. To view this problem through a different lens, we adapted a new phylogenetic modeling approach that accounts for the fact that competition for ecological opportunity only occurs between species that coexist and share similar habitats and diets. Applying this method to trait data for nearly all extant species of landbirds,3 we find a widespread signature of decelerating trait evolution in lineages adapted to similar habitats or diets. The strength of this pattern was consistent across latitudes when comparing tropical and temperate assemblages. Our results provide little support for the idea that increased diversity and tighter packing of niches accentuates evolutionary slowdowns in the tropics and instead suggest that limited ecological opportunity can be an important factor determining the rate of morphological diversification at a global scale.
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Journal articleGuder F, Coatsworth P, Bozkurt O, et al., 2024,
Time-resolved chemical monitoring of whole plant roots with printed electrochemical sensors and machine learning
, Science Advances, Vol: 10, ISSN: 2375-2548Traditional single-point measurements fail to capture dynamic chemical responses of plants, which are complex, nonequilibrium biological systems. We report TETRIS (time-resolved electrochemical technology for plant root environment in situ chemical sensing), a real-time chemical phenotyping system for continuously monitoring chemical signals in the often-neglected plant root environment. TETRIS consisted of low-cost, highly scalable screen-printed electrochemical sensors for monitoring concentrations of salt, pH, and H2O2 in the root environment of whole plants, where multiplexing allowed for parallel sensing operation. TETRIS was used to measure ion uptake in tomato, kale, and rice and detected differences between nutrient and heavy metal ion uptake. Modulation of ion uptake with ion channel blocker LaCl3 was monitored by TETRIS and machine learning used to predict ion uptake. TETRIS has the potential to overcome the urgent “bottleneck” in high-throughput screening in producing high-yielding plant varieties with improved resistance against stress.
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Journal articleCretois B, Bick IA, Balantic C, et al., 2024,
Snowmobile noise alters bird vocalization patterns during winter and pre-breeding season
, Journal of Applied Ecology, Vol: 61, Pages: 340-350, ISSN: 0021-8901Noise pollution poses a significant threat to ecosystems worldwide, disrupting animal communication and causing cascading effects on biodiversity. In this study, we focus on the impact of snowmobile noise on avian vocalizations during the non-breeding winter season, a less-studied area in soundscape ecology. We developed a pipeline relying on deep learning methods to detect snowmobile noise and applied it to a large acoustic monitoring dataset collected in Yellowstone National Park. Our results demonstrate the effectiveness of the snowmobile detection model in identifying snowmobile noise and reveal an association between snowmobile passage and changes in avian vocalization patterns. Snowmobile noise led to a decrease in the frequency of bird vocalizations during mornings and evenings, potentially affecting winter and pre-breeding behaviours such as foraging, predator avoidance and successfully finding a mate. However, we observed a recovery in avian vocalizations after detection of snowmobiles during mornings and afternoons, indicating some resilience to sporadic noise events. Synthesis and applications: Our findings emphasize the need to consider noise impacts in the non-breeding season and provide valuable insights for natural resource managers to minimize disturbance and protect critical avian habitats. The deep learning approach presented in this study offers an efficient and accurate means of analysing large-scale acoustic monitoring data and contributes to a comprehensive understanding of the cumulative impacts of multiple stressors on avian communities.
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Journal articlePatterson C, Hazime K, Zelenay S, et al., 2024,
Prostaglandin E₂ impacts multiple stages of the natural killer cell antitumor immune response
, European Journal of Immunology, Vol: 54, ISSN: 0014-2980Tumor immune escape is a major factor contributing to cancer progression and unresponsiveness to cancer therapies. Tumors can produce prostaglandin E2 (PGE2), an inflammatory mediator that directly acts on Natural killer (NK) cells to inhibit antitumor immunity. However, precisely how PGE2 influences NK cell tumor-restraining functions remains unclear. Here, we report that following PGE₂ treatment, human NK cells exhibited altered expression of specific activating receptors and a reduced ability to degranulate and kill cancer targets. Transcriptional analysis uncovered that PGE₂ also differentially modulated the expression of chemokine receptors by NK cells, inhibiting CXCR3 but increasing CXCR4. Consistent with this, PGE₂-treated NK cells exhibited decreased migration to CXCL10 but increased ability to migrate toward CXCL12. Using live cell imaging, we showed that in the presence of PGE2, NK cells were slower and less likely to kill cancer target cells following conjugation. Imaging the sequential stages of NK cell killing revealed that PGE₂ impaired NK cell polarization, but not the re-organization of synaptic actin or the release of perforin itself. Together, these findings demonstrate that PGE₂ affects multiple but select NK cell functions. Understanding how cancer cells subvert NK cells is necessary to more effectively harness the cancer-inhibitory function of NK cells in treatments.
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Journal articleHatfield JH, Banks-Leite C, Barlow J, et al., 2024,
Constraints on avian seed dispersal reduce potential for resilience in degraded tropical forests
, Functional Ecology, Vol: 38, Pages: 315-326, ISSN: 0269-8463Seed dispersal is fundamental to tropical forest resilience. Forest loss or degradation typically leads to defaunation, altering seed transfer dynamics and impairing the ability of forested habitats to regenerate or recover from perturbation. However, the extent of defaunation, and its likely impacts on the seed dispersers needed to restore highly degraded or clear-felled areas, remains poorly understood in tropical forest landscapes. To quantify defaunation of seed-dispersing birds, we used field survey data from 499 transects in three forested regions of Brazil, first comparing the observed assemblages with those predicted by geographic range maps, and then assessing habitat associations of frugivores across land cover gradients. We found that current bird assemblages have lower functional diversity (FD) than predicted by species range maps in Amazonia (4%–6%), with a greater reduction in FD (28%) for the Atlantic Forest, which has been more heavily deforested for a longer period. Direct measures of seed dispersal are difficult to obtain, so we focused on potential seed transfer inferred from shared species occurrence. Of 83 predominantly frugivorous bird species recorded in relatively intact forests, we show that 10% were absent from degraded forest, and 57% absent from the surrounding matrix of agricultural land covers, including many large-gaped species. Of 112 frugivorous species using degraded forest, 47% were absent from matrix habitats. Overall, frugivores occurring in both intact forest and matrix habitats were outnumbered by (mostly small-gaped) frugivores occurring in both degraded forest and matrix habitats (23 additional species; 64% higher diversity). These findings suggest that birds have the potential to disperse seeds from intact and degraded forest to adjacent cleared lands, but that direct seed transfer from intact forests is limited, particularly for large-seeded trees. Degraded forests may play a vital role in supporting natural regenerat
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Journal articleAhmadi Y, Umrekar TR, Mutter N, et al., 2024,
DNA origami-enhanced binding of aptamers to Staphylococcus aureus cells
, Biosensors and Bioelectronics: X, Vol: 16The combination of DNA origami nanostructures and aptamers provides a powerful technology for diagnostic assays. Here, we functionalized a DNA origami nanostructure with a Protein-A binding aptamer to target Staphylococcus aureus bacterial cells. Using an enzyme-linked oligonucleotide assay (ELONA), we semi-quantitatively analyzed and compared the interaction of the aptamer and aptamer-modified DNA origamis with Staphylococcus aureus bacterial isolates. The results showed that aptamer-functionalized DNA nanostructures bind with five times higher affinity (KD: 34 ± 5 nM) compared to the aptamer alone (KD: 160 ± 9 nM). Visualising the interaction of bacterial cells and nanostructures with electron cryotomography further confirmed the aptamer-mediated specific interaction of DNA nanostructures with bacterial cells.
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Journal articleKaramanos TK, Matthews S, 2024,
Biomolecular NMR in the AI-assisted structural biology era: Old tricks and new opportunities.
, Biochim Biophys Acta Proteins Proteom, Vol: 1872Over the last 40 years nuclear magnetic resonance (NMR) spectroscopy has established itself as one of the most versatile techniques for the characterization of biomolecules, especially proteins. Given the molecular size limitations of NMR together with recent advances in cryo-electron microscopy and artificial intelligence-assisted protein structure prediction, the bright future of NMR in structural biology has been put into question. In this mini review we argue the contrary. We discuss the unique opportunities solution NMR offers to the protein chemist that distinguish it from all other experimental or computational methods, and how it can benefit from machine learning.
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Journal articleD'Amato R, Taxiarchi C, Galardini M, et al., 2024,
Anti-CRISPR Anopheles mosquitoes inhibit gene drive spread under challenging behavioural conditions in large cages.
, Nat Commun, Vol: 15CRISPR-based gene drives have the potential to spread within populations and are considered as promising vector control tools. A doublesex-targeting gene drive was able to suppress laboratory Anopheles mosquito populations in small and large cages, and it is considered for field application. Challenges related to the field-use of gene drives and the evolving regulatory framework suggest that systems able to modulate or revert the action of gene drives, could be part of post-release risk-mitigation plans. In this study, we challenge an AcrIIA4-based anti-drive to inhibit gene drive spread in age-structured Anopheles gambiae population under complex feeding and behavioural conditions. A stochastic model predicts the experimentally-observed genotype dynamics in age-structured populations in medium-sized cages and highlights the necessity of large-sized cage trials. These experiments and experimental-modelling framework demonstrate the effectiveness of the anti-drive in different scenarios, providing further corroboration for its use in controlling the spread of gene drive in Anopheles.
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Journal articleKeeping T, Harrison SP, Prentice IC, 2024,
Modelling the daily probability of wildfire occurrence in the contiguous United States
, Environmental Research Letters, Vol: 19, ISSN: 1748-9326The development of a high-quality wildfire occurrence model is an essential component in mapping present wildfire risk, and in projecting future wildfire dynamics with climate and land-use change. Here, we develop a new model for predicting the daily probability of wildfire occurrence at 0.1° (∼10 km) spatial resolution by adapting a generalised linear modelling (GLM) approach to include improvements to the variable selection procedure, identification of the range over which specific predictors are influential, and the minimisation of compression, applied in an ensemble of model runs. We develop and test the model using data from the contiguous United States. The ensemble performed well in predicting the mean geospatial patterns of fire occurrence, the interannual variability in the number of fires, and the regional variation in the seasonal cycle of wildfire. Model runs gave an area under the receiver operating characteristic curve (AUC) of 0.85–0.88, indicating good predictive power. The ensemble of runs provides insight into the key predictors for wildfire occurrence in the contiguous United States. The methodology, though developed for the United States, is globally implementable.
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Journal articleLeung PB, Matanza XM, Roche B, et al., 2024,
Shigella sonnei utilises colicins during inter-bacterial competition.
, Microbiology (Reading), Vol: 170The mammalian colon is one of the most densely populated habitats currently recognised, with 1011-1013 commensal bacteria per gram of colonic contents. Enteric pathogens must compete with the resident intestinal microbiota to cause infection. Among these enteric pathogens are Shigella species which cause approximately 125 million infections annually, of which over 90 % are caused by Shigella flexneri and Shigella sonnei. Shigella sonnei was previously reported to use a Type VI Secretion System (T6SS) to outcompete E. coli and S. flexneri in in vitro and in vivo experiments. S. sonnei strains have also been reported to harbour colicinogenic plasmids, which are an alternative anti-bacterial mechanism that could provide a competitive advantage against the intestinal microbiota. We sought to determine the contribution of both T6SS and colicins to the anti-bacterial killing activity of S. sonnei. We reveal that whilst the T6SS operon is present in S. sonnei, there is evidence of functional degradation of the system through SNPs, indels and IS within key components of the system. We created strains with synthetically inducible T6SS operons but were still unable to demonstrate anti-bacterial activity of the T6SS. We demonstrate that the anti-bacterial activity observed in our in vitro assays was due to colicin activity. We show that S. sonnei no longer displayed anti-bacterial activity against bacteria that were resistant to colicins, and removal of the colicin plasmid from S. sonnei abrogated anti-bacterial activity of S. sonnei. We propose that the anti-bacterial activity demonstrated by colicins may be sufficient for niche competition by S. sonnei within the gastrointestinal environment.
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