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Journal articleKourelis J, Malik S, Mattinson O, et al., 2024,
Evolution of a guarded decoy protease and its receptor in solanaceous plants (vol 11, 4393, 2020)
, NATURE COMMUNICATIONS, Vol: 15 -
Journal articleJackson MC, Friberg N, Moliner Cachazo L, et al., 2024,
Regional impacts of warming on biodiversity and biomass in high latitude stream ecosystems across the Northern Hemisphere
, COMMUNICATIONS BIOLOGY, Vol: 7 -
Journal articleSheppard S, Srpan K, Lin W, et al., 2024,
Fatty acid oxidation fuels natural killer cell responses against infection and cancer
, Proceedings of the National Academy of Sciences of USA, Vol: 121, ISSN: 0027-8424Natural killer (NK) cells are a vital part of the innate immune system capable of rapidly clearing mutated or infected cells from the body and promoting an immune response. Here, we find that NK cells activated by viral infection or tumor challenge increase uptake of fatty acids and their expression of carnitine palmitoyltransferase I (CPT1A), a critical enzyme for long-chain fatty acid oxidation. Using a mouse model with an NK cell-specific deletion of CPT1A, combined with stable 13C isotope tracing, we observe reduced mitochondrial function and fatty acid-derived aspartate production in CPT1A-deficient NK cells. Furthermore, CPT1A-deficient NK cells show reduced proliferation after viral infection and diminished protection against cancer due to impaired actin cytoskeleton rearrangement. Together, our findings highlight that fatty acid oxidation promotes NK cell metabolic resilience, processes that can be optimized in NK cell-based immunotherapies.
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Journal articleSmith HE, Mackenzie AM, Seddon C, et al., 2024,
The use of NADH anisotropy to investigate mitochondrial cristae alignment
, SCIENTIFIC REPORTS, Vol: 14, ISSN: 2045-2322 -
Journal articleKogenaru V, Isalan M, Kogenaru M, 2024,
A drug stabilizable GAL80ds for conditional control of gene expression via GAL4-UAS and CRISPR-Cas9 systems in Drosophila
, Scientific Reports, Vol: 14, ISSN: 2045-2322The binary GAL4-UAS expression system has been widely used in Drosophila to achieve tissue-specific expression of genes. To further allow for simultaneous spatial and conditional control of gene expression in existing GAL4 expression lines backgrounds, temperature and chemical controllable GAL80 variants have been engineered. Here we add a new drug stabilizable GAL80ds variant, by fusing it to a low-background DHFR-22-DD. We first quantify both single (DD-GAL80) and double (DD-GAL80-DD) architectures and show varied background and activation levels. Next, we demonstrate the utility of GAL80ds Drosophila line to regulate a cell death gene ectopically, in a drug-dependent manner, by utilizing an existing tissue-specific GAL4 driver that regulates the expression of a cell death gene under a UAS. Finally, we showcase the usefulness of GAL80ds in tight drug-mediated regulation of a target gene, from an endogenous locus, by utilizing an existing tissue-specific GAL4 to drive the expression of a dead Cas9 variant fused to the transcriptional coactivator nejire, under a UAS and in gRNA lines. Overall, these new GAL80ds lines expand the use of the wide variety of existing tissue-specific GAL4 and gene-specific gRNA lines. This enables conditional control of genes, both ectopically and endogenously, for a broad array of gene expression control applications.
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Journal articleRizos G, Lawson J, Mitchell S, et al., 2024,
Propagating variational model uncertainty for bioacoustic call label smoothing
, Patterns, Vol: 5, ISSN: 2666-3899Along with propagating the input toward making a prediction, Bayesian neural networks also propagate uncertainty. This has the potential to guide the training process by rejecting predictions of low confidence, and recent variational Bayesian methods can do so without Monte Carlo sampling of weights. Here, we apply sample-free methods for wildlife call detection on recordings made via passive acoustic monitoring equipment in the animals' natural habitats. We further propose uncertainty-aware label smoothing, where the smoothing probability is dependent on sample-free predictive uncertainty, in order to downweigh data samples that should contribute less to the loss value. We introduce a bioacoustic dataset recorded in Malaysian Borneo, containing overlapping calls from 30 species. On that dataset, our proposed method achieves an absolute percentage improvement of around 1.5 points on area under the receiver operating characteristic (AU-ROC), 13 points in F1, and 19.5 points in expected calibration error (ECE) compared to the point-estimate network baseline averaged across all target classes.
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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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Book chapterQi L, Bennett E, Isalan M, 2024,
A directed evolution protocol for engineering minimal transcription factors, based on CIS display
, Mammalian synthetic systems, Editors: Ceroni, Polizzi, New York, Publisher: Springer, Pages: 1-13, ISBN: 978-1-0716-3718-0Directed evolution is an efficient strategy for obtaining desired biomolecules. Since the 1990s, the emergence of display techniques has enabled high-throughput screening of functional proteins. However, classical methods require library construction by plasmid cloning and are limited by transformation efficiencies, typically limiting library sizes to ~106–107 variants. More recently, in vitro techniques have emerged that avoid cloning, allowing library sizes of >1012 members. One of these, CIS display, is a DNA-based display technique which allows high-throughput selection of biomolecules in vitro. CIS display creates the genotype–phenotype link required for selection by a DNA replication initiator protein, RepA, that binds exclusively to the template from which it has been expressed. This method has been successfully used to evolve new protein–protein interactions but has not been used before to select DNA-binding proteins, which are major components in mammalian synthetic biology. In this chapter, we describe a directed evolution method using CIS display to efficiently select functional DNA-binding proteins from pools of nonbinding proteins. The method is illustrated by enriching the minimal transcription factor Cro from a low starting frequency (1 in 109). This protocol is also applicable to engineering other DNA-binding proteins or transcription factors from combinatorial libraries.
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Journal articleNie R-E, Li L-L, Feijo A, et al., 2024,
Phylogenetic origin of an insect fauna at the boundary of the Palaearctic and Oriental realms: Evidence from 'site-based' mitogenomics
, JOURNAL OF BIOGEOGRAPHY, ISSN: 0305-0270 -
Journal articleChukhutsina VU, Hutchison CDM, van Thor JJ, 2024,
The Carbonyl Group in b2 of the Carotenoid Tunes the Photocycle Kinetics in Orange Carotenoid Protein
, JOURNAL OF MOLECULAR BIOLOGY, Vol: 436, ISSN: 0022-2836 -
Journal articleMazza T, Roumeliotis TI, Garitta E, et al., 2024,
Structural basis for the modulation of MRP2 activity by phosphorylation and drugs
, Nature Communications, Vol: 15, ISSN: 2041-1723Multidrug resistance-associated protein 2 (MRP2/ABCC2) is a polyspecific efflux transporter of organic anions expressed in hepatocyte canalicular membranes. MRP2 dysfunction, in Dubin-Johnson syndrome or by off-target inhibition, for example by the uricosuric drug probenecid, elevates circulating bilirubin glucuronide and is a cause of jaundice. Here, we determine the cryo-EM structure of rat Mrp2 (rMrp2) in an autoinhibited state and in complex with probenecid. The autoinhibited state exhibits an unusual conformation for this class of transporter in which the regulatory domain is folded within the transmembrane domain cavity. In vitro phosphorylation, mass spectrometry and transport assays show that phosphorylation of the regulatory domain relieves this autoinhibition and enhances rMrp2 transport activity. The in vitro data is confirmed in human hepatocyte-like cells, in which inhibition of endogenous kinases also reduces human MRP2 transport activity. The drug-bound state reveals two probenecid binding sites that suggest a dynamic interplay with autoinhibition. Mapping of the Dubin-Johnson mutations onto the rodent structure indicates that many may interfere with the transition between conformational states.
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Journal articleHailu E, Cantillon D, Madrazo C, et al., 2024,
Lack of methoxy- mycolates characterizes the geographically restricted lineage 7 of Mycobacterium tuberculosis complex (May, 10.1099/mgen.0.001011, 2023)
, MICROBIAL GENOMICS, Vol: 10, ISSN: 2057-5858 -
Journal articlevan Thor J, 2024,
Kilohertz droplet-on-demand serial femtosecond crystallography at the European XFEL station FXE
, Structural Dynamics, Vol: 11, ISSN: 2329-7778X-ray Free Electron Lasers (XFELs) allow the collection of high-quality serial femtosecond crystallography data. The next generation of megahertz superconducting FELs promises to drastically reduce data collection times, enabling the capture of more structures with higher signal-to-noise ratios and facilitating more complex experiments. Currently, gas dynamic virtual nozzles (GDVNs) stand as the sole delivery method capable of best utilizing the repetition rate of megahertz sources for crystallography. However, their substantial sample consumption renders their use impractical for many protein targets in serial crystallography experiments. Here, we present a novel application of a droplet-on-demand injection method, which allowed operation at 47 kHz at the European XFEL (EuXFEL) by tailoring a multi-droplet injection scheme for each macro-pulse. We demonstrate a collection rate of 150 000 indexed patterns per hour. We show that the performance and effective data collection rate are comparable to GDVN, with a sample consumption reduction of two orders of magnitude. We present lysozyme crystallographic data using the Large Pixel Detector at the femtosecond x-ray experiment endstation. Significant improvement of the crystallographic statistics was made by correcting for a systematic drift of the photon energy in the EuXFEL macro-pulse train, which was characterized from indexing the individual frames in the pulse train. This is the highest resolution protein structure collected and reported at the EuXFEL at 1.38 Å resolution.
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Journal articleMondal R, Majumdar A, Sarkar S, et al., 2024,
An extensive review of arsenic dynamics and its distribution in soil-aqueous-rice plant systems in south and Southeast Asia with bibliographic and meta-data analysis.
, Chemosphere, Vol: 352Millions of people worldwide are affected by arsenic (As) contamination, particularly in South and Southeast Asian countries, where large-scale dependence on the usage of As-contaminated groundwater in drinking and irrigation is a familiar practice. Rice (Oryza sativa) cultivation is commonly done in South and Southeast Asian countries as a preferable crop which takes up more As than any other cereals. The present article has performed a scientific meta-data analysis and extensive bibliometric analysis to demonstrate the research trend in global rice As contamination scenario in the timeframe of 1980-2023. This study identified that China contributes most with the maximum number of publications followed by India, USA, UK and Bangladesh. The two words 'arsenic' and 'rice' have been identified as the most dominant keywords used by the authors, found through co-occurrence cluster analysis with author keyword association study. The comprehensive perceptive attained about the factors affecting As load in plant tissue and the nature of the micro-environment augment the contamination of rice cultivars in the region. This extensive review analyses soil parameters through meta-data regression assessment that influence and control As dynamics in soil with its further loading into rice grains and presents that As content and OM are inversely related and slightly correlated to the pH increment of the soil. Additionally, irrigation and water management practices have been found as a potential modulator of soil As concentration and bioavailability, presented through a linear fit with 95% confidence interval method.
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Journal articlePeng X, Amend AS, Baltar F, et al., 2024,
Planktonic Marine Fungi: A Review
, Journal of Geophysical Research: Biogeosciences, Vol: 129, ISSN: 2169-8953<jats:title>Abstract</jats:title><jats:p>Fungi in marine ecosystems play crucial roles as saprotrophs, parasites, and pathogens. The definition of marine fungi has evolved over the past century. Currently, “marine fungi” are defined as any fungi recovered repeatedly from marine habitats that are able to grow and/or sporulate in marine environments, form symbiotic relationships with other marine organisms, adapt and evolve at the genetic level, or are active metabolically in marine environments. While there are a number of recent reviews synthesizing our knowledge derived from over a century of research on marine fungi, this review article focuses on the state of knowledge on planktonic marine fungi from the coastal and open ocean, defined as fungi that are in suspension or attached to particles, substrates or in association with hosts in the pelagic zone of the ocean, and their roles in remineralization of organic matter and major biogeochemical cycles. This review differs from previous ones by focusing on biogeochemical impacts of planktonic marine fungi and methodological considerations for investigating their diversity and ecological functions. Importantly, we point out gaps in our knowledge and the potential methodological biases that might have contributed to these gaps. Finally, we highlight recommendations that will facilitate future studies of marine fungi. This article first provides a brief overview of the diversity of planktonic marine fungi, followed by a discussion of the biogeochemical impacts of planktonic marine fungi, and a wide range of methods that can be used to study marine fungi.</jats:p>
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Journal articleBentham AR, Wang W, Trusch F, et al., 2024,
The WY Domain of an RxLr Effector Drives Interactions with a Host Target Phosphatase to Mimic Host Regulatory Proteins and Promote Phytophthora infestans Infection.
, Mol Plant Microbe Interact, Vol: 37, Pages: 239-249, ISSN: 0894-0282Plant pathogens manipulate the cellular environment of the host to facilitate infection and colonization that often lead to plant diseases. To accomplish this, many specialized pathogens secrete virulence proteins called effectors into the host cell, which subvert processes such as immune signaling, gene transcription, and host metabolism. Phytophthora infestans, the causative agent of potato late blight, employs an expanded repertoire of RxLR effectors with WY domains to manipulate the host through direct interaction with protein targets. However, our understanding of the molecular mechanisms underlying the interactions between WY effectors and their host targets remains limited. In this study, we performed a structural and biophysical characterization of the P. infestans WY effector Pi04314 in complex with the potato Protein Phosphatase 1-c (PP1c). We elucidate how Pi04314 uses a WY domain and a specialized C-terminal loop carrying a KVxF motif that interact with conserved surfaces on PP1c, known to be used by host regulatory proteins for guiding function. Through biophysical and in planta analyses, we demonstrate that Pi04314 WY or KVxF mutants lose their ability to bind PP1c. The loss of PP1c binding correlates with changes in PP1c nucleolar localization and a decrease in lesion size in plant infection assays. This study provides insights into the manipulation of plant hosts by pathogens, revealing how effectors exploit key regulatory interfaces in host proteins to modify their function and facilitate disease. [Formula: see text] Copyright © 2024 The Author(s). This is an open access article distributed under the CC BY 4.0 International license.
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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 articleDunning J, Burke T, Schroeder J, 2024,
Divorce is linked with extra-pair paternity in a monogamous passerine
, JOURNAL OF AVIAN BIOLOGY, Vol: 2024, ISSN: 0908-8857 -
Journal articleChan AHH, Liu J, Burke T, et al., 2024,
Comparison of manual, machine learning, and hybrid methods for video annotation to extract parental care data
, JOURNAL OF AVIAN BIOLOGY, Vol: 2024, ISSN: 0908-8857 -
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
, Nature Ecology and Evolution, Vol: 8, Pages: 500-510, ISSN: 2397-334XThe 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 articleKowal J, Pino-Bodas R, Arrigoni E, et al., 2024,
Assessing above and belowground recovery from ammonium sulfate addition and wildfire in a lowland heath: mycorrhizal fungi as potential indicators
, RESTORATION ECOLOGY, Vol: 32, ISSN: 1061-2971 -
Journal articleKing FJ, Yuen ELH, Bozkurt O, 2024,
Border control: manipulation of the host–pathogeninterface by perihaustorial oomycete effectors
, Molecular Plant-Microbe Interactions, Vol: 37, Pages: 220-226, 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.
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Journal articleKing FJ, Yuen ELH, Bozkurt TO, 2024,
Border control: manipulation of the host-pathogen interface by perihaustorial oomycete effectors
, Molecular Plant-Microbe Interactions, Vol: 37, Pages: 220-226, 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 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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ReportMoffett E, Gayford J, Woodward G, et al., 2024,
Biodiversity and ecosystem function: a global analysis of trends
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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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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
, COMMUNICATIONS BIOLOGY, Vol: 7 -
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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