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  • Journal article
    Tonkin R, Kloeckner A, Najer A, Simoes da Silva CJ, Echalier C, Dionne MS, Edwards AM, Stevens M, Tonkin R, Kloeckner A, Najer A, Simoes da Silva C, Echalier C, Dionne M, Edwards A, Stevens Met al., 2022,

    Bacterial toxin-triggered release of antibiotics from capsosomes protects a fly model from lethal methicillin-resistant Staphylococcus aureus (MRSA) infection

    , Advanced Healthcare Materials, Vol: 11, Pages: 1-14, ISSN: 2192-2640

    Antibiotic resistance is a severe global health threat and hence demands rapid action to develop novel therapies, including microscale drug delivery systems. Herein, a hierarchical microparticle system is developed to achieve bacteria-activated single- and dual-antibiotic drug delivery for preventing methicillin-resistant Staphylococcus aureus (MRSA) bacterial infections. The designed system is based on a capsosome structure, which consists of a mesoporous silica microparticle coated in alternating layers of oppositely charged polymers and antibiotic-loaded liposomes. The capsosomes are engineered and shown to release their drug payloads in the presence of MRSA toxins controlled by the Agr quorum sensing system. MRSA-activated single drug delivery of vancomycin and synergistic dual delivery of vancomycin together with an antibacterial peptide successfully kills MRSA in vitro. The capability of capsosomes to selectively deliver their cargo in the presence of bacteria, producing a bactericidal effect to protect the host organism, is confirmed in vivo using a Drosophila melanogaster MRSA infection model. Thus, the capsosomes serve as a versatile multidrug, subcompartmentalized microparticle system for preventing antibiotic-resistant bacterial infections, with potential applications to protect wounds or medical device implants from infections.

  • Journal article
    Yu X, Zhao G, Wang D, Wang S, Li R, Li A, Wang H, Nollet M, Chun YY, Zhao T, Yustos R, Li H, Zhao J, Li J, Cai M, Vyssotski A, Li Y, Dong H, Franks N, Wisden Wet al., 2022,

    A specific circuit in the midbrain detects stress and induces restorative sleep

    , Science, Vol: 377, Pages: 1-10, ISSN: 1095-9203

    In mice, social defeat stress (SDS), an ethological model for psychosocial stress, induces sleep. Such sleep could enable resilience, but how stress promotes sleep is unclear. Activity - dependent tagging revealed a subset of ventral tegmental area GABA-somatostatin (VTAVgat-Sst) cells that sense stress and drive NREM and REM sleep via the lateral hypothalamus, andalso inhibit corticotropin-releasing factor (CRF) release in the paraventricular hypothalamus. Transient stress enhances the activity of VTA Vgat-Sst cells for several hours, allowing them to exert their sleep effects persistently. Lesioning of VTAVgat-Sst cells abolished SDS-induced sleep; without it, anxiety and corticosterone levels remained elevated after stress. Thus, aspecific circuit allows animals to restore mental and body functions via sleeping, potentially providing a refined route for treating anxiety disorders.

  • Journal article
    Patil RH, Kotta-Loizou I, Palyzová A, Pluháček T, Coutts RHA, Stevens DA, Havlíček Vet al., 2022,

    Correction: Patil et al. Freeing Aspergillus fumigatus of Polymycovirus Infection Renders It More Resistant to Competition with Pseudomonas aeruginosa Due to Altered Iron-Acquiring Tactics. J. Fungi 2021, 7, 497

    , Journal of Fungi, Vol: 8, ISSN: 2309-608X

    In the original publication [...].

  • Journal article
    Cheng S, Jin Y, Harrison SP, Quilodran-Casas C, Prentice IC, Guo Y-K, Arcucci Ret al., 2022,

    Parameter flexible wildfire prediction using machine learning techniques:forward and inverse modelling

    , Remote Sensing, ISSN: 2072-4292
  • Journal article
    Smith T, Stemkovski M, Koontz A, Pearse Wet al., 2022,

    AREAdata: a worldwide climate dataset averaged across spatial units at different scales through time

    , Data in Brief, ISSN: 2352-3409

    In an era of increasingly cross-discipline collaborative science,it is imperative to produce data resources which can be quicklyand easily utilised by non-specialists. In particular, climate dataoften require heavy processing before they can be used for analyses. Here we describe AREAdata, a continually updated, freeto-use online global climate dataset, pre-processed to providethe averages of various climate variables across different administrative units (e.g., countries, states). These are daily estimates, based on the Copernicus Climate Data Store’s ERA-5data, regularly updated to the near-present and provided as directdownloads from our website (https://pearselab.github.io/areadata/). The daily climate estimates from AREAdataare consistent with other openly available data, but at much finergrained spatial and temporal scales than available elsewhere.AREAdata complements the existing suite of climate resourcesby providing these data in a form more readily usable by researchers unfamiliar with GIS data-processing methods, and weanticipate these resources being of particular use to environmental and epidemiological researchers.

  • Journal article
    Macé K, Vadakkepat AK, Redzej A, Lukoyanova N, Oomen C, Braun N, Ukleja M, Lu F, Dias da Costa T, Orlova EV, Baker D, Cong Q, Waksman Get al., 2022,

    Cryo-EM structure of a type IV secretion system

    , Nature, Vol: 607, ISSN: 0028-0836

    Bacterial conjugation is the fundamental process of unidirectional transfer of DNAs, often plasmid DNAs, from a donor cell to a recipient cell1. It is the primary means by which antibiotic resistance genes spread among bacterial populations2,3. In Gram-negative bacteria, conjugation is mediated by a large transport apparatus-the conjugative type IV secretion system (T4SS)-produced by the donor cell and embedded in both its outer and inner membranes. The T4SS also elaborates a long extracellular filament-the conjugative pilus-that is essential for DNA transfer4,5. Here we present a high-resolution cryo-electron microscopy (cryo-EM) structure of a 2.8 megadalton T4SS complex composed of 92 polypeptides representing 8 of the 10 essential T4SS components involved in pilus biogenesis. We added the two remaining components to the structural model using co-evolution analysis of protein interfaces, to enable the reconstitution of the entire system including the pilus. This structure describes the exceptionally large protein-protein interaction network required to assemble the many components that constitute a T4SS and provides insights on the unique mechanism by which they elaborate pili.

  • Journal article
    Gisriel CJ, Cardona Londono T, Bryant DA, Brudvig GWet al., 2022,

    Molecular evolution of far-red light-acclimated photosystem II

    , Microorganisms, Vol: 10, Pages: 1-19, ISSN: 2076-2607

    Cyanobacteria are major contributors to global carbon fixation and primarily use visible light (400−700 nm) to drive oxygenic photosynthesis. When shifted into environments where visible light is attenuated, a small, but highly diverse and widespread number of cyanobacteria can express modified pigments and paralogous versions of photosystem subunits and phycobiliproteins that confer far-red light (FRL) absorbance (700−800 nm), a process termed far-red light photoacclimation, or FaRLiP. During FaRLiP, alternate photosystem II (PSII) subunits enable the complex to bind chlorophylls d and f, which absorb at lower energy than chlorophyll a but still support water oxidation. How the FaRLiP response arose remains poorly studied. Here, we report ancestral sequence reconstruction and structure-based molecular evolutionary studies of the FRL-specific subunits of FRL-PSII. We show that the duplications leading to the origin of two PsbA (D1) paralogs required to make chlorophyll f and to bind chlorophyll d in water-splitting FRL-PSII are likely the first to have occurred prior to the diversification of extant cyanobacteria. These duplications were followed by those leading to alternative PsbC (CP43) and PsbD (D2) subunits, occurring early during the diversification of cyanobacteria, and culminating with those leading to PsbB (CP47) and PsbH paralogs coincident with the radiation of the major groups. We show that the origin of FRL-PSII required the accumulation of a relatively small number of amino acid changes and that the ancestral FRL-PSII likely contained a chlorophyll d molecule in the electron transfer chain, two chlorophyll f molecules in the antenna subunits at equivalent positions, and three chlorophyll a molecules whose site energies were altered. The results suggest a minimal model for engineering far-red light absorbance into plant PSII for biotechnological applications.

  • Journal article
    Andujar C, Arribas P, Lopez H, Arjona Y, Perez-Delgado A, Oromi P, Vogler AP, Emerson BCet al., 2022,

    Community assembly and metaphylogeography of soil biodiversity: Insights from haplotype-level community DNA metabarcoding within an oceanic island

    , MOLECULAR ECOLOGY, Vol: 31, Pages: 4078-4094, ISSN: 0962-1083
  • Journal article
    Iglesias-Carrasco M, Tobias JA, Duchene DA, 2022,

    Bird lineages colonizing urban habitats have diversified at high rates across deep time

    , GLOBAL ECOLOGY AND BIOGEOGRAPHY, Vol: 31, Pages: 1784-1793, ISSN: 1466-822X
  • Journal article
    Giannos P, 2022,

    Gene expression changes of murine cortex homeostasis in response to sleep deprivation imply dysregulated aging-like transcriptional responses

    , Brain Sciences, ISSN: 2076-3425

    Sleep deprivation leads to the deterioration in physiological functioning of the brain, cognitive decline, and many neurodegenerative diseases, all which progress with advancing age. Sleep insufficiency and impairments in cognitive function are characterized by progressive neuronal losses in the cerebral cortex. In this study, we analysed gene expression profiles following sleep deprived murine models and circadian matched controls to identify genes that might underlie cortical homeostasis in response to sleep deprivation. Screening of the literature resulted in three murine (Mus musculus) gene expression datasets (GSE6514, GSE78215, and GSE33491) that included cortical tissue biopsies from mice that were sleep deprived for 6 hours (n = 15) and from circadian controls that were left undisturbed (n = 15). Cortical differentially expressed genes were used to construct a network of encoded proteins that were ranked based on their interactome according to 11 topological algorithms. The analysis revealed three genes– NFKBIA, EZR and SGK1 – which exhibited the highest multi-algorithmic topological significance. These genes are strong markers of increased brain inflammation, cytoskeletal aberrations, and glucocorticoid resistance, changes that imply aging-like transcriptional responses during sleep deprivation in the murine cortex. Their potential role as candidate markers of local homeostatic response to sleep loss in the murine cortex warrants further experimental validation.

  • Journal article
    Casadio R, Mathews DH, Sternberg MJE, 2022,

    Computational Resources for Molecular Biology 2022

    , Journal of Molecular Biology, Vol: 434, ISSN: 0022-2836
  • Journal article
    Malladi S, Powell HR, David A, Islam SA, Copeland MM, Kundrotas PJ, Sternberg MJE, Vakser Iet al., 2022,

    GWYRE: A resource for mapping variants onto experimental and modeled structures of human protein complexes

    , Journal of Molecular Biology, Vol: 434, ISSN: 0022-2836

    Rapid progress in structural modeling of proteins and their interactions is powered by advances in knowledge-based methodologies along with better understanding of physical principles of protein structure and function. The pool of structural data for modeling of proteins and protein–protein complexes is constantly increasing due to the rapid growth of protein interaction databases and Protein Data Bank. The GWYRE (Genome Wide PhYRE) project capitalizes on these developments by advancing and applying new powerful modeling methodologies to structural modeling of protein–protein interactions and genetic variation. The methods integrate knowledge-based tertiary structure prediction using Phyre2 and quaternary structure prediction using template-based docking by a full-structure alignment protocol to generate models for binary complexes. The predictions are incorporated in a comprehensive public resource for structural characterization of the human interactome and the location of human genetic variants. The GWYRE resource facilitates better understanding of principles of protein interaction and structure/function relationships. The resource is available at http://www.gwyre.org.

  • Journal article
    Casadio R, Mathews DH, Sternberg MJE, 2022,

    Computational Resources for Molecular Biology 2022

    , JOURNAL OF MOLECULAR BIOLOGY, Vol: 434, ISSN: 0022-2836
  • Journal article
    Low WW, Wong J, Beltran L, Seddon C, David S, Kwong H-S, Bizeau T, Wang F, Pena A, Costa TRD, Pham B, Chen M, Egelman E, Beis K, Frankel Get al., 2022,

    Mating pair stabilization mediates bacterial conjugation species specificity

    , Nature Microbiology, Vol: 7, Pages: 1016-1027, ISSN: 2058-5276

    Bacterial conjugation mediates contact-dependent transfer of DNA from donor to recipient bacteria, thus facilitating thespread of virulence and resistance plasmids. Here we describe how variants of the plasmid-encoded donor outer membrane(OM) protein TraN cooperate with distinct OM receptors in recipients to mediate mating pair stabilization and efficient DNAtransfer. We show that TraN from the plasmids pKpQIL (Klebsiella pneumoniae), R100-1 (Shigella flexneri) and pSLT (SalmonellaTyphimurium), and the prototypical F plasmid (Escherichia coli) interact with OmpK36, OmpW and OmpA, respectively.Cryo-EM analysis revealed that TraN pKpQIL interacts with OmpK36 through the insertion of a β-hairpin in the tip of TraN intoa monomer of the OmpK36 trimer. Combining bioinformatic analysis with AlphaFold structural predictions, we identified afourth TraN structural variant that mediates mating pair stabilization by binding OmpF. Accordingly, we devised a classifica-tion scheme for TraN homologues on the basis of structural similarity and their associated receptors: TraNα (OmpW), TraNβ(OmpK36), TraNγ (OmpA), TraNδ (OmpF). These TraN-OM receptor pairings have real-world implications as they reflect thedistribution of resistance plasmids within clinical Enterobacteriaceae isolates, demonstrating the importance of mating pairstabilization in mediating conjugation species specificity. These findings will allow us to predict the distribution of emergingresistance plasmids in high-risk bacterial pathogens.

  • Journal article
    Ciechonska M, Sturrock M, Grob A, Larrouy-Maumus G, Shahrezaei V, Isalan Met al., 2022,

    Emergent expression of fitness-conferring genes by phenotypic selection

    , PNAS Nexus, ISSN: 2752-6542

    Genotypic and phenotypic adaptation is the consequence of ongoing natural selection in populations and is key to predicting and preventing drug resistance. Whereas classic antibiotic persistence is all-or-nothing, here we demonstrate that an antibiotic resistance gene displays linear dose-responsive selection for increased expression in proportion to rising antibiotic concentration in growing E. coli populations. Furthermore, we report the potentially wide-spread nature of this form of emergent gene expression by instantaneous phenotypic selection process under bactericidal and bacteriostatic antxibiotic treatment, as well as an amino acid synthesis pathway enzyme under a range of auxotrophic conditions. We propose an analogy to Ohm’s law in electricity (V=IR) where selection pressure acts similarly to voltage (V), gene expression to current (I), and resistance (R) to cellular machinery constraints and costs. Lastly, mathematical modelling using agent-based models of stochastic gene expression in growing populations and Bayesian model selection reveal that the emergent gene expression mechanism requires variability in gene expression within an isogenic population, and a cellular ‘memory’ from positive feedbacks between growth and expression of any fitness-conferring gene. Finally, we discuss the connection of the observed phenomenon to a previously described general fluctuation-response relationship in biology.

  • Journal article
    Triantis KA, Rigal F, Whittaker RJ, Hume JP, Sheard C, Poursanidis D, Rolland J, Sfenthourakis S, Matthews TJ, Thebaud C, Tobias JAet al., 2022,

    Deterministic assembly and anthropogenic extinctions drive convergence of island bird communities

    , GLOBAL ECOLOGY AND BIOGEOGRAPHY, Vol: 31, Pages: 1741-1755, ISSN: 1466-822X
  • Journal article
    Qin B, Craven GB, Hou P, Chesti J, Lu X, Child ES, Morgan RML, Niu W, Zhao L, Armstrong A, Mann DJ, Cui Set al., 2022,

    Acrylamide fragment inhibitors that induce unprecedented conformational distortions in enterovirus 71 3C and SARS-CoV-2 main protease.

    , Acta Pharm Sin B, ISSN: 2211-3835

    RNA viruses are critically dependent upon virally encoded proteases to cleave the viral polyproteins into functional proteins. Many of these proteases exhibit a similar fold and contain an essential catalytic cysteine, offering the opportunity to inhibit these enzymes with electrophilic small molecules. Here we describe the successful application of quantitative irreversible tethering (qIT) to identify acrylamide fragments that target the active site cysteine of the 3C protease (3Cpro) of Enterovirus 71, the causative agent of hand, foot and mouth disease in humans, altering the substrate binding region. Further, we re-purpose these hits towards the main protease (Mpro) of SARS-CoV-2 which shares the 3C-like fold and a similar active site. The hit fragments covalently link to the catalytic cysteine of Mpro to inhibit its activity. We demonstrate that targeting the active site cysteine of Mpro can have profound allosteric effects, distorting secondary structures to disrupt the active dimeric unit.

  • Journal article
    Fiorillo C, Yen P-S, Colantoni A, Mariconti M, Azevedo N, Lombardo F, Failloux A-B, Arca Bet al., 2022,

    MicroRNAs and other small RNAs in Aedes aegypti saliva and salivary glands following chikungunya virus infection

    , SCIENTIFIC REPORTS, Vol: 12, ISSN: 2045-2322
  • Journal article
    Mullish BH, Martinez-Gili L, Chekmeneva E, Correia GDS, Lewis MR, Der Sluis VH-V, McDonald JAK, Pechlivanis A, Walters JRF, McClure EL, Marchesi JR, Allegretti JRet al., 2022,

    Fecal bile acid profiles predict recurrence in patients with primary <i>Clostridioides difficile</i> infection

    <jats:label>1.</jats:label><jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Factors that influence recurrence risk in primary <jats:italic>Clostridioides difficile</jats:italic> infection (CDI) are poorly understood, and tools to predict recurrence are lacking. Perturbations in microbial-derived bile acids (BAs) contribute to CDI pathogenesis and may be relevant to primary disease prognosis.</jats:p></jats:sec><jats:sec><jats:title>Aims</jats:title><jats:p>To define stool bile acid profiles and microbial bile-metabolising functionality in primary CDI patients, and explore signatures predicting recurrence.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Weekly stool samples were collected from primary CDI patients from the last day of anti-CDI therapy until recurrence, or through eight weeks post-completion otherwise. Ultra-high performance liquid chromatography-mass spectrometry (UHPLC-MS) was used to profile bile acids, and bacterial bile salt hydrolase (BSH) activity was measured to determine primary BA deconjugation capacity. Multivariate and univariate models were used to define differential BA trajectories in recurrers <jats:italic>versus</jats:italic> non-recurrers, and assess fecal bile acids as predictive markers for recurrence.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Twenty (36%) out of 56 patients (median age 57, 64% male) recurred, with 80% of recurrence occurring within the first nine days post-antibiotic treatment. Principal component analysis (PCA) of stool bile acid profiles demonstrated clustering of samples by recurrence status and post-treatment time point. Longitudinal fecal bile acid trajectories in non-recurrers showed a recovery of secondary bile acids and their derivatives in non-r

  • Journal article
    Marbiah M, Kotidis P, Donini R, Gómez IA, Jimenez Del Val I, Haslam SM, Polizzi KM, Kontoravdi Cet al., 2022,

    Rapid antibody glycoengineering in Chinese hamster ovary cells.

    , Journal of Visualized Experiments, Vol: 184, Pages: 1-19, ISSN: 1940-087X

    Recombinant monoclonal antibodies bind specific molecular targets and, subsequently, induce an immune response or inhibit the binding of other ligands. However, monoclonal antibody functionality and half-life may be reduced by the type and distribution of host-specific glycosylation. Attempts to produce superior antibodies have inspired the development of genetically modified producer cells that synthesize glyco-optimized antibodies. Glycoengineering typically requires the generation of a stable knockout or knockin cell line using methods such as clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein 9. Monoclonal antibodies produced by engineered cells are then characterized using mass spectrometric methods to determine if the desired glycoprofile has been obtained. This strategy is time-consuming, technically challenging, and requires specialists. Therefore, an alternative strategy that utilizes streamlined protocols for genetic glycoengineering and glycan detection may assist endeavors toward optimal antibodies. In this proof-of-concept study, an IgG-producing Chinese hamster ovary cell served as an ideal host to optimize glycoengineering. Short interfering RNA targeting the Fut8 gene was delivered to Chinese hamster ovary cells, and the resulting changes in FUT8 protein expression were quantified. The results indicate that knockdown by this method was efficient, leading to a ~60% reduction in FUT8. Complementary analysis of the antibody glycoprofile was performed using a rapid yet highly sensitive technique: capillary gel electrophoresis and laser-induced fluorescence detection. All knockdown experiments showed an increase in afucosylated glycans; however, the greatest shift achieved in this study was ~20%. This protocol simplifies glycoengineering efforts by harnessing in silico design tools, commercially synthesized gene targeting reagents, and rapid quantification assays that do not require extensive prior experience. As such, t

  • Journal article
    Banks-Leite C, Betts MG, Ewers RM, Orme CDL, Pigot ALet al., 2022,

    The macroecology of landscape ecology

    , Trends in Ecology and Evolution, Vol: 37, ISSN: 0169-5347

    One of landscape ecology's main goals is to unveil how biodiversity is impacted by habitat transformation. However, the discipline suffers from significant context dependency in observed spatial and temporal trends, hindering progress towards understanding the mechanisms driving species declines and preventing the development of accurate estimates of future biodiversity change. Here, we discuss recent evidence that populations' and species' responses to habitat change at the landscape scale are modulated by factors and processes occurring at macroecological scales, such as historical disturbance rates, distance to geographic range edges, and climatic suitability. We suggest that placing landscape ecology studies in a macroecological lens will help to explain seemingly inconsistent results and will ultimately create better predictive models to help mitigate the biodiversity crisis.

  • Journal article
    Tomaz D, Pereira PM, Guerra N, Dyson J, Gould K, Henriques Ret al., 2022,

    Nanoscale Colocalization of NK Cell Activating and Inhibitory Receptors Controls Signal Integration

    , FRONTIERS IN IMMUNOLOGY, Vol: 13, ISSN: 1664-3224
  • Journal article
    Giannos P, Triantafyllidis KK, Giannos G, Kechagias Ket al., 2022,

    SPP1 in infliximab resistant ulcerative colitis and associated colorectal cancer: an analysis of differentially expressed genes

    , European Journal of Gastroenterology and Hepatology, Vol: 34, Pages: 598-606, ISSN: 0954-691X

    Objective:Infliximab, a tumour necrosis factor-α (TNFα) antagonist, has advanced the management of ulcerative colitis. Although efficacious, considerable percentage of patients are resistant to treatment. Accumulative inflammatory burden in long-term ulcerative colitis patients refractory to therapy increases the risk of developing colorectal cancer (CRC). Our study investigated anti-TNFα-naïve patients with active ulcerative colitis to identify gene biomarkers whose dysregulated expression correlated with resistance to infliximab (IFX) treatment and poor prognosis in CRC.Methods:Differentially expressed genes (DEGs) from two studies (GSE73661 and GSE14580) with colonic mucosal samples were retrieved. Noninflammatory bowel disease controls were compared with those with active ulcerative colitis that either responded or were resistant to IFX before treatment. DEGs from ulcerative colitis samples resistant to IFX were used to construct a protein–protein interaction network, and clustering gene modules were identified. Module DEGs that overlapped with ulcerative colitis samples responsive to IFX were analysed, based on topological closeness and radiality. Hub genes were obtained, and their correlation with CRC progression was evaluated. Their expression in CRC tissues and their tumour microenvironment immune status was estimated.Results:Three clusters composed of 582 DEGs from ulcerative colitis samples resistant to IFX were retrieved. Comparative analysis identified 305 overlapping DEGs with ulcerative colitis samples responsive to IFX. Topological analysis revealed a hub gene – SPP1 – whose overexpression in CRC tissues and patients correlated with increased infiltration of immune signatures and poor prognosis.Conclusion:SPP1 may serve as potential gene biomarker and predictor of resistance to IFX therapy in ulcerative colitis and CRC development.

  • Journal article
    Duarte A, Pym A, Garrood WT, Troczka BJ, Zimmer CT, Davies TGE, Nauen R, O'Reilly AO, Bass Cet al., 2022,

    P450 gene duplication and divergence led to the evolution of dual novel functions and insecticide cross-resistance in the brown planthopper Nilaparvata lugens

    , PLOS GENETICS, Vol: 18, ISSN: 1553-7404
  • Journal article
    Oliver-Huidobro M, Tica J, Wachter G, Isalan Met al., 2022,

    Synthetic spatial patterning in bacteria: advances based on novel diffusible signals

    , Microbial Biotechnology, Vol: 15, Pages: 1685-1694, ISSN: 1751-7907

    Engineering multicellular patterning may help in the understanding of some fundamental laws of pattern formation and thus may contribute to the field of developmental biology. Furthermore, advanced spatial control over gene expression may revolutionize fields such as medicine, through organoid or tissue engineering. To date, foundational advances in spatial synthetic biology have often been made in prokaryotes, using artificial gene circuits. In this review, engineered patterns are classified into four levels of increasing complexity, ranging from spatial systems with no diffusible signals to systems with complex multi-diffusor interactions. This classification highlights how the field was held back by a lack of diffusible components. Consequently, we provide a summary of both previously characterized and some new potential candidate small-molecule signals that can regulate gene expression in Escherichia coli. These diffusive signals will help synthetic biologists to successfully engineer increasingly intricate, robust and tuneable spatial structures.

  • Journal article
    Miracca G, Anuncibay Soto B, Tossell K, Yustos R, Vyssotski A, Franks N, Wisden Wet al., 2022,

    NMDA receptors in the lateral preoptic hypothalamus are essential for sustaining NREM and REM sleep

    , The Journal of Neuroscience, Vol: 42, Pages: 5389-5409, ISSN: 0270-6474

    The lateral preoptic (LPO) hypothalamus is a center for NREM and REM sleep induction and NREM sleep homeostasis. Although LPO is needed for NREM sleep, we found that calcium signals were, surprisingly, highest in REM sleep. Furthermore, and equally surprising, NMDA26 receptors in LPO were the main drivers of excitation. Deleting the NMDA receptor GluN1 subunit from LPO abolished calcium signals in all cells and produced insomnia. Mice of both sexes had highly fragmented NREM sleep-wake patterns and could not generate conventionally classified REM sleep. The sleep phenotype produced by deleting NMDA receptors depended on where in the hypothalamus the receptors were deleted. Deleting receptors from the anterior hypothalamic area did not influence sleep-wake states. The sleep fragmentation originated from NMDA receptors on GABA neurons in LPO. Sleep fragmentation could be transiently overcome with sleeping medication (zolpidem) or sedatives (dexmedetomidine). By contrast, fragmentation persisted under high sleeppressure produced by sleep deprivation - mice had a high propensity to sleep but woke up. By analyzing changes in delta power, sleep homeostasis (also referred to as “sleep drive”) remained intact after NMDA receptor ablation. We suggest NMDA glutamate receptor activation stabilizes firing of sleep-on neurons, and that mechanisms of sleep maintenance differ from that of the sleep drive itself.

  • Journal article
    Ellis D, Avraam GP, Hoermann A, Wyer CASP, Ong YX, Christophides GP, Windbichler Net al., 2022,

    Testing non-autonomous antimalarial gene drive effectors using self-eliminating drivers in the African mosquito vector Anopheles gambiae

    , PLOS GENETICS, Vol: 18, ISSN: 1553-7404
  • Conference paper
    Mountain K, MacIntyre D, Chan D, Hyde A, Lee Y, Brown R, David A, Dell A, Ten F, Haslam S, Liu Y, Lewis H, Norman J, Stock S, Teoh TG, Terzidou V, Kundu S, Bennett P, Sykes Let al., 2022,

    Blood group antigens influence host-microbe interactions and risk of early preterm birth

    , Publisher: WILEY, Pages: 55-56, ISSN: 1470-0328
  • Journal article
    Sanchez Garrido J, Ruano-Gallego D, Choudhary JS, Frankel Get al., 2022,

    The type III secretion system effector network hypothesis

    , Trends in Microbiology, Vol: 30, Pages: 524-533, ISSN: 0966-842X

    Type III secretion system (T3SS) effectors are key virulence factors that underpin the infection strategy of many clinically important Gram-negative pathogens, including Salmonella enterica, Shigella spp, enteropathogenic and enterohaemorrhagic Escherichia coli and their murine equivalent, Citrobacter rodentium. The cellular processes or proteins targeted by the effectors can be common to multiple pathogens or pathogen-specific. The main approach to understanding T3SS-mediated pathogenesis has been to determine the contribution of one effector at a time, with the aim to piece together individual functions and unveil infection mechanisms. However, in contrast to this prevailing approach, simultaneous deletion of multiple effectors revealed that they function as an interconnected network in vivo, uncoveringeffector co-dependency and context-dependent effector essentiality. This paradigm shift in T3SS biology is at the heart of this opinion.

  • Journal article
    Prokopidis K, Giannos P, Katsikas Triantafyllidis K, Kechagias KS, Mesinovic J, Witard OC, Scott Det al., 2022,

    Effect of vitamin D monotherapy on indices of sarcopenia in community‐dwelling older adults: a systematic review and meta‐analysis

    , Journal of Cachexia, Sarcopenia and Muscle, Vol: 13, Pages: 1642-1652, ISSN: 2190-5991

    BackgroundVitamin D supplementation is proposed as a potentially effective nutritional intervention to mitigate the risk of sarcopenia. The aim of this systematic review and meta-analysis was to investigate the impact of vitamin D supplementation monotherapy on indices of sarcopenia in community-dwelling older adults.MethodsA comprehensive search of the literature was conducted in PubMed, Web of Science, Scopus, and Cochrane Library. Eligible randomized controlled trials (RCTs) compared the effect of vitamin D supplementation (as monotherapy) with placebo on indices of sarcopenia in older (>50 years) adults. Using the random effects inverse-variance model, we calculated the mean difference (MD) in handgrip strength (HGS), short physical performance battery (SPPB), timed up and go (TUG), and appendicular lean mass (ALM) between groups. We also calculated the standardized mean difference (SMD) in general muscle strength and general physical performance (composite plot of all muscle strength and physical performance outcomes, respectively) between groups.ResultsTen RCTs were included in the meta-analysis. A significant decrease in SPPB scores was observed with vitamin D supplementation compared with placebo (MD: −0.23; 95% CI −0.40 to −0.06; I2 = 0%; P = 0.007). Vitamin D supplementation conferred no effect on HGS (MD: −0.07 kg; 95% CI −0.70 to 0.55; I2 = 51%, P = 0.82), TUG (MD: 0.07 s; 95% CI −0.08 to 0.22; I2 = 0%, P = 0.35), ALM (MD: 0.06 kg/m2; 95% CI: −0.32 to 0.44; I2 = 73%, P = 0.77), general muscle strength (SMD: −0.01; 95% CI −0.17 to 0.15; I2 = 42%, P = 0.90), or general physical performance (SMD: −0.02; 95% CI −0.23 to 0.18; I2 = 71%, P = 0.83).ConclusionsVitamin D supplementation did not improve any sarcopenia indices in community-dwelling older adults and may compromise some aspects of physical performance. Future studies are warranted to investigate the impact of vitamin D supplementati

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