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  • Journal article
    Savolainen V, Bailey NW, Diamond L, Swift-Gallant A, Gavrilets S, Raymond M, Verweij KJHet al., 2024,

    A broader cultural view is necessary to study the evolution of sexual orientation

    , Nature Ecology and Evolution, Vol: 8, Pages: 181-183, ISSN: 2397-334X

    The causation of sexual orientation is likely to be complex and influenced by multiple factors1. We advocate incorporating a broader cultural view into evolutionary andgenetic studies to account for differences in how sexual orientation is experienced, expressed, and understood in both human and non-human animals.

  • Journal article
    Waring BG, 2024,

    Grand challenges in ecosystem restoration

    , FRONTIERS IN ENVIRONMENTAL SCIENCE, Vol: 11
  • Journal article
    Zhang X, Gao F, Ye F, Zhang B, Cronin N, Buck Met al., 2024,

    Structural basis of s54 displacement and promoter escape in bacterial transcription

    , Proceedings of the National Academy of Sciences of USA, ISSN: 0027-8424

    Gene transcription is a fundamental cellular process carried out by RNA polymerase (RNAP). Transcription initiation is highly regulated and in bacteria, transcription initiation is mediated by sigma (σ) factors. σ recruits RNAP to the promoter DNA region, located upstream oftranscription start site (TSS), and facilitates open complex formation, where double stranded DNA is opened up into a transcription bubble and template strand DNA is positioned inside RNAP for initial RNA synthesis. During initial transcription, RNAP remains bound to sigma andupstream DNA, presumably with an enlarging transcription bubble. The release of RNAP fromupstream DNA is required for promoter escape and processive transcription elongation. Bacteria sigma factors can be broadly separated into two classes with the majority belonging to the σ70 class, represented by the σ70 that regulates housekeeping genes. σ54 forms a class on its own and regulates stress response genes. Extensive studies on σ70 have revealed the molecularmechanisms of σ70 dependent process while how σ54 transitions from initial transcription to elongation is currently unknown. Here we present a series of cryo electron microscopy structures of the RNAP-σ54 initial transcribing complexes with progressively longer RNA, which reveal structural changes that lead to promoter escape. Our data show that initially, the transcription bubble enlarges, DNA strands scrunch, reducing the interactions between σ54 and DNA strands in the transcription bubble. RNA extension and further DNA scrunching help to release RNAP from σ54 and upstream DNA, enabling the transition to elongation.

  • Journal article
    Grob A, Enrico Bena C, Di Blasi R, Pessina D, Sood M, Yunyue Z, Bosia C, Isalan M, Ceroni Fet al., 2024,

    Mammalian cell growth characterisation by a non-invasive plate reader assay

    , Nature Communications, Vol: 15, ISSN: 2041-1723

    Automated and non-invasive mammalian cell analysis is currently lagging behind due to a lack of methods suitable for a variety of cell lines and applications. Here, we report the development of a high throughput non-invasive method for tracking mammalian cell growth and performance based on plate reader measurements. We show the method to be suitable for both suspension and adhesion cell lines, and we demonstrate it can be adopted when cells are grown under different environmental conditions. We establish that the method is suitable to inform on effective drug treatments to be used depending on the cell line considered, and that it can support characterisation of engineered mammalian cells over time. This work provides the scientific community with an innovative approach to mammalian cell screening, also contributing to the current efforts towards high throughput and automated mammalian cell engineering.

  • Book chapter
    McArthur HCW, Bajur AT, Spillane KM, 2024,

    Quantifying force-mediated antigen extraction in the B cell immune synapse using DNA-based tension sensors

    , Methods in Cell Biology

    B cells exert pulling forces against antigen-presenting cells (APCs) to extract antigens for internalization. The application of tugging forces on B cell receptor (BCR)-antigen bonds promotes discrimination of antigen affinities and sensing of APC physical properties. Here, we describe a protocol for preparing antigen-functionalized DNA tension sensors for quantifying force-mediated antigen extraction in the B cell immune synapse. We describe how to attach the sensors to planar lipid bilayers, quantify their surface density, use them to stimulate B cell activation, and analyze the efficiency of antigen extraction in fixed cells by fluorescence microscopy and image analysis. These techniques should be broadly applicable to studies of force-mediated transfer of molecules in cell-cell contacts.

  • Journal article
    Ono M, 2024,

    Unraveling T-cell dynamics using fluorescent timer: Insights from the Tocky system

    , Biophysics and physicobiology, Vol: 21

    Understanding the temporal dynamics of T-cell activities is crucial for insights into immune cell function and development. In this study, we show the features of the Timer-of-Cell-Kinetics-and-Activity (Tocky) system, which enables analysis of temporal dynamics of cell activities and differentiation, leveraging Fluorescent Timer protein, which spontaneously changes its emission spectrum from blue to red fluorescence in known kinetics, as reporters. The current study examines the properties of the Tocky system, highlighting the Timer-Angle approach, which is a core algorithm of Tocky analysis and converts Timer Blue and Red fluorescence into Timer Angle and Intensity by trigonometric transformation. Importantly, Tocky analyzes time-related events within individual cells by the two phases of measurements, distinguishing between (1) the temporal sequence of cellular activities and differentiation within the time domain, and (2) the transcription frequency within the frequency domain. The transition from time measurement to frequency analysis, particularly at the Persistent locus that bridges these domains, highlights that system’s unique property in what is measured and analyzed by Tocky. Intriguingly, the sustained transcriptional activities observed in cells at the Persistent locus may have unique biological features as demonstrated in activated regulatory T-cells (Treg) and pathogenic T-cells, respectively, using Foxp3-Tocky and Nr4a3-Tocky models. In conclusion, the Tocky system can provide crucial data for advancing our understanding of T-cell dynamics and function.

  • Journal article
    Sugiura M, Kimura M, Shimamoto N, Nakamura M, Koyama K, Selles J, Boussac A, Rutherford Aet al., 2024,

    Tuning of the ChlD1 and ChlD2 properties in photosystem II by site-directed mutagenesis of neighbouring amino acids

    , BBA: Bioenergetics, Vol: 1865, ISSN: 0005-2728

    Photosystem II is the water/plastoquinone photo-oxidoreductase of photosynthesis. The photochemistry and catalysis occur in a quasi-symmetrical heterodimer, D1D2, that evolved from a homodimeric ancestor. Here, we studied site-directed mutants in PSII from the thermophilic cyanobacterium Thermosynechoccocus elongatus, focusing on the primary electron donor chlorophyll a in D1, ChlD1, and on its symmetrical counterpart in D2, ChlD2, which does not play a direct photochemical role. The main conserved amino acid specific to ChlD1 is D1/T179, which H-bonds the water ligand to its Mg2+, while its counterpart near ChlD2 is the non-H-bonding D2/I178. The symmetrical-swapped mutants, D1/T179I and D2/I178T, and a second ChlD2 mutant, D2/I178H, were studied. The D1 mutations affected the 686 nm absorption attributed to ChlD1, while the D2 mutations affected a 663 nm feature, tentatively attributed to ChlD2. The mutations had little effect on enzyme activity and forward electron transfer, reflecting the robustness of the overall enzyme function. In contrast, the mutations significantly affected photodamage and protective mechanisms, reflecting the importance of redox tuning in these processes. In D1/T179I, the radical pair recombination triplet on ChlD1 was shared onto a pheophytin, presumably PheD1 and the detection of 3PheD1 supports the proposed mechanism for the anomalously short lifetime of 3ChlD1; e.g. electron transfer quenching by QA− of 3PheD1 after triplet transfer from 3ChlD1. In D2/I178T, a charge separation could occur between ChlD2 and PheD2, a reaction that is thought to occur in ancestral precursors of PSII. These mutants help understand the evolution of asymmetry in PSII.

  • Book chapter
    Prentice IC, Cowling SA, 2024,

    Dynamic Global Vegetation Models

    , Encyclopedia of Biodiversity, Third Edition: Volume 1-7

    Dynamic global vegetation models encapsulate our knowledge of plant and ecosystem function. They have many potential applications but not all of these are well developed, and large differences among model predictions are a concern. Fields of application include analysis of land–atmosphere biophysical interactions, carbon and water cycling, climate impacts on vegetation structure, fire, atmospheric trace gas composition, Quaternary vegetation and environmental changes, and ecosystem structure and function through Earth history. There is scope to improve models using a wider range of information from plant functional ecology, ecophysiology, environmental remote sensing, and atmospheric measurement, Quaternary paleoecology, and paleobotany.

  • Journal article
    Seddon C, Frankel G, Beis K, 2024,

    Structure of the outer membrane porin OmpW from the pervasive pathogen Klebsiella pneumoniae

    , Acta Crystallographica Section F: Structural Biology and Crystallization Communications Online, Vol: 80, Pages: 22-27, ISSN: 1744-3091

    Conjugation is the process by which plasmids, including those that carry antibiotic-resistance genes, are mobilized from one bacterium (the donor) to another (the recipient). The conjugation efficiency of IncF-like plasmids relies on the formation of mating-pair stabilization via intimate interactions between outer membrane proteins on the donor (a plasmid-encoded TraN isoform) and recipient bacteria. Conjugation of the R100-1 plasmid into Escherichia coli and Klebsiella pneumoniae (KP) recipients relies on pairing between the plasmid-encoded TraNα in the donor and OmpW in the recipient. Here, the crystal structure of K. pneumoniae OmpW (OmpWKP) is reported at 3.2 Å resolution. OmpWKP forms an eight-stranded β-barrel flanked by extracellular loops. The structures of E. coli OmpW (OmpWEC) and OmpWKP show high conservation despite sequence variability in the extracellular loops.

  • Journal article
    Heath BE, Suzuki R, LePenru NP, Skinner J, Orme CDL, Ewers RM, Sethi SS, Picinali Let al., 2024,

    Spatial ecosystem monitoring with a Multichannel Acoustic Autonomous Recording Unit (MAARU)

    , Methods in Ecology and Evolution

    Multi-microphone recording adds spatial information to recorded audio with emerging applications in ecosystem monitoring. Specifically placing sounds in space can improve animal count accuracy, locate illegal activity like logging and poaching, track animals to monitor behaviour and habitat use and allow for ‘beamforming’ to amplify sounds from target directions for downstream classification. Studies have shown many advantages of spatial acoustics, but uptake remains limited as the equipment is often expensive, complicated, inaccessible or only suitable for short-term deployments. With an emphasis on enhanced uptake and usability, we present a low-cost, open-source, six-channel recorder built entirely from commercially available components which can be integrated into a solar-powered, online system. The MAARU (Multichannel Acoustic Autonomous Recording Unit) works as an independent node in long-term autonomous, passive and/or short-term deployments. Here, we introduce MAARU's hardware and software and present the results of lab and field tests investigating the device's durability and usability. MAARU records multichannel audio with similar costs and power demands to equivalent omnidirectional recorders. MAARU devices have been deployed in the United Kingdom and Brazil, where we have shown MAARUs can accurately localise pure tones up to 6 kHz and bird calls as far as 8 m away (±10° range, 100% and >60% of signals, respectively). Louder calls may have even further detection radii. We also show how beamforming can be used with MAARUs to improve species ID confidence scores. MAARU is an accessible, low-cost option for those looking to explore spatial acoustics accurately and easily with a single device, and without the formidable expenses and processing complications associated with establishing arrays. Ultimately, the added directional element of the multichannel recording provided by MAARU allows for enhanced recording of sonic environments

  • Journal article
    Beltrán L, Torsilieri H, Patkowski JB, Yang JE, Casanova J, Costa TRD, Wright ER, Egelman EHet al., 2024,

    The mating pilus of E. coli pED208 acts as a conduit for ssDNA during horizontal gene transfer

    , mBio, Vol: 15, ISSN: 2150-7511

    Bacteria are constantly exchanging DNA, which constitutes horizontal gene transfer. While some of these occurs by a non-specific process called natural transformation, some occurs by a specific mating between a donor and a recipient cell. In specific conjugation, the mating pilus is extended from the donor cell to make contact with the recipient cell, but whether DNA is actually transferred through this pilus or by another mechanism involving the type IV secretion system complex without the pilus has been an open question. Using Escherichia coli, we show that DNA can be transferred through this pilus between a donor and a recipient cell that has not established a tight mating junction, providing a new picture for the role of this pilus.

  • Journal article
    Gonzalez A, Vihervaara P, Balvanera P, Bates AE, Bayraktarov E, Bellingham PJ, Bruder A, Campbell J, Catchen MD, Cavender-Bares J, Chase J, Coops N, Costello MJ, Czucz B, Delavaud A, Dornelas M, Dubois G, Duffy EJ, Eggermont H, Fernandez M, Fernandez N, Ferrier S, Geller GN, Gill M, Gravel D, Guerra CA, Guralnick R, Harfoot M, Hirsch T, Hoban S, Hughes AC, Hugo W, Hunter ME, Isbell F, Jetz W, Juergens N, Kissling WD, Krug CB, Kullberg P, Le Bras Y, Leung B, Londono-Murcia MC, Lord J-M, Loreau M, Luers A, Ma K, MacDonald AJ, Maes J, McGeoch M, Mihoub JB, Millette KL, Molnar Z, Montes E, Mori AS, Muller-Karger FE, Muraoka H, Nakaoka M, Navarro L, Newbold T, Niamir A, Obura D, O'Connor M, Paganini M, Pelletier D, Pereira H, Poisot T, Pollock LJ, Purvis A, Radulovici A, Rocchini D, Roeoesli C, Schaepman M, Schaepman-Strub G, Schmeller DS, Schmiedel U, Schneider FD, Shakya MM, Skidmore A, Skowno AL, Takeuchi Y, Tuanmu M-N, Turak E, Turner W, Urban MC, Urbina-Cardona N, Valbuena R, Van de Putte A, van Havre B, Wingate VR, Wright E, Torrelio CZet al., 2024,

    A global biodiversity observing system to unite monitoring and guide action (AUG, 10.1038/s41559-023-02171-0, 2023)

    , NATURE ECOLOGY & EVOLUTION, Vol: 8, Pages: 175-175, ISSN: 2397-334X
  • Journal article
    Panstruga R, Spanu P, 2024,

    Transfer RNA and ribosomal RNA fragments - emerging players in plant-microbe interactions

    , NEW PHYTOLOGIST, Vol: 241, Pages: 567-577, ISSN: 0028-646X
  • Journal article
    Di Pilato V, Codda G, Niccolai C, Willison E, Wong JLC, Coppo E, Frankel G, Marchese A, Rossolini GMet al., 2024,

    Functional features of KPC-109, a novel 270-loop KPC-3 mutant mediating resistance to avibactam-based ,B-lactamase inhibitor combinations and cefiderocol

    , INTERNATIONAL JOURNAL OF ANTIMICROBIAL AGENTS, Vol: 63, ISSN: 0924-8579
  • Journal article
    Ren Y, Wang H, Harrison SP, Prentice IC, Atkin OK, Smith NG, Mengoli G, Stefanski A, Reich PBet al., 2024,

    Reduced global plant respiration due to the acclimation of leaf dark respiration coupled to photosynthesis

    , New Phytologist, Vol: 241, Pages: 578-591, ISSN: 0028-646X

    Leaf dark respiration (Rd) acclimates to environmental changes. However, the magnitude, controls and time scales of acclimation remain unclear and are inconsistently treated in ecosystem models. We hypothesized that Rd and Rubisco carboxylation capacity (Vcmax) at 25°C (Rd,25, Vcmax,25) are coordinated so that Rd,25 variations support Vcmax,25 at a level allowing full light use, with Vcmax,25 reflecting daytime conditions (for photosynthesis), and Rd,25/Vcmax,25 reflecting night-time conditions (for starch degradation and sucrose export). We tested this hypothesis temporally using a 5-yr warming experiment, and spatially using an extensive field-measurement data set. We compared the results to three published alternatives: Rd,25 declines linearly with daily average prior temperature; Rd at average prior night temperatures tends towards a constant value; and Rd,25/Vcmax,25 is constant. Our hypothesis accounted for more variation in observed Rd,25 over time (R2 = 0.74) and space (R2 = 0.68) than the alternatives. Night-time temperature dominated the seasonal time-course of Rd, with an apparent response time scale of c. 2 wk. Vcmax dominated the spatial patterns. Our acclimation hypothesis results in a smaller increase in global Rd in response to rising CO2 and warming than is projected by the two of three alternative hypotheses, and by current models.

  • Journal article
    Moriel DG, Piccioli D, Raso MM, Pizza Met al., 2024,

    The overlooked bacterial pandemic

    , SEMINARS IN IMMUNOPATHOLOGY, Vol: 45, Pages: 481-491, ISSN: 1863-2297
  • Journal article
    Kawaguchi S, Atkinson A, Bahlburg D, Bernard KS, Cavan EL, Cox MJ, Hill SL, Meyer B, Veytia Det al., 2024,

    Climate change impacts on Antarctic krill behaviour and population dynamics

    , NATURE REVIEWS EARTH & ENVIRONMENT, Vol: 5, Pages: 43-58
  • Conference paper
    David A, Hanna G, Pennica C, Islam S, Sternberg MJEet al., 2024,

    Missense3D suite: harnessing the power of 3D protein structures to predict the effect of missense variants

    , 56th Annual Conference of the European-Society-of-Human-Genetics (ESHG), Publisher: SPRINGERNATURE, Pages: 297-297, ISSN: 1018-4813
  • Journal article
    Ono M, Satou Y, 2024,

    Spectrum of Treg and self-reactive T cells: single cell perspectives from old friend HTLV-1.

    , Discov Immunol, Vol: 3

    Despite extensive regulatory T cell (Treg) research, fundamental questions on in vivo dynamics remain to be answered. The current study aims to dissect several interwoven concepts in Treg biology, highlighting the 'self-reactivity' of Treg and their counterparts, namely naturally-arising memory-phenotype T-cells, as a key mechanism to be exploited by a human retroviral infection. We propose the novel key concept, Periodic T cell receptor (TCR)-signalled T-cells, capturing self-reactivity in a quantifiable manner using the Nr4a3-Timer-of-cell-kinetics-and-activity (Tocky) technology. Periodic and brief TCR signals in self-reactive T-cells contrast with acute TCR signals during inflammation. Thus, we propose a new two-axis model for T-cell activation by the two types of TCR signals or antigen recognition, elucidating how Foxp3 expression and acute TCR signals actively regulate Periodic TCR-signalled T-cells. Next, we highlight an underappreciated branch of immunological research on Human T-cell Leukemia Virus type 1 (HTLV-1) that precedes Treg studies, illuminating the missing link between the viral infection, CD25, and Foxp3. Based on evidence by single-cell analysis, we show how the viral infection exploits the regulatory mechanisms for T-cell activation and suggests a potential role of periodic TCR signalling in infection and malignant transformation. In conclusion, the new perspectives and models in this study provide a working framework for investigating Treg within the self-reactive T-cell spectrum, expected to advance understanding of HTLV-1 infection, cancer, and immunotherapy strategies for these conditions.

  • Book chapter
    Dey S, Majumdar A, 2024,

    Current Status of Pollution in Major Rivers and Tributaries of India and Protection-Restoration Strategies

    , Rivers of India, Publisher: Springer International Publishing, Pages: 69-93, ISBN: 9783031491627
  • Journal article
    Tissot FS, Gonzalez-Anton S, Lo Celso C, 2024,

    Intravital Microscopy to Study the Effect of Matrix Metalloproteinase Inhibition on Acute Myeloid Leukemia Cell Migration in the Bone Marrow.

    , Methods Mol Biol, Vol: 2747, Pages: 211-227

    Hematopoiesis is the process through which all mature blood cells are formed and takes place in the bone marrow (BM). Acute myeloid leukemia (AML) is a blood cancer of the myeloid lineage. AML progression causes drastic remodeling of the BM microenvironment, making it no longer supportive of healthy hematopoiesis and leading to clinical cytopenia in patients. Understanding the mechanisms by which AML cells shape the BM to their benefit would lead to the development of new therapeutic strategies. While the role of extracellular matrix (ECM) in solid cancer has been extensively studied during decades, its role in the BM and in leukemia progression has only begun to be acknowledged. In this context, intravital microscopy (IVM) gives the unique insight of direct in vivo observation of AML cell behavior in their environment during disease progression and/or upon drug treatments. Here we describe our protocol for visualizing and analyzing MLL-AF9 AML cell dynamics upon systemic inhibition of matrix metalloproteinases (MMP), combining confocal and two-photon microscopy and focusing on cell migration.

  • Journal article
    Chow LJ, Nesbit ML, Hill T, Tranter C, Evison SEF, Hughes WOH, Graystock Pet al., 2024,

    Identification of fungi isolated from commercial bumblebee colonies

    , PeerJ, Vol: 12, ISSN: 2167-8359

    Fungi can have important beneficial and detrimental effects on animals, yet our understanding of the diversity and function of most bee-associated fungi is poor. Over 2 million bumblebee colonies are traded globally every year, but the presence and transport of viable fungi within them is unknown. Here, we explored whether any culturable fungi could be isolated from commercial bumblebee nests. We collected samples of various substrates from within 14 bumblebee colonies, including the honey, honey cup wall, egg cup wall, and frass then placed them on agar and recorded any growth. Fungal morphotypes were then subcultured and their ITS region sequenced for identification. Overall, we cultured 11 fungal species from the various nest substrates. These included both pathogenic and non-pathogenic fungi, such as Aspergillus sp., Penicillium sp., and Candida sp. Our results provide the first insights into the diversity of viable fungal communities in commercial bumblebee nests. Further research is needed to determine if these fungi are unique to commercial colonies or prevalent in wild bumblebee nests, and crucially to determine the ecological and evolutionary implications of these fungi in host colonies.

  • Journal article
    Herzog MK-M, Cazzaniga M, Peters A, Shayya N, Beldi L, Hapfelmeier S, Heimesaat MMM, Bereswill S, Frankel G, Gahan CGM, Hardt W-Det al., 2023,

    Mouse models for bacterial enteropathogen infections: insights into the role of colonization resistance

    , GUT MICROBES, Vol: 15, ISSN: 1949-0976
  • Journal article
    Matanza XM, Clements A, 2023,

    Pathogenicity and virulence of <i>Shigella sonnei</i>: A highly drug-resistant pathogen of increasing prevalence

    , VIRULENCE, Vol: 14, ISSN: 2150-5594
  • Journal article
    Gonzalez-Ferreras AM, Barquin J, Blyth PSA, Hawksley J, Kinsella H, Lauridsen R, Morris OF, Penas FJ, Thomas GE, Woodward G, Zhao L, O'Gorman EJet al., 2023,

    Chronic exposure to environmental temperature attenuates the thermal sensitivity of salmonids

    , NATURE COMMUNICATIONS, Vol: 14
  • Book chapter
    Shocket M, Caldwell J, Huxley P, Lippi C, Windram F, Keyel Aet al., 2023,

    Modelling the effects of climate and climate change on transmission of vector-borne disease

    , Planetary health approaches to understand and control vector-borne diseases, Editors: Fornace, Conn, Mureb, Chaves, Logan, Publisher: BRILL, Pages: 253-318, ISBN: 9789004688650

    Mathematical and statistical models are critical tools for both understanding how climate can influence patterns of vector-borne disease transmission, and predicting how climate change might affect these patterns in the future. This chapter focuses primarily on quantitative approaches for modelling the effects of climate on mosquito-borne disease (MBD), although we also briefly consider tick-borne disease. We initially describe how the biological mechanisms that contribute to transmission of vector-borne disease can respond to changes in climate and other environmental factors. Importantly, transmission of MBD responds nonlinearly over gradients of both temperature and rainfall. When building or interpreting models for the effects of climate on MBD dynamics, it is important to consider that the effects of temperature and rainfall on disease may be positive, negative, or both depending on circumstance. This context-dependence can limit the transferability of models beyond the setting in which they were fit. Next, we provide an overview of important concepts and approaches for modelling vector-borne diseases using mechanistic and statistical models. This includes the most commonly used modelling methods, techniques for model evaluation and validation, and climate re-analysis products used as model predictors. The best choices of methods for model construction and evaluation depend on the goals of the model and the structure of the underlying data, including their spatial and temporal scales. Then, we explore three case studies of MBD in more detail and use them to illustrate representative modelling approaches across a gradient of spatiotemporal scales: (1) local time series models of dengue fever in San Juan, Puerto Rico; (2) regional models of West Nile virus in the United States; and (3) continental and global models for how climate change may impact future transmission risk for malaria and dengue fever. Finally, we note some key challenges, knowledge gaps, and res

  • Journal article
    Ghani L, Kim S, Ehsan M, Lan B, Poulsen IH, Dev C, Katsube S, Byrne B, Guan L, Loland CJ, Liu X, Im W, Chae PSet al., 2023,

    Melamine-cored glucosides for membrane protein solubilization and stabilization: importance of water-mediated intermolecular hydrogen bonding in detergent performance

    , Chemical Science, Vol: 14, Pages: 13014-13024, ISSN: 2041-6520

    Membrane proteins play essential roles in a number of biological processes, and their structures are important in elucidating such processes at the molecular level and also for rational drug design and development. Membrane protein structure determination is notoriously challenging compared to that of soluble proteins, due largely to the inherent instability of their structures in non-lipid environments. Micelles formed by conventional detergents have been widely used for membrane protein manipulation, but they are suboptimal for long-term stability of membrane proteins, making downstream characterization difficult. Hence, there is an unmet need for the development of new amphipathic agents with enhanced efficacy for membrane protein stabilization. In this study, we designed and synthesized a set of glucoside amphiphiles with a melamine core, denoted melamine-cored glucosides (MGs). When evaluated with four membrane proteins (two transporters and two G protein-coupled receptors), MG-C11 conferred notably enhanced stability compared to the commonly used detergents, DDM and LMNG. These promising findings are mainly attributed to a unique feature of the MGs, i.e., the ability to form dynamic water-mediated hydrogen-bond networks between detergent molecules, as supported by molecular dynamics simulations. Thus, MG-C11 is the first example of a non-peptide amphiphile capable of forming intermolecular hydrogen bonds within a protein-detergent complex environment. Detergent micelles formed via a hydrogen-bond network could represent the next generation of highly effective membrane-mimetic systems useful for membrane protein structural studies.

  • Journal article
    Scopa C, Barnada SM, Cicardi ME, Singer M, Trotti D, Trizzino Met al., 2023,

    JUN upregulation drives aberrant transposable element mobilization, associated innate immune response, and impaired neurogenesis in Alzheimer’s disease

    , Nature Communications, Vol: 14, ISSN: 2041-1723

    Adult neurogenic decline, inflammation, and neurodegeneration are phenotypic hallmarks of Alzheimer’s disease (AD). Mobilization of transposable elements (TEs) in heterochromatic regions was recently reported in AD, but the underlying mechanisms are still underappreciated. Combining functional genomics with the differentiation of familial and sporadic AD patient derived-iPSCs into hippocampal progenitors, CA3 neurons, and cerebral organoids, we found that the upregulation of the AP-1 subunit, c-Jun, triggers decondensation of genomic regions containing TEs. This leads to the cytoplasmic accumulation of HERVK-derived RNA-DNA hybrids, the activation of the cGAS-STING cascade, and increased levels of cleaved caspase-3, suggesting the initiation of programmed cell death in AD progenitors and neurons. Notably, inhibiting c-Jun effectively blocks all these downstream molecular processes and rescues neuronal death and the impaired neurogenesis phenotype in AD progenitors. Our findings open new avenues for identifying therapeutic strategies and biomarkers to counteract disease progression and diagnose AD in the early, pre-symptomatic stages.

  • Journal article
    Eberhart-Hertel LJ, Rodrigues LF, Krietsch J, Hertel AG, Cruz-Lopez M, Vazquez-Rojas KA, Gonzalez-Medina E, Schroeder J, Kuepper Cet al., 2023,

    Egg size variation in the context of polyandry: a case study using long-term field data from snowy plovers

    , EVOLUTION, Vol: 77, Pages: 2590-2605, ISSN: 0014-3820
  • Journal article
    Kourelis J, 2023,

    Interplay between cell-surface receptor and intracellular NLR-mediated immune responses

    , New Phytologist, Vol: 240, Pages: 2218-2226, ISSN: 0028-646X

    The functional link between cell-surface receptors and intracellular NLR immune receptors is a critical aspect of plant immunity. To establish disease, successful pathogens have evolved mechanisms to suppress cell-surface immune signalling. In response, plants have adapted by evolving NLRs that recognize pathogen effectors involved in this suppression, thereby counteracting their immune-suppressing function. This ongoing co-evolutionary struggle has seemingly resulted in intertwined signalling pathways in some plant species, where NLRs form a separate signalling branch downstream of activated cell-surface receptor complexes essential for full immunity. Understanding these interconnected receptor networks could lead to novel strategies for developing durable disease resistance.

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