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  • Journal article
    Endres R, Cavanagh H, Mosbach A, Scalliet G, Lind Ret al., 6424,

    Physics-informed deep learning characterizes morphodynamics of Asian soybean rust disease

    , Nature Communications, Vol: 12, Pages: 1-8, ISSN: 2041-1723

    Medicines and agricultural biocides are often discovered using large phenotypic screens across hundreds of compounds, where visible effects of whole organisms are compared to gauge efficacy and possible modes of action. However, such analysis is often limited to human-defined and static features. Here, we introduce a novel framework that can characterize shape changes (morphodynamics) for cell-drug interactions directly from images, and use it to interpret perturbed development of Phakopsora pachyrhizi, the Asian soybean rust crop pathogen. We describe population development over a 2D space of shapes (morphospace) using two models with condition-dependent parameters: a top-down Fokker-Planck model of diffusive development over Waddington-type landscapes, and a bottom-up model of tip growth. We discover a variety of landscapes, describing phenotype transitions during growth, and identify possible perturbations in the tip growth machinery that cause this variation. This demonstrates a widely-applicable integration of unsupervised learning and biophysical modeling.

  • Conference paper
    Tossell K, Yu X, Soto BA, Vicente M, Miracca G, Giannos P, Miao A, Hsieh B, Ma Y, Yustos R, Vyssotski AL, Constandinou T, Franks NP, Wisden Wet al., 2022,


    , Publisher: ELSEVIER, Pages: S20-S20, ISSN: 1389-9457
  • Journal article
    Beis K, 2022,

    Identification of inhibitors of the Schistosoma mansoni VKR2 kinase domain

    , ACS Medicinal Chemistry Letters, ISSN: 1948-5875
  • Journal article
    Ransome E, Hobbs F, Jones S, Coleman CM, Harris ND, Woodward G, Bell T, Trew J, Kolarević S, Kračun-Kolarević M, Savolainen Vet al., 2022,

    Evaluating the transmission risk of SARS-CoV-2 from sewage pollution.

    , Sci Total Environ

    The presence of SARS-CoV-2 in untreated sewage has been confirmed in many countries but its incidence and infection risk in contaminated waters is poorly understood. The River Thames in the UK receives untreated sewage from 57 Combined Sewer Overflows (CSOs), with many discharging dozens of times per year. This study investigated if such discharges provide a pathway for environmental transmission of SARS-CoV-2. Samples of wastewater, surface water, and sediment collected close to six CSOs on the River Thames were assayed over eight months for SARS-CoV-2 RNA and infectious virus. Bivalves were also sampled as an indicator species of viral bioaccumulation. Sediment and water samples from the Danube and Sava rivers in Serbia, where raw sewage is also discharged in high volumes, were assayed as a positive control. No evidence of SARS-CoV-2 RNA or infectious virus was found in UK samples, in contrast to RNA positive samples from Serbia. Furthermore, this study shows that infectious SARS-CoV-2 inoculum is stable in Thames water and sediment for <3 days, while SARS-CoV-2 RNA is detectable for at least seven days. This indicates that dilution of wastewater likely limits environmental transmission, and that detection of viral RNA alone is not an indication of pathogen spillover.

  • Journal article
    Zhu Z, Wang H, Harrison SP, Prentice IC, Qiao S, Tan Set al., 2022,

    Optimality principles explaining divergent responses of alpine vegetation to environmental change

    , Global Change Biology, ISSN: 1354-1013
  • Journal article
    Mullish BH, Martinez Gili L, Chekmeneva E, Dos Santos Correia GDS, Lewis MR, Horneffer-van der Sluis V, Roberts LA, McDonald JAK, Pechlivanis A, Walters JRF, McClure EL, Marchesi JR, Allegretti JRet al., 2022,

    Assessing the clinical value of faecal bile acid profiling to predict recurrence in primary Clostridioides difficile infection

    , Alimentary Pharmacology and Therapeutics, ISSN: 0269-2813
  • Journal article
    Vincent CM, Beckwith EJ, Simoes da Silva CJ, Pearson WH, Kierdorf K, Gilestro GF, Dionne MSet al., 2022,

    Infection increases activity via Toll dependent and independent mechanisms in Drosophila melanogaster.

    , PLoS Pathog, Vol: 18

    Host behavioural changes are among the most apparent effects of infection. 'Sickness behaviour' can involve a variety of symptoms, including anorexia, depression, and changed activity levels. Here, using a real-time tracking and behavioural profiling platform, we show that in Drosophila melanogaster, several systemic bacterial infections cause significant increases in physical activity, and that the extent of this activity increase is a predictor of survival time in some lethal infections. Using multiple bacteria and D. melanogaster immune and activity mutants, we show that increased activity is driven by at least two different mechanisms. Increased activity after infection with Micrococcus luteus, a Gram-positive bacterium rapidly cleared by the immune response, strictly requires the Toll ligand spätzle. In contrast, increased activity after infection with Francisella novicida, a Gram-negative bacterium that cannot be cleared by the immune response, is entirely independent of both Toll and the parallel IMD pathway. The existence of multiple signalling mechanisms by which bacterial infections drive increases in physical activity implies that this effect may be an important aspect of the host response.

  • Journal article
    Fu Z, Ciais P, Feldman A, Gentine P, Makowski D, Prentice IC, Stoy PC, Bastos A, Wigneron J-Pet al., 2022,

    Critical soil moisture thresholds of plant water stress in terrestrial cosystems

    , Science Advances, ISSN: 2375-2548

    Plant water stress occurs at the point when soil moisture (SM) limits transpiration, defining a critical SM threshold (θcrit). Knowledge of the spatial distribution of θcrit is crucial for future projections of climate and water resources. Here, we use global eddy-covariance observations to quantify θcrit and evaporative fraction (EF) regimes. Three canonical variables describe how EF is controlled by SM: the maximum EF (EFmax), θcrit, and slope (S) between EF and SM. We find systematic differences of these three variables across biomes. Variation in θcrit, S, and EFmax is mostly explained by soil texture, vapor pressure deficit and precipitation, respectively, as well as vegetation structure. Dryland ecosystems tend to operate at low θcrit and show adaptation to water deficits. The negative relationship between θcrit and S indicates that dryland ecosystems minimize θcrit through mechanisms of sustained SM extraction and transport by xylem. Our results further suggest an optimal adaptation of local EF–SM response, that maximizes growing-season evapotranspiration and photosynthesis.

  • Journal article
    Wu G, Grassi P, MacIntyre D, Molina BG, Sykes L, Kundu S, Hsiao C-T, Khoo K-H, Bennett P, Dell A, Haslam Set al., 2022,

    N-Glycosylation of cervicovaginal fluid reflects microbial community, immune activity, and pregnancy status

    , Scientific Reports, ISSN: 2045-2322

    Human cervicovaginal fluid (CVF) is a complex, functionally important and glycan rich biological fluid, fundamental in mediating physiological events associated with reproductive health. Using a comprehensive glycomic strategy we reveal an extremely rich and complex N-glycome in CVF of pregnant and non-pregnant women, abundant in paucimannose and highmannose glycans, complex glycans with 2-4 N-Acetyllactosamine (LacNAc) antennae, and Poly-LacNAc glycans decorated with fucosylation and sialylation. N-glycosylation variations were observed to differ in relation to pregnancy status, microbial composition, immune activation, and pregnancy outcome. Compared to CVF from women experiencing term birth, CVF from women who subsequently experienced preterm birth showed lower sialylation, which correlated to the presence of a diverse microbiome, and higher fucosylation, which correlated positively to pro-inflammatory cytokine concentration. This study is the first step towards better understanding the role of cervicovaginal glycans in reproductive health, their contribution to the mechanism of microbial driven preterm birth, and their potential forpreventative therapy.

  • Journal article
    Kreutzberger MAB, Sonani RR, Liu J, Chatterjee S, Wang F, Sebastian AL, Biswas P, Ewing C, Zheng W, Poly F, Frankel G, Luisi BF, Calladine CR, Krupovic M, Scharf BE, Egelman EHet al., 2022,

    Convergent evolution in the supercoiling of prokaryotic flagellar filaments.

    , Cell, Vol: 185, Pages: 3487-3500.e14

    The supercoiling of bacterial and archaeal flagellar filaments is required for motility. Archaeal flagellar filaments have no homology to their bacterial counterparts and are instead homologs of bacterial type IV pili. How these prokaryotic flagellar filaments, each composed of thousands of copies of identical subunits, can form stable supercoils under torsional stress is a fascinating puzzle for which structural insights have been elusive. Advances in cryoelectron microscopy (cryo-EM) make it now possible to directly visualize the basis for supercoiling, and here, we show the atomic structures of supercoiled bacterial and archaeal flagellar filaments. For the bacterial flagellar filament, we identify 11 distinct protofilament conformations with three broad classes of inter-protomer interface. For the archaeal flagellar filament, 10 protofilaments form a supercoil geometry supported by 10 distinct conformations, with one inter-protomer discontinuity creating a seam inside of the curve. Our results suggest that convergent evolution has yielded stable superhelical geometries that enable microbial locomotion.

  • Journal article
    Wong J, David S, Sanchez Garrido J, Woo J, Low WW, Morecchiato F, Giani T, Rossolini GM, Beis K, Brett S, Clements A, Aaenensen D, Rouskin S, Frankel Get al., 2022,

    Recurrent emergence of Klebsiella pneumoniae carbapenem resistance mediated by an inhibitory ompK36 mRNA secondary structure

    , Proceedings of the National Academy of Sciences of USA, Vol: 119, Pages: 1-12, ISSN: 0027-8424

    Outer membrane porins in Gram-negative bacteria facilitate antibiotic influx. In Klebsiella pneumoniae (KP), modifications in the porin OmpK36 are implicated in increasing resistance to carbapenems. Analysis of large KP genome collections, encompassing major healthcare-associated clones, revealed the recurrent emergence of a synonymous cytosine to thymine transition at position 25 (25c>t) in ompK36. We show that the 25c>t transition increases carbapenem resistance through depletion of OmpK36 from the outer membrane. The mutation attenuates KP in a murine pneumonia model, which accounts for its limited clonal expansion observed by phylogenetic analysis. However, in the context of carbapenem treatment, the 25c>t transition tips the balance towards treatment failure, thus accounting for its recurrent emergence. Mechanistically, the 25c>t transition mediates an intramolecular mRNA interaction between a uracil encoded by 25t and the first adenine within the Shine-Dalgarno sequence. This specific interaction leads to the formation of an RNA stem structure, which obscures the ribosomal binding site thus disrupting translation. While mutations reducing OmpK36 expression via transcriptional silencing are known, we uniquely demonstrate the repeated selection of a synonymous ompK36 mutation mediating translational suppression in response to antibiotic pressure.

  • Journal article
    Maree JP, Tvardovskiy A, Ravnsborg T, Jensen ON, Rudenko G, Patterton H-Get al., 2022,

    Trypanosoma brucei histones are heavily modified with combinatorial post-translational modifications and mark Pol II transcription start regions with hyperacetylated H2A

  • Journal article
    Weng Y, Shepherd D, Liu Y, Krishnan N, Robertson BD, Platt N, Larrouy-Maumus G, Platt FMet al., 2022,

    Inhibition of the Niemann-Pick C1 protein is a conserved feature of multiple strains of pathogenic mycobacteria

    , Nature Communications, Vol: 13, Pages: 1-16, ISSN: 2041-1723

    Mycobacterium tuberculosis (Mtb) survives and replicates within host macrophages (MΦ) and subverts multiple antimicrobial defense mechanisms. Previously, we reported that lipids shed by pathogenic mycobacteria inhibit NPC1, the lysosomal membrane protein deficient in the lysosomal storage disorder Niemann-Pick disease type C (NPC). Inhibition of NPC1 leads to a drop in lysosomal calcium levels, blocking phagosome-lysosome fusion leading to mycobacterial survival. We speculated that the production of specific cell wall lipid(s) that inhibit NPC1 could have been a critical step in the evolution of pathogenicity. We therefore investigated whether lipid extracts from clinical Mtb strains from multiple Mtb lineages, Mtb complex (MTBC) members and non-tubercular mycobacteria (NTM) inhibit the NPC pathway. We report that inhibition of the NPC pathway was present in all clinical isolates from Mtb lineages 1, 2, 3 and 4, Mycobacterium bovis and the NTM, Mycobacterium abscessus and Mycobacterium avium. However, lipid extract from Mycobacterium canettii, which is considered to resemble the common ancestor of the MTBC did not inhibit the NPC1 pathway. We conclude that the evolution of NPC1 inhibitory mycobacterial cell wall lipids evolved early and post divergence from Mycobacterium canettii-related mycobacteria and that this activity contributes significantly to the promotion of disease.

  • Journal article
    Kotta-Loizou I, 2022,

    Molecular origins of transcriptional heterogeneity in diazotrophic Klebsiella oxytoca

    , mSystems, ISSN: 2379-5077

    Phenotypic heterogeneity in clonal bacterial batch cultures has been shown for a range of bacterial systems; however, the molecular origins of such heterogeneity and its magnitude are not well understood. Under conditions of extreme low-nitrogen stress in the model diazotroph Klebsiella oxytoca, we found remarkably high heterogeneity of nifHDK gene expression, which codes for the structural genes of nitrogenase, one key enzyme of the global nitrogen cycle. This heterogeneity limited the bulk observed nitrogen-fixing capacity of the population. Using dual-probe, single-cell RNA fluorescent in situ hybridization, we correlated nifHDK expression with that of nifLA and glnK-amtB, which code for the main upstream regulatory components. Through stochastic transcription models and mutual information analysis, we revealed likely molecular origins for heterogeneity in nitrogenase expression. In the wild type and regulatory variants, we found that nifHDK transcription was inherently bursty, but we established that noise propagation through signaling was also significant. The regulatory gene glnK had the highest discernible effect on nifHDK variance, while noise from factors outside the regulatory pathway were negligible. Understanding the basis of inherent heterogeneity of nitrogenase expression and its origins can inform biotechnology strategies seeking to enhance biological nitrogen fixation. Finally, we speculate on potential benefits of diazotrophic heterogeneity in natural soil environments.

  • Journal article
    Chen JM, Wang R, Liu Y, He L, Croft H, Luo X, Wang H, Smith NG, Keenan TF, Prentice IC, Zhang Y, Ju W, Dong Net al., 2022,

    Global datasets of leaf photosynthetic capacity for ecological and earth system research

    , Earth System Science Data, Vol: 14, Pages: 4077-4093, ISSN: 1866-3508

    The maximum rate of Rubisco carboxylation (Vcmax) determines leaf photosynthetic capacity and is a keyparameter for estimating the terrestrial carbon cycle, but its spatial information is lacking, hindering global ecologicalresearch. Here, we convert leaf chlorophyll content (LCC) retrieved from satellite data to Vcmax, based on plants’ optimaldistribution of nitrogen between light harvesting and carboxylation pathways. We also derive Vcmax from satellite (GOME-2)observations of sun-induced chlorophyll fluorescence (SIF) as a proxy of leaf photosynthesis using a data assimilationtechnique. These two independent global Vcmax products agree well (r2=0.79, RMSE=15.46 μmol m-2s-1 25 , P<0.001) andcompare well with 3672 ground-based measurements (r2=0.68, RMSE=13.55 μmol m-2s-1and P<0.001 for SIF; r2=0.55,RMSE=17.55 μmol m-2s-1 and P<0.001 for LCC). The LCC-derived Vcmax product is also used to constrain the retrieval ofVcmax from TROPOMI SIF data to produce an optimized Vcmax product using both SIF and LCC information. The globaldistributions of these products are compatible with Vcmax computed from an ecological optimality theory using meteorological variables, but importantly reveal additional information on the influence of land cover, irrigation, soil pH andleaf nitrogen on leaf photosynthetic capacity. These satellite-based approaches and spatial Vcmax products are primed to play amajor role in global ecosystem research. The three remote sensing Vcmax products based on SIF, LCC and SIF+LCC areavailable at (Chen et al., 2020) and the code for implementing the ecologicaloptimality theory is available at (Smith, 2020).

  • Journal article
    Langley J, Purchase R, Viola S, Fantuzzi A, Davis GA, Shen J-R, Rutherford AW, Krausz E, Cox Net al., 2022,

    <b>Simulating the low-temperature, metastable electrochromism of Photosystem I: </b><b>Applications to <i>Thermosynechococcus vulcanus </i>and<i> Chroococcidiopsis thermalis</i></b>

    , The Journal of Chemical Physics, ISSN: 0021-9606

    <jats:p> Low-temperature, metastable electrochromism has been used as a tool to assign pigments in Photosystem I (PS I) from Thermosynechococcus vulcanus and both the white light (WL) and far-red light (FRL) forms of Chroococcidiopsis thermalis. We find a minimum of seven pigments is required to satisfactorily model the electrochromism of PS I. Using our model, we provide a short list of candidates for the chlorophyll f pigment in FRL C. thermalis that absorbs at 756 nm, whose identity to date has proven to be controversial. Specifically, we propose the linker pigments A40 and B39, and two antenna pigments A26 and B24 as defined by crystal structure 1JB0. The pros and cons of these assignments are discussed, and we propose further experiments to better understand the functioning of FRL C. thermalis. </jats:p>

  • Journal article
    Viola S, Roseby W, Santabarbara S, Nürnberg D, Assunção R, Dau H, Sellés J, Boussac A, Fantuzzi A, Rutherford Aet al., 2022,

    Impact of energy limitations on function and resilience in long-wavelength photosystem II

    , eLife, Vol: 11, ISSN: 2050-084X

    Photosystem II (PSII) uses the energy from red light to split water and reduce quinone, an energy-demanding process based on chlorophyll a (Chl-a) photochemistry. Two types of cyanobacterial PSII can use chlorophyll d (Chl-d) and chlorophyll f (Chl-f) to perform the same reactions using lower energy, far-red light. PSII from Acaryochloris marina has Chl-d replacing all but one of its 35 Chl-a, while PSII from Chroococcidiopsis thermalis, a facultative far-red species, has just 4 Chl-f and 1 Chl-d and 30 Chl-a. From bioenergetic considerations, the far-red PSII were predicted to lose photochemical efficiency and/or resilience to photodamage. Here, we compare enzyme turnover efficiency, forward electron transfer, back-reactions and photodamage in Chl-f-PSII, Chl-d-PSII and Chl-a-PSII. We show that: i) all types of PSII have a comparable efficiency in enzyme turnover; ii) the modified energy gaps on the acceptor side of Chl-d-PSII favour recombination via PD1+Phe- repopulation, leading to increased singlet oxygen production and greater sensitivity to high-light damage compared to Chl-a-PSII and Chl-f-PSII; iii) the acceptor-side energy gaps in Chl-f-PSII are tuned to avoid harmful back reactions, favouring resilience to photodamage over efficiency of light usage. The results are explained by the differences in the redox tuning of the electron transfer cofactors Phe and QA and in the number and layout of the chlorophylls that share the excitation energy with the primary electron donor. PSII has adapted to lower energy in two distinct ways, each appropriate for its specific environment but with different functional penalties.

  • Journal article
    Cheng S, Prentice IC, Huang Y, Jin Y, Guo Y-K, Arcucci Ret al., 2022,

    Data-driven surrogate model with latent data-assimilation: application to wildfire forecasting

    , Journal of Computational Physics, Vol: 464, ISSN: 0021-9991

    The large and catastrophic wildfires have been increasing across the globe in the recent decade, highlighting the importance of simulating and forecasting fire dynamics in near real-time. This is extremely challenging due to the complexities of physical models and geographical features. Running physics-based simulations for large wildfire events in near real-time are computationally expensive, if not infeasible. In this work, we develop and test a novel data-model integration scheme for fire progression forecasting, that combines Reduced-order modelling, recurrent neural networks (Long-Short-Term Memory), data assimilation, and error covariance tuning. The Reduced-order modelling and the machine learning surrogate model ensure the efficiency of the proposed approach while the data assimilation enables the system to adjust the simulation with observations. We applied this algorithm to simulate and forecast three recent large wildfire events in California from 2017 to 2020. The deep-learning-based surrogate model runs around 1000 times faster than the Cellular Automata simulation which is used to generate training data-sets. The daily fire perimeters derived from satellite observation are used as observation data in Latent Assimilation to adjust the fire forecasting in near real-time. An error covariance tuning algorithm is also performed in the reduced space to estimate prior simulation and observation errors. The evolution of the averaged relative root mean square error (R-RMSE) shows that data assimilation and covariance tuning reduce the RMSE by about 50% and considerably improves the forecasting accuracy. As a first attempt at a reduced order wildfire spread forecasting, our exploratory work showed the potential of data-driven machine learning models to speed up fire forecasting for various applications.

  • Conference paper
    Rutherford WA, Viola S, Davis G, Fantuzzi Aet al., 2022,

    Photosystem II bioenergetics: redox tuning, the red limit and beyond

    , Publisher: ELSEVIER, Pages: 3-4, ISSN: 0005-2728
  • Journal article
    Lawson J, Whitworth A, Banks-Leite C, 2022,

    Soundscapes show disruption across the diel cycle in human modified tropical landscapes

    , Ecological Indicators, ISSN: 1470-160X

    1. Fluctuations in the diel cycle, especially when compared across different land-use types, can reveal key changes in acoustic activity and the biological community. Yet few studies have assessed the effects of land use change on soundscapes across the diel cycle. The emergence of passive acoustic monitoring (PAM) allows us to monitor landscapes over longer and continuous periods, providing data on temporal variability across the diel cycle.2. Using AudioMoth acoustic recorders we collected data at 120 sites on the Osa Peninsula, Costa Rica, across a gradient of land use intensity. Information was extracted from recordings using a suite of nine acoustic indices. Principal component analysis reduced the indices into two axes, the first reflecting acoustic activity in the mid frequency bands, where the majority of biotic sound is present, and the second, representing acoustic activity in the upper frequency bands and the ratio of activity between the lower and mid-frequency bands.3. In disturbed land use types we found reduced acoustic activity during the characteristic dawn and dusk peaks in the diel cycle; known as the dawn and dusk chorus. Palm oil plantations showed a complete loss of these peaks, while teak plantations retained evidence of a weaker dawn and dusk chorus. Restricting the analysis to narrower temporal windows masks these differences among habitats.4. Synthesis and applications. Evaluating acoustic diversity at specific times of the day, which is common practice in bioacoustics studies, may be misleading, as pronounced changes in acoustic activity at dawn and duskwere obscured. By assessing trends across the diel cycle, we can gain a much better representation of the changes in acoustic activity. Our results show that in disturbed ecosystems there is a deviation in acoustic activity from that seen in a healthy native forest ecosystem, suggesting that there are likely changes within the biotic community in these ecosystems.

  • Conference paper
    Viola S, Roseby W, Santabarabara S, Nurnberg D, Assuncao R, Dau H, Selles J, Boussac A, Fantuzzi A, Rutherford AWet al., 2022,

    Abstract The energetics of the two types of far-red Photosystem II

    , Publisher: ELSEVIER, Pages: 81-81, ISSN: 0005-2728
  • Journal article
    Dong N, Wright IJ, Chen JM, Luo X, Wang H, Keenan T, Smith NG, Prentice ICet al., 2022,

    Rising CO2 and warming reduce global canopy deman for nitrogen

    , New Phytologist, Vol: 235, Pages: 1692-1700, ISSN: 0028-646X

    Nitrogen (N) limitation has been considered as a constraint on terrestrial carbon uptake in response to rising CO2 and climate change. By extension, it has been suggested that declining carboxylation capacity (Vcmax) and leaf N content in enhanced-CO2 experiments and satellite records signify increasing N limitation of primary production. We predicted Vcmax using the coordination hypothesis, and estimated changes in leaf-level photosynthetic N for 1982–2016 assuming proportionality with leaf-level Vcmax at 25˚C. Whole-canopy photosynthetic N was derived using satellite-based leaf area index (LAI) data and an empirical extinction coefficient for Vcmax, and converted to annual N demand using estimated leaf turnover times. The predicted spatial pattern of Vcmax shares key features with an independent reconstruction from remotely-sensed leaf chlorophyll content. Predicted leaf photosynthetic N declined by 0.27 % yr-1, while observed leaf (total) N declined by 0.2–0.25 % yr-1. Predicted global canopy N (and N demand) declined from 1996 onwards, despite increasing LAI. Leaf-level responses to rising CO2, and to a lesser extent temperature, may have reduced the canopy requirement for N by more than rising LAI has increased it. This finding provides an alternative explanation for declining leaf N that does not depend on increasing N limitation.

  • Journal article
    Liu M, Prentice IC, Menviel L, Harrison SPet al., 2022,

    Past rapid warmings as a constraint on greenhouse-gas climate feedbacks

    , Communications Earth & Environment, Vol: 3, ISSN: 2662-4435

    There are large uncertainties in the estimation of greenhouse-gas climate feedback. Recent observations do not provide strong constraints because they are short and complicated by human interventions, while model-based estimates differ considerably. Rapid climate changes during the last glacial period (Dansgaard-Oeschger events), observed near-globally, were comparable in both rate and magnitude to current and projected 21st century climate warming and therefore provide a relevant constraint on feedback strength. Here we use these events to quantify the centennial-scale feedback strength of CO2, CH4 and N2O by relating global mean temperature changes, simulated by an appropriately forced low-resolution climate model, to the radiative forcing of these greenhouse gases derived from their concentration changes in ice-core records. We derive feedback estimates (expressed as dimensionless gain) of 0.14 ± 0.04 for CO2, 0.10 ± 0.02 for CH4, and 0.09 ± 0.03 for N2O. This indicates that much lower or higher estimates of gains, particularly some previously published values for CO2, are unrealistic.

  • Journal article
    Kolli SK, Molina-Cruz A, Araki T, Geurten FJA, Ramesar J, Chevalley-Maurel S, Kroeze HJ, Bezemer S, de Korne C, Withers R, Raytselis N, El Hebieshy AF, Kim RQ, Child MA, Kakuta S, Hisaeda H, Kobayashi H, Annoura T, Hensbergen PJ, Franke-Fayard BM, Barillas-Mury C, Scheeren FA, Janse CJet al., 2022,

    Malaria parasite evades mosquito immunity by glutaminyl cyclase-mediated posttranslational protein modification.

    , Proc Natl Acad Sci U S A, Vol: 119

    Glutaminyl cyclase (QC) modifies N-terminal glutamine or glutamic acid residues of target proteins into cyclic pyroglutamic acid (pGlu). Here, we report the biochemical and functional analysis of Plasmodium QC. We show that sporozoites of QC-null mutants of rodent and human malaria parasites are recognized by the mosquito immune system and melanized when they reach the hemocoel. Detailed analyses of rodent malaria QC-null mutants showed that sporozoite numbers in salivary glands are reduced in mosquitoes infected with QC-null or QC catalytically dead mutants. This phenotype can be rescued by genetic complementation or by disrupting mosquito melanization or phagocytosis by hemocytes. Mutation of a single QC-target glutamine of the major sporozoite surface protein (circumsporozoite protein; CSP) of the rodent parasite Plasmodium berghei also results in melanization of sporozoites. These findings indicate that QC-mediated posttranslational modification of surface proteins underlies evasion of killing of sporozoites by the mosquito immune system.

  • Journal article
    Hamilton C, Olona A, Leishman S, MacDonald-Ramsahai K, Cockcroft S, Larrouy-Maumus G, Anand Pet al., 2022,

    NLRP3 inflammasome priming and activation are regulated by a phosphatidylinositol-dependent mechanism

    , ImmunoHorizons, Vol: 6, ISSN: 2573-7732

    Imbalance in lipid homeostasis is associated with discrepancies in immune signaling and is tightly linked to metabolic disorders. The diverse ways in which lipids impact immune signaling, however, remain ambiguous. The phospholipid phosphatidylinositol (PI), which is implicated in numerous immune disorders, is chiefly defined by its phosphorylation status. By contrast, the significance of the two fatty acid chains attached to the PI remains unknown. Here, by employing a mass-spectrometry-based assay, we demonstrate a role for PI acyl group chains in regulating both the priming and activation steps of the NLRP3 inflammasome in mouse macrophages. In response to NLRP3 stimuli, cells deficient in ABC transporter ABCB1, which effluxes lipid derivatives, revealed defective inflammasome activation. Mechanistically, Abcb1-deficiency shifted the total PI configuration exhibiting a reduced ratio of short-chain to long-chain PI acyl lipids. Consequently, Abcb1-deficiency initiated the rapid degradation of TIRAP, the TLR adaptor protein which binds PI (4,5)-bisphosphate, resulting in defective TLR-dependent signaling, and thus NLRP3 expression. Moreover, this accompanied increased NLRP3 phosphorylation at the Ser291 position and contributed to blunted inflammasome activation. Exogenously supplementing WT cells with linoleic acid, but not arachidonic acid, reconfigured PI acyl chains. Accordingly, linoleic acid supplementation increased TIRAP degradation, elevated NLRP3 phosphorylation, and abrogated inflammasome activation. Furthermore, NLRP3 Ser291 phosphorylation was dependent on prostaglandin E2-induced protein kinase A signaling as pharmacological inhibition of this pathway in linoleic acid-enriched cells dephosphorylated NLRP3. Altogether, our study reveals a novel metabolic-inflammatory circuit which contributes to calibrating immune responses.

  • Journal article
    Herisson J, Duigou T, du Lac M, Bazi-Kabbaj K, Azad MS, Buldum G, Telle O, El Moubayed Y, Carbonell P, Swainston N, Zulkower V, Kushwaha M, Baldwin GS, Faulon J-Let al., 2022,

    The automated Galaxy-SynBioCAD pipeline for synthetic biology design and engineering

  • Journal article
    Pizzato J, Tang W, Bernabeu S, Bonnin RA, Bille E, Farfour E, Guillard T, Barraud O, Cattoir V, Plouzeau C, Corvec S, Shahrezaei V, Dortet L, Larrouy-Maumus Get al., 2022,

    Discrimination of Escherichia coli, Shigella flexneri, and Shigella sonnei using lipid profiling by MALDI-TOF mass spectrometry paired with machine learning

    , MICROBIOLOGYOPEN, Vol: 11, ISSN: 2045-8827
  • Journal article
    Boeck L, Burbaud S, Skwark M, Pearson WH, Sangen J, Wuest AW, Marshall EKP, Weimann A, Everall I, Bryant JM, Malhotra S, Bannerman BP, Kierdorf K, Blundell TL, Dionne MS, Parkhill J, Floto RAet al., 2022,

    Mycobacterium abscessus pathogenesis identified by phenogenomic analyses

    , NATURE MICROBIOLOGY, Vol: 7, Pages: 1431-+, ISSN: 2058-5276
  • Journal article
    Wang G, Brunel J-M, Preusse M, Mozaheb N, Willger SD, Larrouy-Maumus G, Baatsen P, Haeussler S, Bolla J-M, Van Bambeke Fet al., 2022,

    The membrane-active polyaminoisoprenyl compound NV716 re-sensitizes Pseudomonas aeruginosa to antibiotics and reduces bacterial virulence

  • Journal article
    Pondeville E, Failloux A-B, Simard F, Volf P, Crisanti A, Haghighat-Khah RE, Busquets N, Abad FX, Wilson AJ, Bellini R, Arnaud SM, Kohl A, Veronesi Eet al., 2022,

    Infravec2 guidelines for the design and operation of containment level 2 and 3 insectaries in Europe

    , Pathogens and Global Health, ISSN: 2047-7724

    With the current expansion of vector-based research and an increasing number of facilitiesrearing arthropod vectors and infecting them with pathogens, common measures for containment of arthropods as well as manipulation of pathogens are becoming essential for the designand running of such research facilities to ensure safe work and reproducibility, withoutcompromising experimental feasibility. These guidelines and comments were written byexperts of the Infravec2 consortium, a Horizon 2020-funded consortium integrating the mostsophisticated European infrastructures for research on arthropod vectors of human and animaldiseases. They reflect current good practice across European laboratories with experience ofsafely handling different mosquito species and the pathogens they transmit. As such, theyprovide experience-based advice to assess and manage the risks to work safely with mosquitoes and the pathogens they transmit. This document can also form the basis for research withother arthropods, for example, midges, ticks or sandflies, with some modification to reflectspecific requirements.

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