Role of lysozyme inhibitors in the virulence of avian pathogenic Escherichia coli

Lysozymes are key effectors of the animal innate immunity system that kill bacteria by hydrolyzing peptidoglycan, their major cell wall constituent. Recently, specific inhibitors of the three major lysozyme families occuring in the animal kingdom (c-, g- and i-type) have been discovered in Gram-negative bacteria, and it has been proposed that these may help bacteria to evade lysozyme mediated lysis during interaction with an animal host. Escherichia coli produces two inhibitors that are specific for c-type lysozyme (Ivy, Inhibitor of vertebrate lysozyme; MliC, membrane bound lysozyme inhibitor of c-type lysozyme), and one specific for g-type lysozyme (PliG, periplasmic lysozyme inhibitor of g-type lysozyme). Here, we investigated the role of these lysozyme inhibitors in virulence of Avian Pathogenic E. coli (APEC) using a serum resistance test and a subcutaneous chicken infection model. Knock-out of mliC caused a strong reduction in serum resistance and in in vivo virulence that could be fully restored by genetic complementation, whereas ivy and pliG could be knocked out without effect on serum resistance and virulence. This is the first in vivo evidence for the involvement of lysozyme inhibitors in bacterial virulence. Remarkably, the virulence of a ivy mliC double knock-out strain was restored to almost wild-type level, and this strain also had a substantial residual periplasmic lysozyme inhibitory activity that was higher than that of the single knock-out strains. This suggests the existence of an additional periplasmic lysozyme inhibitor in this strain, and indicates a regulatory interaction in the expression of the different inhibitors

Possible role of anthropogenic climate change in the record-breaking 2020 Lake Victoria levels and floods

Heavy rainfall in eastern Africa between late 2019 and mid 2020 caused devastating floods and landslides throughout the region. These rains drove the levels of Lake Victoria to a record-breaking maximum in the second half of May 2020. The combination of high lake levels, consequent shoreline flooding, and flooding of tributary rivers caused hundreds of casualties and damage to housing, agriculture, and infrastructure in the riparian countries of Uganda, Kenya, and Tanzania. Media and government reports linked the heavy precipitation and floods to anthropogenic climate change, but a formal scientific attribution study has not been carried out so far. In this study, we characterize the spatial extent and impacts of the floods in the Lake Victoria basin and then investigate to what extent human-induced climate change influenced the probability and magnitude of the record-breaking lake levels and associated flooding by applying a multi-model extreme event attribution methodology. Using remote-sensing-based flood mapping tools, we find that more than 29 000 people living within a 50 km radius of the lake shorelines were affected by floods between April and July 2020. Precipitation in the basin was the highest recorded in at least 3 decades, causing lake levels to rise by 1.21 m between late 2019 and mid 2020. The flood, defined as a 6-month rise in lake levels as extreme as that observed in the lead-up to May 2020, is estimated to be a 63-year event in the current climate. Based on observations and climate model simulations, the best estimate is that the event has become more likely by a factor of 1.8 in the current climate compared to a pre-industrial climate and that in the absence of anthropogenic climate change an event with the same return period would have led lake levels to rise by 7 cm less than observed. Nonetheless, uncertainties in the attribution statement are relatively large due to large natural variability and include the possibility of no observed attributable change in the probability of the event (probability ratio, 95 % confidence interval 0.8–15.8) or in the magnitude of lake level rise during an event with the same return period (magnitude change, 95 % confidence interval 0–14 cm). In addition to anthropogenic climate change, other possible drivers of the floods and their impacts include human land and water management, the exposure and vulnerability of settlements and economic activities located in flood-prone areas, and modes of climate variability that modulate seasonal precipitation. The attribution statement could be strengthened by using a larger number of climate model simulations, as well as by quantitatively accounting for non-meteorological drivers of the flood and potential unforced modes of climate variability. By disentangling the role of anthropogenic climate change and natural variability in the high-impact 2020 floods in the Lake Victoria basin, this paper contributes to a better understanding of changing hydrometeorological extremes in eastern Africa and the African Great Lakes region.</p

Modelling the water balance of Lake Victoria (East Africa) – Part 1: Observational analysis

Lake Victoria is the largest lake in Africa and one of the two major sources of the Nile river. The water level of Lake Victoria is determined by its water balance, consisting of precipitation on the lake, evaporation from the lake, inflow from tributary rivers and lake outflow, controlled by two hydropower dams. Due to a scarcity of in situ observations, previous estimates of individual water balance terms are characterized by substantial uncertainties, which means that the water balance is often not closed independently. In this first part of a two-paper series, we present a water balance model for Lake Victoria, using state-of-the-art remote sensing observations, high-resolution reanalysis downscaling and outflow values recorded at the dam. The uncalibrated computation of the individual water balance terms yields lake level fluctuations that closely match the levels retrieved from satellite altimetry. Precipitation is the main cause of seasonal and interannual lake level fluctuations, and on average causes the lake level to rise from May to July and to fall from August to December. Finally, our results indicate that the 2004–2005 drop in lake level can be about half attributed to a drought in the Lake Victoria Basin and about half to an enhanced outflow, highlighting the sensitivity of the lake level to human operations at the outflow dam.</p

Modelling the water balance of Lake Victoria (East Africa) – Part 2: Future projections

Lake Victoria, the second largest freshwater lake in the world, is one of the major sources of the Nile river. The outlet to the Nile is controlled by two hydropower dams of which the allowed discharge is dictated by the Agreed Curve, an equation relating outflow to lake level. Some regional climate models project a decrease in precipitation and an increase in evaporation over Lake Victoria, with potential important implications for its water balance and resulting level. Yet, little is known about the potential consequences of climate change for the water balance of Lake Victoria. In this second part of a two-paper series, we feed a new water balance model for Lake Victoria presented in the first part with climate simulations available through the COordinated Regional Climate Downscaling Experiment (CORDEX) Africa framework. Our results reveal that most regional climate models are not capable of giving a realistic representation of the water balance of Lake Victoria and therefore require bias correction. For two emission scenarios (RCPs 4.5 and 8.5), the decrease in precipitation over the lake and an increase in evaporation are compensated by an increase in basin precipitation leading to more inflow. The future lake level projections show that the dam management scenario and not the emission scenario is the main controlling factor of the future water level evolution. Moreover, inter-model uncertainties are larger than emission scenario uncertainties. The comparison of four idealized future management scenarios pursuing certain policy objectives (electricity generation, navigation reliability and environmental conservation) uncovers that the only sustainable management scenario is mimicking natural lake level fluctuations by regulating outflow according to the Agreed Curve. The associated outflow encompasses, however, ranges from 14&thinsp;m3&thinsp;day−1 (−85&thinsp;%) to 200&thinsp;m3&thinsp;day−1 (+100&thinsp;%) within this ensemble, highlighting that future hydropower generation and downstream water availability may strongly change in the next decades even if dam management adheres to he Agreed Curve. Our results overall underline that managing the dam according to the Agreed Curve is a key prerequisite for sustainable future lake levels, but that under this management scenario, climate change might potentially induce profound changes in lake level and outflow volume.</p

The non-perturbative groundstate of Q.C.D and the local composite operator A_mu^2

We investigate the possibility that the dimension 2 condensate A_mu^2 has a non zero non-perturbative value in Yang-Mills theory. We introduce a multiplicatively renormalisable effective potential for this condensate and show through two loop calculations that a non zero condensate is energetically favoured.Comment: 12 page

Attribution of global lake systems change to anthropogenic forcing

Lake ecosystems are jeopardized by the impacts of climate change on ice seasonality and water temperatures. Yet historical simulations have not been used to formally attribute changes in lake ice and temperature to anthropogenic drivers. In addition, future projections of these properties are limited to individual lakes or global simulations from single lake models. Here we uncover the human imprint on lakes worldwide using hindcasts and projections from five lake models. Reanalysed trends in lake temperature and ice cover in recent decades are extremely unlikely to be explained by pre-industrial climate variability alone. Ice-cover trends in reanalysis are consistent with lake model simulations under historical conditions, providing attribution of lake changes to anthropogenic climate change. Moreover, lake temperature, ice thickness and duration scale robustly with global mean air temperature across future climate scenarios (+0.9 °C °Cair–1, –0.033 m °Cair–1 and –9.7 d °Cair–1, respectively). These impacts would profoundly alter the functioning of lake ecosystems and the services they provide

Clinical characteristics of depressive episodes in Bipolar I and Bipolar II disorders

peer reviewe

Zilucoplan in immune-mediated necrotising myopathy: a phase 2, randomised, double-blind, placebo-controlled, multicentre trial

BACKGROUND: Immune-mediated necrotising myopathy is an autoimmune myopathy characterised by proximal muscle weakness, high creatine kinase concentrations, and autoantibodies recognising 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) or the signal recognition particle (SRP). No approved therapies exist for people with immune-mediated necrotising myopathy. Previous studies have suggested that complement activation might be pathogenic in immune-mediated necrotising myopathy; therefore, zilucoplan, a complement C5 (C5) inhibitor, could be a potential therapy. We aimed to evaluate the efficacy, safety, and tolerability of zilucoplan in adult participants with anti-HMGCR or anti-SRP autoantibody-positive immune-mediated necrotising myopathy. METHODS: IMNM-01 was a phase 2, multicentre, randomised, double-blind, placebo-controlled study done at 15 hospital sites across the USA, the UK, France, and the Netherlands. Participants aged 18–74 years were eligible for inclusion if they had a clinically confirmed diagnosis of immune-mediated necrotising myopathy, positive serology for anti-HMGCR or anti-SRP autoantibodies, clinical evidence of weakness, serum total creatine kinase concentration of more than 1000 U/L at screening, and no change in glucocorticoids or other immunosuppressive therapies for 30 days before baseline or expected during the first 8 weeks of the study. Participants were randomly assigned (1:1) to receive daily subcutaneous zilucoplan (0·3 mg/kg) or placebo for 8 weeks by use of a computerised randomisation algorithm; with optional enrolment in the study open-label extension. Randomisation was stratified by autoantibody status. Participants and study staff were masked to treatment group assignment. Primary efficacy endpoint (in the intent-to-treat population, defined as all participants who were randomly assigned to a treatment group) was percent change from baseline to week 8 in creatine kinase concentrations. Safety analyses were performed on the safety population (participants who received at least one dose of study drug during the main study, irrespective of whether they continued to the extension period—study participants were analysed on the basis of the treatment received). This study is registered with ClinicalTrials.gov, NCT04025632. FINDINGS: Between Nov 7, 2019, and Jan 7, 2021, we randomly assigned 27 participants (13 female and 14 male) to receive zilucoplan (n=12) or placebo (n=15). All 27 participants completed the 8-week main study. At week 8 there were no significant differences between treatment groups in median percent change of creatine kinase concentrations versus baseline (–15·1% [IQR –31·1 to 3·2] in the zilucoplan group vs –16·3% [–43·8 to 5·9] in the placebo group; p=0·46) and no clinically relevant improvement over time within the treatment group despite target engagement based on mode of action. There were no unexpected adverse safety or tolerability findings. Treatment-emergent adverse events were reported in nine (75%) of 12 participants in the zilucoplan group, and in 13 (87%) of 15 participants in the placebo group, and serious treatment-emergent adverse events were reported in zero participants in the zilucoplan group and three (20%) participants in the placebo group. The most frequent treatment-emergent adverse events were headache (four [33%] participants in the zilucoplan group and four [27%] participants in the placebo group) and nausea (three [25%] participants in the zilucoplan group and three [20%] participants in the placebo group). INTERPRETATION: C5 inhibition does not appear to be an efficacious treatment modality for people with immune-mediated necrotising myopathy. Rather than being the primary driver for disease activity, complement activation might be secondary to muscle injury. FUNDING: Ra Pharmaceuticals (now part of UCB Pharma)

A New Family of Lysozyme Inhibitors Contributing to Lysozyme Tolerance in Gram-Negative Bacteria

Lysozymes are ancient and important components of the innate immune system of animals that hydrolyze peptidoglycan, the major bacterial cell wall polymer. Bacteria engaging in commensal or pathogenic interactions with an animal host have evolved various strategies to evade this bactericidal enzyme, one recently proposed strategy being the production of lysozyme inhibitors. We here report the discovery of a novel family of bacterial lysozyme inhibitors with widespread homologs in gram-negative bacteria. First, a lysozyme inhibitor was isolated by affinity chromatography from a periplasmic extract of Salmonella Enteritidis, identified by mass spectrometry and correspondingly designated as PliC (periplasmic lysozyme inhibitor of c-type lysozyme). A pliC knock-out mutant no longer produced lysozyme inhibitory activity and showed increased lysozyme sensitivity in the presence of the outer membrane permeabilizing protein lactoferrin. PliC lacks similarity with the previously described Escherichia coli lysozyme inhibitor Ivy, but is related to a group of proteins with a common conserved COG3895 domain, some of them predicted to be lipoproteins. No function has yet been assigned to these proteins, although they are widely spread among the Proteobacteria. We demonstrate that at least two representatives of this group, MliC (membrane bound lysozyme inhibitor of c-type lysozyme) of E. coli and Pseudomonas aeruginosa, also possess lysozyme inhibitory activity and confer increased lysozyme tolerance upon expression in E. coli. Interestingly, mliC of Salmonella Typhi was picked up earlier in a screen for genes induced during residence in macrophages, and knockout of mliC was shown to reduce macrophage survival of S. Typhi. Based on these observations, we suggest that the COG3895 domain is a common feature of a novel and widespread family of bacterial lysozyme inhibitors in gram-negative bacteria that may function as colonization or virulence factors in bacteria interacting with an animal host