66 research outputs found
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
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 m3 day−1 (−85 %) to 200 m3 day−1 (+100 %)
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
ID Water Scarcity Synthesis Report: Participatory workshop for the interdisciplinary research on water scarcity and climate change in the Ewaso Ng’iro North River Basin.
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
Heat stored in the Earth system 1960–2020: where does the energy go?
The Earth climate system is out of energy balance, and heat has
accumulated continuously over the past decades, warming the ocean, the land,
the cryosphere, and the atmosphere. According to the Sixth Assessment Report
by Working Group I of the Intergovernmental Panel on Climate Change,
this planetary warming over multiple decades is human-driven and results in
unprecedented and committed changes to the Earth system, with adverse
impacts for ecosystems and human systems. The Earth heat inventory provides
a measure of the Earth energy imbalance (EEI) and allows for quantifying
how much heat has accumulated in the Earth system, as well as where the heat is
stored. Here we show that the Earth system has continued to accumulate
heat, with 381±61 ZJ accumulated from 1971 to 2020. This is equivalent to a
heating rate (i.e., the EEI) of 0.48±0.1 W m−2. The majority,
about 89 %, of this heat is stored in the ocean, followed by about 6 %
on land, 1 % in the atmosphere, and about 4 % available for melting
the cryosphere. Over the most recent period (2006–2020), the EEI amounts to
0.76±0.2 W m−2. The Earth energy imbalance is the most
fundamental global climate indicator that the scientific community and the
public can use as the measure of how well the world is doing in the task of
bringing anthropogenic climate change under control. Moreover, this
indicator is highly complementary to other established ones like global mean
surface temperature as it represents a robust measure of the rate of climate
change and its future commitment. We call for an implementation of the
Earth energy imbalance into the Paris Agreement's Global Stocktake based on
best available science. The Earth heat inventory in this study, updated from
von Schuckmann et al. (2020), is underpinned by worldwide multidisciplinary
collaboration and demonstrates the critical importance of concerted
international efforts for climate change monitoring and community-based
recommendations and we also call for urgently needed actions for enabling
continuity, archiving, rescuing, and calibrating efforts to assure improved
and long-term monitoring capacity of the global climate observing system. The data for the Earth heat inventory are publicly available, and more details are provided in Table 4.</p
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