Sepsis is a systemic host response to invasive infection by bacteria. Despite treatment with antibiotics, current mortality rates are in the range of 20%-25%, which makes sepsis the most important ...cause of death in intensive care. Gram-negative bacteria are a prominent cause of sepsis. Lipopolysaccharide (LPS), one of the major constituents of the outer membrane of Gram-negative bacteria, plays a major role in activating the host's immune response by binding to monocytes and other cells. Several proteins are involved in neutralization and clearance of LPS from the bloodstream. Here, we provide evidence that β2-glycoprotein I (β2GPI) is a scavenger of LPS. In vitro, β2GPI inhibited LPS-induced expression of tissue factor and IL-6 from monocytes and endothelial cells. Binding of β2GPI to LPS caused a conformational change in β2GPI that led to binding of the β2GPI-LPS complex to monocytes and ultimately clearance of this complex. Furthermore, plasma levels of β2GPI were inversely correlated with temperature rise and the response of inflammatory markers after a bolus injection of LPS in healthy individuals. Together, these observations provide evidence that β2GPI is involved in the neutralization and clearance of LPS and identify β2GPI as a component of innate immunity.
Respiratory viral infections are major drivers of chronic obstructive pulmonary disease (COPD) exacerbations. Interferon-β is naturally produced in response to viral infection, limiting replication. ...This exploratory study aimed to demonstrate proof-of-mechanism, and evaluate the efficacy and safety of inhaled recombinant interferon-β1a (SNG001) in COPD. Part 1 assessed the effects of SNG001 on induced sputum antiviral interferon-stimulated gene expression, sputum differential cell count, and respiratory function. Part 2 compared SNG001 and placebo on clinical efficacy, sputum and serum biomarkers, and viral clearance.
In Part 1, patients (N = 13) with stable COPD were randomised 4:1 to SNG001 or placebo once-daily for three days. In Part 2, patients (N = 109) with worsening symptoms and a positive respiratory viral test were randomised 1:1 to SNG001 or placebo once-daily for 14 days in two Groups: A (no moderate exacerbation); B (moderate COPD exacerbation i.e., acute worsening of respiratory symptoms treated with antibiotics and/or oral corticosteroids).
In Part 1, SNG001 upregulated sputum interferon gene expression. In Part 2, there were minimal SNG001-placebo differences in the efficacy endpoints; however, whereas gene expression was initially upregulated by viral infection, then declined on placebo, levels were maintained with SNG001. Furthermore, the proportion of patients with detectable rhinovirus (the most common virus) on Day 7 was lower with SNG001. In Group B, serum C-reactive protein and the proportion of patients with purulent sputum increased with placebo (suggesting bacterial infection), but not with SNG001. The overall adverse event incidence was similar with both treatments.
Overall, SNG001 was well-tolerated in patients with COPD, and upregulated lung antiviral defences to accelerate viral clearance. These findings warrant further investigation in a larger study.
EU clinical trials register (2017-003679-75), 6 October 2017.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Understanding physiological and behavioral mechanisms underlying the diversity of observed life‐history strategies is challenging because of difficulties in obtaining long‐term measures of fitness ...and in relating fitness to these mechanisms. We evaluated effects of experimentally elevated testosterone on male fitness in a population of dark‐eyed juncos studied over nine breeding seasons using a demographic modeling approach. Elevated levels of testosterone decreased survival rates but increased success of producing extra‐pair offspring. Higher overall fitness for testosterone‐treated males was unexpected and led us to consider indirect effects of testosterone on offspring and females. Nest success was similar for testosterone‐treated and control males, but testosterone‐treated males produced smaller offspring, and smaller offspring had lower postfledging survival. Older, more experienced females preferred to mate with older males and realized higher reproductive success when they did so. Treatment of young males increased their ability to attract older females yet resulted in poor reproductive performance. The higher fitness of testosterone‐treated males in the absence of a comparable natural phenotype suggests that the natural phenotype may be constrained. If this phenotype were to arise, the negative social effects on offspring and mates suggest that these effects might prevent high‐testosterone phenotypes from spreading in the population.
On the Sellafield site there are several legacy storage tanks and silos containing sludge of uncertain properties. While there are efforts to determine the chemical and radiological properties of the ...sludge, to clean out and decommission these vessels, the physical properties need to be ascertained as well. Shear behaviour, density and temperature are the key parameters to be understood before decommissioning activities commence. However, limited access, the congested nature of the tanks and presence of radioactive, hazardous substances severely limit sampling and usage of sophisticated characterisation devices within these tanks and therefore, these properties remain uncertain. This paper describes the development of a cheap, compact, and robust device to analyse the rheological properties of sludge, without the need to extract materials from the site in order to be analysed. Analysis of a sludge test material has been performed to create a suitable benchmark material for the rheological measurements with the prototype. Development of the device is being undertaken with commercial off the shelf (COTS) components and modern rapid prototyping techniques. Using these techniques, an initial prototype for measuring shear parameters of sludge has been developed, using a micro-controller for remote control and data gathering. The device is also compact enough to fit through a 75 mm opening, maximising deployment capabilities.
Spatial heterogeneity in ecological systems can result from animal‐driven top–down processes, but despite some theoretical attention, the emergence of spatial heterogeneity from feedbacks caused by ...animals is not well understood empirically. Interactions between predators and prey influence animal movement and associated nutrient transport and release, generating spatial heterogeneity that cascades throughout ecological systems. Here, we synthesize the existing literature to evaluate the mechanisms by which terrestrial predators can generate spatial heterogeneity in biogeochemical processes through consumptive and non‐consumptive effects. Overall, we propose that predators increase heterogeneity in ecosystems whenever predation is intense and spatially variable, whereas predator–prey interactions homogenize ecosystems whenever predation is weak or diffuse in space. This leads to several testable hypotheses: 1) that predation and carcass deposition at high‐predation risk sites stimulate positive feedbacks between predation risk and nutrient availability; 2) that prey generate nutrient hotspots when they concentrate activity in safe habitats, but instead generate nutrient subsidies when they migrate daily between safe and risky habitats; 3) that herbivore body size mediates risk effects, such that megaherbivores are more likely to homogenize ecosystems and predator loss in general will tend to homogenize ecosystems. Testing these hypotheses will advance our understanding of whether predators amplify landscape heterogeneity in ecological systems.
Autism spectrum disorders (ASD) are highly heritable and genetically complex conditions. Although highly penetrant mutations in multiple genes have been identified, they account for the etiology of ...<1/3 of cases. There is also strong evidence for environmental contribution to ASD, which can be mediated by still poorly explored epigenetic modifications. We searched for methylation changes on blood DNA of 53 male ASD patients and 757 healthy controls using a methylomic array (450K Illumina), correlated the variants with transcriptional alterations in blood RNAseq data, and performed a case-control association study of the relevant findings in a larger cohort (394 cases and 500 controls). We found 700 differentially methylated CpGs, most of them hypomethylated in the ASD group (83.9%), with cis-acting expression changes at 7.6% of locations. Relevant findings included: (1) hypomethylation caused by rare genetic variants (meSNVs) at six loci (ERMN, USP24, METTL21C, PDE10A, STX16 and DBT) significantly associated with ASD (q-value <0.05); and (2) clustered epimutations associated to transcriptional changes in single-ASD patients (n=4). All meSNVs and clustered epimutations were inherited from unaffected parents. Resequencing of the top candidate genes also revealed a significant load of deleterious mutations affecting ERMN in ASD compared with controls. Our data indicate that inherited methylation alterations detectable in blood DNA, due to either genetic or epigenetic defects, can affect gene expression and contribute to ASD susceptibility most likely in an additive manner, and implicate ERMN as a novel ASD gene.
The stretching of a single chain of phenolic polymer is studied using density functional theory (DFT) and the reactive force field (ReaxFF) potential. The most detailed studies are performed at 0 K, ...which shows the breaking of the C(ring)-CH2 bridge bond can be delayed to longer polymer length by a ring opening mechanism that relieves the strain. Molecular dynamics (MD) simulations, using the DFT approach, show that C–CH2 bridge bond breaking occurs much more frequently than the ring opening. The stretching potentials determined using ReaxFF compare favorably with the DFT results. Using ReaxFF, stretching of cross-linked systems were considered and compared to single chains. The effect of changing the linking group on the bond stretching portion of the potential is found to be relatively small, but the effect on the bond energies can be significant.
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•Density functional theory (DFT) and the reactive force field (ReaxFF) are used to study the stretching of single phenolic polymer chains.•The DFT and ReaxFF potentials agree on the location of the bond rupture and energy profiles during deformation.•Ring opening is a stress reduction mechanism for othro–othro isomer but not for the ortho–para isomer.•Varying the linking groups is shown to change the length of the polymer, the strength of the bridge bonds, and the stretching potentials.
Nuclear sites require regular measurements of the air, soil, and groundwater to ensure the safety of the surrounding environment from potentially hazardous levels of contamination. Although ...high-energy beta and gamma emitters can often be detected instantly using fixed dosimeters, the detection of low-energy beta emitters is a difficult challenge, especially in groundwater, as its radiation is easily self-absorbed by the surrounding medium. Therefore, it is common practice to sample groundwater and transfer it to a laboratory for analysis using Liquid Scintillation Counting. This work demonstrates a new detector design for the real-time monitoring of tritiated water, a weak beta emitter. This design utilizes a flow cell filled with a granulated scintillator to maximize the surface area of the sample. The cavity is made from plastic sheets, which allow rapid manufacture using readily available lamination sheets. A column of SiPMs in coincidence counting mode has been implemented to reduce noise and allow future extensions to the flow cell for greater detection rates while allowing the detector to fit within limited spaces such as groundwater monitoring boreholes. Using multiple concentrations of tritiated water, this detector has been validated and calibrated, obtaining a minimum detection activity of 26.356 ± 0.889 Bq/mL for a 1-day counting period.
Calcium Bushinsky, David A; Monk, Rebeca D
The Lancet (British edition),
07/1998, Letnik:
352, Številka:
9124
Journal Article
Recenzirano
Abnormalities in serum calcium concentration may have profound effects on neurological, gastrointestinal, and renal function. Maintenance of the normal serum calcium is a result of tightly regulated ...ion transport by the kidney, intestinal tract, and bone, mediated by calcaemic hormones especially parathyroid hormone and 1,25-dihydroxyvitamin D3. Abnormalities in calcium transport that result in uncompensated influx into, or efflux from, the extracellular fluid, will result in hypercalcaemia or hypocalcaemia, respectively. When possible the biologically important ionised calcium concentration should be measured. A variety of common disorders are responsible for abnormalities in the serum calcium. Treatment of both hypercalcaemia and hypocalcaemia is dependent on the underlying disorder, the magnitude of the deviation of the serum calcium, and the severity of symptoms. Fortunately, in the case of hypercalcaemia, there is a broad selection of effective medications, especially the bisphosphonates. Treatment of hypocalcaemia relies on the provision of calcium and often vitamin D. In this article we review the mechanisms responsible for abnormalities in calcium homoeostatisis, the differential diagnosis of hypercalcaemia and hypocalcaemia, and appropriate therapy.
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