Resistance to the intestinal parasitic helminth Trichuris muris requires T-helper 2 (T
2) cellular and associated IgG1 responses, with expulsion typically taking up to 4 weeks in mice. Here, we show ...that the time-of-day of the initial infection affects efficiency of worm expulsion, with strong T
2 bias and early expulsion in morning-infected mice. Conversely, mice infected at the start of the night show delayed resistance to infection, and this is associated with feeding-driven metabolic cues, such that feeding restriction to the day-time in normally nocturnal-feeding mice disrupts parasitic expulsion kinetics. We deleted the circadian regulator BMAL1 in antigen-presenting dendritic cells (DCs) in vivo and found a loss of time-of-day dependency of helminth expulsion. RNAseq analyses revealed that IL-12 responses to worm antigen by circadian-synchronised DCs were dependent on BMAL1. Therefore, we find that circadian machinery in DCs contributes to the T
1/T
2 balance, and that environmental, or genetic perturbation of the DC clock results in altered parasite expulsion kinetics.
The transport of moisture in the tropics is a critical process for the global energy budget and on geologic timescales, has markedly influenced continental landscapes, migratory pathways, and ...biological evolution. Here we present a continuous, first-of-its-kind 1.3-My record of continental hydroclimate and lake-level variability derived from drill core data from Lake Malawi, East Africa (9–15° S). Over the Quaternary, we observe dramatic shifts in effective moisture, resulting in large-scale changes in one of the world’s largest lakes and most diverse freshwater ecosystems. Results show evidence for 24 lake level drops of more than 200 m during the Late Quaternary, including 15 lowstands when water levels were more than 400 m lower than modern. A dramatic shift is observed at the Mid-Pleistocene Transition (MPT), consistent with far-field climate forcing, which separates vastly different hydroclimate regimes before and after ∼800,000 years ago. Before 800 ka, lake levels were lower, indicating a climate drier than today, and water levels changed frequently. Following the MPT high-amplitude lake level variations dominate the record. From 800 to 100 ka, a deep, often overfilled lake occupied the basin, indicating a wetter climate, but these highstands were interrupted by prolonged intervals of extreme drought. Periods of high lake level are observed during times of high eccentricity. The extreme hydroclimate variability exerted a profound influence on the Lake Malawi endemic cichlid fish species flock; the geographically extensive habitat reconfiguration provided novel ecological opportunities, enabling new populations to differentiate rapidly to distinct species.
Legionella pneumophila is the causative agent of Legionnaires' disease, a potentially fatal lung infection. Alveolar macrophages support intracellular replication of L. pneumophila, however the ...contributions of other immune cell types to bacterial killing during infection are unclear. Here, we used recently described methods to characterise the major inflammatory cells in lung after acute respiratory infection of mice with L. pneumophila. We observed that the numbers of alveolar macrophages rapidly decreased after infection coincident with a rapid infiltration of the lung by monocyte-derived cells (MC), which, together with neutrophils, became the dominant inflammatory cells associated with the bacteria. Using mice in which the ability of MC to infiltrate tissues is impaired it was found that MC were required for bacterial clearance and were the major source of IL12. IL12 was needed to induce IFNγ production by lymphoid cells including NK cells, memory T cells, NKT cells and γδ T cells. Memory T cells that produced IFNγ appeared to be circulating effector/memory T cells that infiltrated the lung after infection. IFNγ production by memory T cells was stimulated in an antigen-independent fashion and could effectively clear bacteria from the lung indicating that memory T cells are an important contributor to innate bacterial defence. We also determined that a major function of IFNγ was to stimulate bactericidal activity of MC. On the other hand, neutrophils did not require IFNγ to kill bacteria and alveolar macrophages remained poorly bactericidal even in the presence of IFNγ. This work has revealed a cooperative innate immune circuit between lymphoid cells and MC that combats acute L. pneumophila infection and defines a specific role for IFNγ in anti-bacterial immunity.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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•Over 70 tyres analysed for 19 elements to give a tyre fingerprint.•This fingerprint can be used in source apportionment or environmental modelling.•It is not possible to distinguish ...individual manufacturers based on elemental profile.
The purpose of this study was to identify a characteristic elemental tyre fingerprint that can be utilised in atmospheric source apportionment calculations. Currently zinc is widely used as a single element tracer to quantify tyre wear, however several authors have highlighted issues with this approach. To overcome this, tyre rubber tread was digested and has been analysed for 25 elements by ICP-MS to generate a multielement profile. Additionally, to estimate the percentage of the tyre made up of inert fillers, thermogravimetric analysis was performed on a subset. Comparisons were made between passenger car and heavy goods vehicle tyre composition, and a subset of tyres had both tread and sidewall sampled for further comparison. 19 of the 25 elements were detected in the analysis. The mean mass fraction of zinc detected was 11.17 g/kg, consistent with previous estimates of 1% of the tyre mass. Aluminium, iron, and magnesium were found to be the next most abundant elements. Only one source profile for tyre wear exists in both the US and EU air pollution species profile databases, highlighting the need for more recent data with better coverage of tyre makes and models. This study provides data on new tyres which are currently operating on-road in Europe and is therefore relevant for ongoing atmospheric studies assessing the levels of tyre wear particles in urban areas.
Previous randomised renal denervation studies did not show consistent efficacy in reducing blood pressure. The objective of our study was to evaluate the effect of renal denervation on blood pressure ...in the absence of antihypertensive medications.
SPYRAL HTN-OFF MED was a multicentre, international, single-blind, randomised, sham-controlled, proof-of-concept trial. Patients were enrolled at 21 centres in the USA, Europe, Japan, and Australia. Eligible patients were drug-naive or discontinued their antihypertensive medications. Patients with an office systolic blood pressure (SBP) of 150 mm Hg or greater and less than 180 mm Hg, office diastolic blood pressure (DBP) of 90 mm Hg or greater, and a mean 24-h ambulatory SBP of 140 mm Hg or greater and less than 170 mm Hg at second screening underwent renal angiography and were randomly assigned to renal denervation or sham control. Patients, caregivers, and those assessing blood pressure were blinded to randomisation assignments. The primary endpoint, change in 24-h blood pressure at 3 months, was compared between groups. Drug surveillance was done to ensure patient compliance with absence of antihypertensive medication. The primary analysis was done in the intention-to-treat population. Safety events were assessed at 3 months. This study is registered with ClinicalTrials.gov, number NCT02439749.
Between June 25, 2015, and Jan 30, 2017, 353 patients were screened. 80 patients were randomly assigned to renal denervation (n=38) or sham control (n=42) and followed up for 3 months. Office and 24-h ambulatory blood pressure decreased significantly from baseline to 3 months in the renal denervation group: 24-h SBP −5·5 mm Hg (95% CI −9·1 to −2·0; p=0·0031), 24-h DBP −4·8 mm Hg (−7·0 to −2·6; p<0·0001), office SBP −10·0 mm Hg (−15·1 to −4·9; p=0·0004), and office DBP −5·3 mm Hg (−7·8 to −2·7; p=0·0002). No significant changes were seen in the sham-control group: 24-h SBP −0·5 mm Hg (95% CI −3·9 to 2·9; p=0·7644), 24-h DBP −0·4 mm Hg (−2·2 to 1·4; p=0·6448), office SBP −2·3 mm Hg (−6·1 to 1·6; p=0·2381), and office DBP −0·3 mm Hg (−2·9 to 2·2; p=0·8052). The mean difference between the groups favoured renal denervation for 3-month change in both office and 24-h blood pressure from baseline: 24-h SBP −5·0 mm Hg (95% CI −9·9 to −0·2; p=0·0414), 24-h DBP −4·4 mm Hg (−7·2 to −1·6; p=0·0024), office SBP −7·7 mm Hg (−14·0 to −1·5; p=0·0155), and office DBP −4·9 mm Hg (−8·5 to −1·4; p=0·0077). Baseline-adjusted analyses showed similar findings. There were no major adverse events in either group.
Results from SPYRAL HTN-OFF MED provide biological proof of principle for the blood-pressure-lowering efficacy of renal denervation.
Medtronic.
•Novel algorithm developed for calculating the methane number of liquefied natural gas.•Algorithm shows good agreement with existing methods for calculating MN.•The algorithm also determines the ...uncertainty associated with the calculated MN.•Relative expanded uncertainty in MN values vary between 0.3 and 0.8%.•Reporting the uncertainty in MN significantly aids interpretation of the result.
Liquefied natural gas (LNG) is increasing in importance both as an energy carrier and as a transport fuel. While the developments for an improved infrastructure for LNG are significantly advanced, no commonly agreed method for the characterization of LNG mixtures in terms of the so-called methane number (MN) exist. In this work we present a novel, simple and robust algorithm for calculating the methane number from LNG composition. It combines the detailed experimental data used to develop the commonly used method by AVL (“Anstalt für Verbrennungsmotoren Prof. H. List”) with automated calculation and optimisation routines that guarantee for a high degree of repeatability and reproducibility. This is in accordance with other modern MN calculation tools. The algorithm shows good agreement with other popular methods for a set of exemplar LNG mixtures covering a broad MN range between 60 and 99. Our comparison indicates that the observed differences between the methods might stem from different approaches used for the higher hydrocarbon and inert gas corrections. For the first time to our knowledge the algorithm also determines the uncertainty associated with the calculated MN yielding expanded uncertainties that vary between 0.2 and 0.7MN depending on the composition of the mixture. We believe that incorporating the uncertainty associated with the calculation of the MN is important for developing a legislation for LNG quality as it would significantly enhance the confidence provided by the results of the calculation tools. In this context the definition of reasonable uncertainty limits in addition to a lower MN limit is recommended.
Fine control of macrophage activation is needed to prevent inflammatory disease, particularly at barrier sites such as the lungs. However, the dominant mechanisms that regulate the activation of ...pulmonary macrophages during inflammation are poorly understood. We found that alveolar macrophages (AlvMs) were much less able to respond to the canonical type 2 cytokine IL-4, which underpins allergic disease and parasitic worm infections, than macrophages from lung tissue or the peritoneal cavity. We found that the hyporesponsiveness of AlvMs to IL-4 depended upon the lung environment but was independent of the host microbiota or the lung extracellular matrix components surfactant protein D (SP-D) and mucin 5b (Muc5b). AlvMs showed severely dysregulated metabolism relative to that of cavity macrophages. After removal from the lungs, AlvMs regained responsiveness to IL-4 in a glycolysis-dependent manner. Thus, impaired glycolysis in the pulmonary niche regulates AlvM responsiveness during type 2 inflammation.
ABSTRACT
The incidence of inflammatory bowel disease (IBD) is steadily on the rise in Western and in developing countries paralleling the increase of westernized diets, characterized by high protein ...and fat as well as excessive sugar intake, with less vegetables and fiber. Furthermore, nutrition is involved in several aspects of pediatric IBD, ranging from disease etiology to induction and maintenance of remission of disease. Exclusive enteral nutrition (EEN) has been shown to induce remission, including in patients with isolated colonic disease, and leads to mucosal healing in Crohn disease. One hypothesis for the beneficial effect of this modality is exclusion of dietary components thought to cause dysbiosis or impair innate immune mechanisms such as the mucous layer, intestinal permeability or colonization and adherence with adherent‐invasive Escherichia coli. Although there is not yet definitive data illustrating a role for EEN in the management of active ulcerative colitis (UC), there are several lines of evidence that illustrate that dietary interventions may be helpful. In particular, the key mechanisms of the activity of EEN (namely, changes in the intestinal microflora in Crohn disease) are likely also relevant to UC. Furthermore, the use of EEN in pediatric UC patients may add to a better bone health. Prospective studies are now required to evaluate the role of EEN in UC in children.
Food-related quality of life (FRQoL) encompasses the psychosocial elements of eating and drinking. The FRQoL of children and adolescents with inflammatory bowel disease has not yet been assessed. ...This study aimed to evaluate the utility of the validated FR-Qol-29 instrument in children with Crohn's disease (CD).
Children diagnosed with CD, a shared home environment healthy sibling, and healthy control subjects 6 to 17 years of age were recruited to this single-center, prospective, cross-sectional study. Children or their parent or guardian completed the FR-QoL-29 instrument. Internal consistency was assessed by completing Cronbach's α. Construct validity was established by correlating the CD FR-QoL-29 sum scores with the Physician Global Assessment and Pediatric Crohn Disease Activity Index scores. The discriminant validity was analyzed using a 1-way analysis of variance, and a Spearman's correlation coefficient test was completed to identify any correlations associated with FRQoL.
Sixty children or their parent or guardian completed the FR-QoL-29 instrument (10 children in each subgroup). The internal consistency was excellent (Cronbach's α = 0.938). The mean FR-QoL-29 sum scores were 94.3 ± 27.6 for CD, 107.6 ± 20 for siblings, and 113.7 ± 13.8 for control subjects (P = .005). Those with higher disease activity had worse FRQoL (Physician Global Assessment P = .021 and Pediatric Crohn Disease Activity Index P = .004). Inflammatory bowel disease FR-QoL-29 sum scores correlated with weight (P = .027), height (P = .035), body mass index (P = .023), and age (P = .015).
FRQoL is impaired in children with CD. Healthy siblings also have poorer FRQoL than control subjects. Several clinical factors are associated with poorer FRQoL in children with CD including age and level of nutritional risk (weight, height, and body mass index). Further research is required validate these findings and to develop strategies for the prevention or treatment of impaired FRQoL in children with CD.
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