Mannan detecting C-type lectin receptor probes recognise immune epitopes with diverse chemical, spatial and phylogenetic heterogeneity in fungal cell walls

Funding Information: This work was supported by the Wellcome Trust Investigator, Collaborative, Equipment, Strategic and Biomedical Resource awards (086827, 075470, 097377, 101873, 200208, 093378 and 099197), the Applied Molecular Biosciences Unit-UCIBIO (FCT/MCTES UID/Multi/04378/2019), Wellcome Trust Biomedical Resource grant (108430/Z/15/Z), March of Dimes (Arlington, Virginia, U.S.A.) Prematurity Research Center grant (22-FY18-821) and by the MRC Centre for Medical Mycology (N006364/1). The University of Aberdeen funded a studentship to IV as part of NARG?s Wellcome Senior Investigator Award. https://wellcome.ac.uk/ - Wellcome. https://mrc.ukri.org/ - MRC. https:// www.requimte.pt/ucibio/ - the Applied Molecular Biosciences Unit-UCIBIO. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Publisher Copyright: © 2020 Vendele et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Peer reviewedPublisher PD

Direct molecular versus culture-based assessment of Gram-positive cocci in biopsies of patients with major abscesses and diabetic foot infections

Major abscesses and diabetic foot infections (DFIs) are predominant subtypes of complicated skin and skin structure infections (cSSSIs), and are mainly caused by Staphylococcus aureus and β-hemolytic streptococci. This study evaluates the potential benefit of direct pathogen-specific real-time polymerase chain reaction (PCR) assays in the identification of causative organisms of cSSSIs. One-hundred and fifty major abscess and 128 DFI biopsy samples were collected and microbial DNA was extracted by using the Universal Microbe Detection kit for tissue samples. Pathogen-specific PCRs were developed for S. aureus and its virulence factor Panton–Valentine leukocidin (PVL), Streptococcus pyogenes, S. agalactiae, S. dysgalactiae, and the S. anginosus group. Identification by pathogen-specific PCRs was compared to routine culture and both methods were considered as the gold standard for determination of the sensitivity and specificity of each assay. Direct real-time PCR assays of biopsy samples resulted in a 34 % higher detection of S. aureus, 37 % highe

Host genetic signatures of susceptibility to fungal disease

Our relative inability to predict the development of fungal disease and its clinical outcome raises fundamental questions about its actual pathogenesis. Several clinical risk factors are described to predispose to fungal disease, particularly in immunocompromised and severely ill patients. However, these alone do not entirely explain why, under comparable clinical conditions, only some patients develop infection. Recent clinical and epidemiological studies have reported an expanding number of monogenic defects and common polymorphisms associated with fungal disease. By directly implicating genetic variation in the functional regulation of immune mediators and interacting pathways, these studies have provided critical insights into the human immunobiology of fungal disease. Most of the common genetic defects reported were described or suggested to impair fungal recognition by the innate immune system. Here, we review common genetic variation in pattern recognition receptors and its impact on the immune response against the two major fungal pathogens Candida albicans and Aspergillus fumigatus. In addition, we discuss potential strategies and opportunities for the clinical translation of genetic information in the field of medical mycology. These approaches are expected to transfigure current clinical practice by unleashing an unprecedented ability to personalize prophylaxis, therapy and monitoring for fungal disease.This work was supported by the Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (FEDER) (NORTE-01-0145-FEDER-000013), the Fundação para a Ciência e Tecnologia (FCT) (IF/00735/2014 to AC, and SFRH/BPD/96176/2013 to CC), the Institut Mérieux (Mérieux Research Grant 2017 to CC), and the European Society of Clinical Microbiology and Infectious Diseases (ESCMID Research Grant 2017 to AC)

The Large Observatory for x-ray timing

The Large Observatory For x-ray Timing (LOFT) was studied within ESA M3 Cosmic Vision framework and participated in the final down-selection for a launch slot in 2022-2024. Thanks to the unprecedented combination of effective area and spectral resolution of its main instrument, LOFT will study the behaviour of matter under extreme conditions, such as the strong gravitational field in the innermost regions of accretion flows close to black holes and neutron stars, and the supra-nuclear densities in the interior of neutron stars. The science payload is based on a Large Area Detector (LAD, 10 m2 effective area, 2-30 keV, 240 eV spectral resolution, 1° collimated field of view) and a WideField Monitor (WFM, 2-50 keV, 4 steradian field of view, 1 arcmin source location accuracy, 300 eV spectral resolution). The WFM is equipped with an on-board system for bright events (e.g. GRB) localization. The trigger time and position of these events are broadcast to the ground within 30 s from discovery. In this paper we present the status of the mission at the end of its Phase A study

Narrowband Searches for Continuous and Long-duration Transient Gravitational Waves from Known Pulsars in the LIGO-Virgo Third Observing Run

Isolated neutron stars that are asymmetric with respect to their spin axis are possible sources of detectable continuous gravitational waves. This paper presents a fully coherent search for such signals from eighteen pulsars in data from LIGO and Virgo's third observing run (O3). For known pulsars, efficient and sensitive matched-filter searches can be carried out if one assumes the gravitational radiation is phase-locked to the electromagnetic emission. In the search presented here, we relax this assumption and allow both the frequency and the time derivative of the frequency of the gravitational waves to vary in a small range around those inferred from electromagnetic observations. We find no evidence for continuous gravitational waves, and set upper limits on the strain amplitude for each target. These limits are more constraining for seven of the targets than the spin-down limit defined by ascribing all rotational energy loss to gravitational radiation. In an additional search, we look in O3 data for long-duration (hours-months) transient gravitational waves in the aftermath of pulsar glitches for six targets with a total of nine glitches. We report two marginal outliers from this search, but find no clear evidence for such emission either. The resulting duration-dependent strain upper limits do not surpass indirect energy constraints for any of these targets. © 2022. The Author(s). Published by the American Astronomical Society

Lesion size is associated with genetic polymorphisms in TLR1, TLR6, and TIRAP genes in patients with major abscesses and diabetic foot infections

Genetic variation in Toll-like receptors (TLRs) has previously been associated with susceptibility to complicated skin and skin structure infections (cSSSIs). The aim of this study was to investigate associations between the severity of cSSSIs, i.e., major abscesses and diabetic foot infections (DFIs), and a set of genetic polymorphisms in the Toll-like receptor pathway. A total of 121 patients with major abscesses and 132 with DFIs participating in a randomized clinical trial were genotyped for 13 nonsynonymous single-nucleotide polymorphisms (SNPs) in genes coding for TLRs and the signaling adaptor molecule TIRAP. Infection severity was defined by lesion size at clinical presentation for both types of infections. The PEDIS infection score was also used to define severity of DFIs. Linear regression models were used to study factors independently associated with severity. In patients with large abscesses, hetero- or homozygosity for the allelic variant TLR6 (P249S) was associated with significantly smaller lesions while homozygosity for the allelic variant TLR1 (R80T) was associated with significantly larger lesions. PRRs genes were not significantly associated with PEDIS. However, patients with DFI hetero- or homozygous for the allelic variant TLR1 (S248N) had significantly larger lesions. Polymorphisms in TLR1 and TLR6 influence the severity of cSSSIs as assessed by the lesion size of major abscesses and DFIs. Identifier: NCT 0040272

An observational study of innate immune responses in patients with acute appendicitis

Contains fulltext : 226185.pdf (publisher's version ) (Open Access

European Pulsar Timing Array Limits on Continuous Gravitational Waves from Individual Supermassive Black Hole Binaries

We have searched for continuous gravitational wave (CGW) signals produced by individually resolvable, circular supermassive black hole binaries (SMBHBs) in the latest EPTA dataset, which consists of ultra-precise timing data on 41 millisecond pulsars. We develop frequentist and Bayesian detection algorithms to search both for monochromatic and frequency-evolving systems. None of the adopted algorithms show evidence for the presence of such a CGW signal, indicating that the data are best described by pulsar and radiometer noise only. Depending on the adopted detection algorithm, the 95\% upper limit on the sky-averaged strain amplitude lies in the range $6\times 10^{-15}<A<1.5\times10^{-14}$ at $5{\rm nHz}<f<7{\rm nHz}$. This limit varies by a factor of five, depending on the assumed source position, and the most constraining limit is achieved towards the positions of the most sensitive pulsars in the timing array. The most robust upper limit -- obtained via a full Bayesian analysis searching simultaneously over the signal and pulsar noise on the subset of ours six best pulsars -- is $A\approx10^{-14}$. These limits, the most stringent to date at $f<10{\rm nHz}$, exclude the presence of sub-centiparsec binaries with chirp mass $\cal{M}_c>10^9$M$_\odot$ out to a distance of about 25Mpc, and with $\cal{M}_c>10^{10}$M$_\odot$ out to a distance of about 1Gpc ($z\approx0.2$). We show that state-of-the-art SMBHB population models predict $<1\%$ probability of detecting a CGW with the current EPTA dataset, consistent with the reported non-detection. We stress, however, that PTA limits on individual CGW have improved by almost an order of magnitude in the last five years. The continuing advances in pulsar timing data acquisition and analysis techniques will allow for strong astrophysical constraints on the population of nearby SMBHBs in the coming years.Comment: 16 pages, 11 figures, accepted for publication in MNRA

European Pulsar Timing Array Limits On An Isotropic Stochastic Gravitational-Wave Background

24 pages, 5 tables, 17 figuresInternational audienceWe present new limits on an isotropic stochastic gravitational-wave background (GWB) using a six pulsar dataset spanning 18 yr of observations from the 2015 European Pulsar Timing Array data release. Performing a Bayesian analysis, we fit simultaneously for the intrinsic noise parameters for each pulsar, along with common correlated signals including clock, and Solar System ephemeris errors, obtaining a robust 95$\%$ upper limit on the dimensionless strain amplitude $A$ of the background of $A<3.0\times 10^{-15}$ at a reference frequency of $1\mathrm{yr^{-1}}$ and a spectral index of $13/3$, corresponding to a background from inspiralling super-massive black hole binaries, constraining the GW energy density to $\Omega_\mathrm{gw}(f)h^2 < 1.1\times10^{-9}$ at 2.8 nHz. We also present limits on the correlated power spectrum at a series of discrete frequencies, and show that our sensitivity to a fiducial isotropic GWB is highest at a frequency of $\sim 5\times10^{-9}$~Hz. Finally we discuss the implications of our analysis for the astrophysics of supermassive black hole binaries, and present 95$\%$ upper limits on the string tension, $G\mu/c^2$, characterising a background produced by a cosmic string network for a set of possible scenarios, and for a stochastic relic GWB. For a Nambu-Goto field theory cosmic string network, we set a limit $G\mu/c^2<1.3\times10^{-7}$, identical to that set by the {\it Planck} Collaboration, when combining {\it Planck} and high-$\ell$ Cosmic Microwave Background data from other experiments. For a stochastic relic background we set a limit of $\Omega^\mathrm{relic}_\mathrm{gw}(f)h^2<1.2 \times10^{-9}$, a factor of 9 improvement over the most stringent limits previously set by a pulsar timing array

Recognition of DHN-melanin by a C-type lectin receptor is required for immunity to Aspergillus

Resistance to infection is critically dependent on the ability of pattern recognition receptors to recognize microbial invasion and induce protective immune responses. One such family of receptors are the C-type lectins, which are central to antifungal immunity. These receptors activate key effector mechanisms upon recognition of conserved fungal cell-wall carbohydrates. However, several other immunologically active fungal ligands have been described; these include melanin, for which the mechanism of recognition is hitherto undefined. Here we identify a C-type lectin receptor, melanin-sensing C-type lectin receptor (MelLec), that has an essential role in antifungal immunity through recognition of the naphthalene-diol unit of 1,8-dihydroxynaphthalene (DHN)-melanin. MelLec recognizes melanin in conidial spores of Aspergillus fumigatus as well as in other DHN-melanized fungi. MelLec is ubiquitously expressed by CD31+endothelial cells in mice, and is also expressed by a sub-population of these cells that co-express epithelial cell adhesion molecule and are detected only in the lung and the liver. In mouse models, MelLec was required for protection against disseminated infection with A. fumigatus. In humans, MelLec is also expressed by myeloid cells, and we identified a single nucleotide polymorphism of this receptor that negatively affected myeloid inflammatory responses and significantly increased the susceptibility of stem-cell transplant recipients to disseminated Aspergillus infections. MelLec therefore recognizes an immunologically active component commonly found on fungi and has an essential role in protective antifungal immunity in both mice and humans