Genetic Control of Canine Leishmaniasis: Genome-Wide Association Study and Genomic Selection Analysis

Background: the current disease model for leishmaniasis suggests that only a proportion of infected individuals develop clinical disease, while others are asymptomatically infected due to immune control of infection. The factors that determine whether individuals progress to clinical disease following Leishmania infection are unclear, although previous studies suggest a role for host genetics. Our hypothesis was that canine leishmaniasis is a complex disease with multiple loci responsible for the progression of the disease from Leishmania infection. Methodology/Principal Findings: genome-wide association and genomic selection approaches were applied to a population-based case-control dataset of 219 dogs from a single breed (Boxer) genotyped for ~170,000 SNPs. Firstly, we aimed to identify individual disease loci; secondly, we quantified the genetic component of the observed phenotypic variance; and thirdly, we tested whether genome-wide SNP data could accurately predict the disease. Conclusions/Significance: we estimated that a substantial proportion of the genome is affecting the trait and that its heritability could be as high as 60%. Using the genome-wide association approach, the strongest associations were on chromosomes 1, 4 and 20, although none of these were statistically significant at a genome-wide level and after correcting for genetic stratification and lifestyle. Amongst these associations, chromosome 4: 61.2-76.9 Mb maps to a locus that has previously been associated with host susceptibility to human and murine leishmaniasis, and genomic selection estimated markers in this region to have the greatest effect on the phenotype. We therefore propose these regions as candidates for replication studies. An important finding of this study was the significant predictive value from using the genomic information. We found that the phenotype could be predicted with an accuracy of ~0.29 in new samples and that the affection status was correctly predicted in 60% of dogs, significantly higher than expected by chance, and with satisfactory sensitivity-specificity values (AUC = 0.63)

Fcγ Receptor I Alpha Chain (CD64) Expression in Macrophages Is Critical for the Onset of Meningitis by Escherichia coli K1

Neonatal meningitis due to Escherichia coli K1 is a serious illness with unchanged morbidity and mortality rates for the last few decades. The lack of a comprehensive understanding of the mechanisms involved in the development of meningitis contributes to this poor outcome. Here, we demonstrate that depletion of macrophages in newborn mice renders the animals resistant to E. coli K1 induced meningitis. The entry of E. coli K1 into macrophages requires the interaction of outer membrane protein A (OmpA) of E. coli K1 with the alpha chain of Fcγ receptor I (FcγRIa, CD64) for which IgG opsonization is not necessary. Overexpression of full-length but not C-terminal truncated FcγRIa in COS-1 cells permits E. coli K1 to enter the cells. Moreover, OmpA binding to FcγRIa prevents the recruitment of the γ-chain and induces a different pattern of tyrosine phosphorylation of macrophage proteins compared to IgG2a induced phosphorylation. Of note, FcγRIa−/− mice are resistant to E. coli infection due to accelerated clearance of bacteria from circulation, which in turn was the result of increased expression of CR3 on macrophages. Reintroduction of human FcγRIa in mouse FcγRIa−/− macrophages in vitro increased bacterial survival by suppressing the expression of CR3. Adoptive transfer of wild type macrophages into FcγRIa−/− mice restored susceptibility to E. coli infection. Together, these results show that the interaction of FcγRI alpha chain with OmpA plays a key role in the development of neonatal meningitis by E. coli K1

Preconditioning-induced ischemic tolerance: a window into endogenous gearing for cerebroprotection

Ischemic tolerance defines transient resistance to lethal ischemia gained by a prior sublethal noxious stimulus (i.e., preconditioning). This adaptive response is thought to be an evolutionarily conserved defense mechanism, observed in a wide variety of species. Preconditioning confers ischemic tolerance if not in all, in most organ systems, including the heart, kidney, liver, and small intestine. Since the first landmark experimental demonstration of ischemic tolerance in the gerbil brain in early 1990's, basic scientific knowledge on the mechanisms of cerebral ischemic tolerance increased substantially. Various noxious stimuli can precondition the brain, presumably through a common mechanism, genomic reprogramming. Ischemic tolerance occurs in two temporally distinct windows. Early tolerance can be achieved within minutes, but wanes also rapidly, within hours. Delayed tolerance develops in hours and lasts for days. The main mechanism involved in early tolerance is adaptation of membrane receptors, whereas gene activation with subsequent de novo protein synthesis dominates delayed tolerance. Ischemic preconditioning is associated with robust cerebroprotection in animals. In humans, transient ischemic attacks may be the clinical correlate of preconditioning leading to ischemic tolerance. Mimicking the mechanisms of this unique endogenous protection process is therefore a potential strategy for stroke prevention. Perhaps new remedies for stroke are very close, right in our cells

Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference

Search for gravitational waves from Scorpius X-1 in the second Advanced LIGO observing run with an improved hidden Markov model

We present results from a semicoherent search for continuous gravitational waves from the low-mass x-ray binary Scorpius X-1, using a hidden Markov model (HMM) to track spin wandering. This search improves on previous HMM-based searches of LIGO data by using an improved frequency domain matched filter, the J-statistic, and by analyzing data from Advanced LIGO's second observing run. In the frequency range searched, from 60 to 650 Hz, we find no evidence of gravitational radiation. At 194.6 Hz, the most sensitive search frequency, we report an upper limit on gravitational wave strain (at 95% confidence) of h095%=3.47×10-25 when marginalizing over source inclination angle. This is the most sensitive search for Scorpius X-1, to date, that is specifically designed to be robust in the presence of spin wandering. © 2019 American Physical Society

Search for gravitational waves from Scorpius X-1 in the second Advanced LIGO observing run with an improved hidden Markov model

We present results from a semicoherent search for continuous gravitational waves from the low-mass x-ray binary Scorpius X-1, using a hidden Markov model (HMM) to track spin wandering. This search improves on previous HMM-based searches of LIGO data by using an improved frequency domain matched filter, the J-statistic, and by analyzing data from Advanced LIGO’s second observing run. In the frequency range searched, from 60 to 650 Hz, we find no evidence of gravitational radiation. At 194.6 Hz, the most sensitive search frequency, we report an upper limit on gravitational wave strain (at 95% confidence) of h95%0=3.47×10−25 when marginalizing over source inclination angle. This is the most sensitive search for Scorpius X-1, to date, that is specifically designed to be robust in the presence of spin wandering

First Measurement of the Hubble Constant from a Dark Standard Siren using the Dark Energy Survey Galaxies and the LIGO/Virgo Binary-Black-hole Merger GW170814

We present a multi-messenger measurement of the Hubble constant H 0 using the binary–black-hole merger GW170814 as a standard siren, combined with a photometric redshift catalog from the Dark Energy Survey (DES). The luminosity distance is obtained from the gravitational wave signal detected by the Laser Interferometer Gravitational-Wave Observatory (LIGO)/Virgo Collaboration (LVC) on 2017 August 14, and the redshift information is provided by the DES Year 3 data. Black hole mergers such as GW170814 are expected to lack bright electromagnetic emission to uniquely identify their host galaxies and build an object-by-object Hubble diagram. However, they are suitable for a statistical measurement, provided that a galaxy catalog of adequate depth and redshift completion is available. Here we present the first Hubble parameter measurement using a black hole merger. Our analysis results in ${H}_{0}={75}_{-32}^{+40}\,\mathrm{km}\,{{\rm{s}}}^{-1}\,{\mathrm{Mpc}}^{-1}$, which is consistent with both SN Ia and cosmic microwave background measurements of the Hubble constant. The quoted 68% credible region comprises 60% of the uniform prior range [20, 140] km s−1 Mpc−1, and it depends on the assumed prior range. If we take a broader prior of [10, 220] km s−1 Mpc−1, we find {H}_{0 {78}_{-24}^{+96}\,\mathrm{km}\,{{\rm{s}}}^{-1}\,{\mathrm{Mpc}}^{-1} (57% of the prior range). Although a weak constraint on the Hubble constant from a single event is expected using the dark siren method, a multifold increase in the LVC event rate is anticipated in the coming years and combinations of many sirens will lead to improved constraints on H 0

Search for gravitational waves associated with gamma-ray bursts detected by Fermi and Swift during the LIGO–Virgo run O3b

We search for gravitational-wave signals associated with gamma-ray bursts (GRBs) detected by the Fermi and Swift satellites during the second half of the third observing run of Advanced LIGO and Advanced Virgo (2019 November 1 15:00 UTC–2020 March 27 17:00 UTC). We conduct two independent searches: a generic gravitational-wave transients search to analyze 86 GRBs and an analysis to target binary mergers with at least one neutron star as short GRB progenitors for 17 events. We find no significant evidence for gravitational-wave signals associated with any of these GRBs. A weighted binomial test of the combined results finds no evidence for subthreshold gravitational-wave signals associated with this GRB ensemble either. We use several source types and signal morphologies during the searches, resulting in lower bounds on the estimated distance to each GRB. Finally, we constrain the population of low-luminosity short GRBs using results from the first to the third observing runs of Advanced LIGO and Advanced Virgo. The resulting population is in accordance with the local binary neutron star merger rate