Resolution of inflammation: a new therapeutic frontier

Dysregulated inflammation is a central pathological process in diverse disease states. Traditionally, therapeutic approaches have sought to modulate the pro- or anti-inflammatory limbs of inflammation, with mixed success. However, insight into the pathways by which inflammation is resolved has highlighted novel opportunities to pharmacologically manipulate these processes — a strategy that might represent a complementary (and perhaps even superior) therapeutic approach. This Review discusses the state of the art in the biology of resolution of inflammation, highlighting the opportunities and challenges for translational research in this field

Gene expression profile of AIDS-related Kaposi's sarcoma

BACKGROUND: Kaposi's Sarcoma (KS) is a proliferation of aberrant vascular structures lined by spindle cells, and is caused by a gammaherpes virus (HHV8/KSHV). Its course is aggravated by co-infection with HIV-1, where the timing of infection with HIV-1 and HHV8 is important for the clinical outcome. METHODS: In order to better understand the pathogenesis of KS, we have analysed tissue from two AIDS-KS lesions, and from normal skin by serial analysis of gene expression (SAGE). Semi-quantitative RT-PCR was then used to validate the results. RESULTS: The expression profile of AIDS-related KS (AIDS-KS) reflects an active process in the skin. Transcripts of HHV8 were found to be very low, and HIV-1 mRNA was not detected by SAGE, although it could be found using RT-PCR. Comparing the expression profile of AIDS-KS tissue with publicly available SAGE libraries suggested that AIDS-KS mRNA levels are most similar to those in an artificially mixed library of endothelial cells and leukocytes, in line with the description of KS lesions as containing spindle cells with endothelial characteristics, and an inflammatory infiltrate. At least 64 transcripts were found to be significantly elevated, and 28 were statistically downregulated in AIDS-KS compared to normal skin. Five of the upregulated mRNAs, including Tie 1 and sialoadhesin/CD169, were confirmed by semi-quantitative PCR to be elevated in additional AIDS-KS biopsies. Antibodies to sialoadhesin/CD169, a known marker of activated macrophages, were shown to specifically label tumour macrophages. CONCLUSION: The expression profile of AIDS-KS showed 64 genes to be significantly upregulated, and 28 genes downregulated, compared with normal skin. One of the genes with increased expression was sialoadhesin (CD169). Antibodies to sialoadhesin/CD169 specifically labelled tumour-associated macrophages, suggesting that macrophages present in AIDS-KS lesions belong to a subset of human CD169+ macrophages

Genome-Wide Fitness and Expression Profiling Implicate Mga2 in Adaptation to Hydrogen Peroxide

Caloric restriction extends lifespan, an effect once thought to involve attenuation of reactive oxygen species (ROS) generated by aerobic metabolism. However, recent evidence suggests that caloric restriction may in fact raise ROS levels, which in turn provides protection from acute doses of oxidant through a process called adaptation. To shed light on the molecular mechanisms of adaptation, we designed a series of genome-wide deletion fitness and mRNA expression screens to identify genes involved in adaptation to hydrogen peroxide. Combined with known transcriptional interactions, the integrated data implicate Yap1 and Skn7 as central transcription factors of both the adaptive and acute oxidative responses. They also identify the transcription factors Mga2 and Rox1 as active exclusively in the adaptive response and show that Mga2 is essential for adaptation. These findings are striking because Mga2 and Rox1 have been thought to control the response to hypoxic, not oxidative, conditions. Expression profiling of mga2Δ and rox1Δ knockouts shows that these factors most strongly regulate targets in ergosterol, fatty-acid, and zinc metabolic pathways. Direct quantitation of ergosterol reveals that its basal concentration indeed depends on Mga2, but that Mga2 is not required for the decrease in ergosterol observed during adaptation

Hydrogen in Drinking Water Reduces Dopaminergic Neuronal Loss in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine Mouse Model of Parkinson's Disease

It has been shown that molecular hydrogen (H2) acts as a therapeutic antioxidant and suppresses brain injury by buffering the effects of oxidative stress. Chronic oxidative stress causes neurodegenerative diseases such as Parkinson's disease (PD). Here, we show that drinking H2-containing water significantly reduced the loss of dopaminergic neurons in PD model mice using both acute and chronic administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The concentration-dependency of H2 showed that H2 as low as 0.08 ppm had almost the same effect as saturated H2 water (1.5 ppm). MPTP-induced accumulation of cellular 8-oxoguanine (8-oxoG), a marker of DNA damage, and 4-hydroxynonenal (4-HNE), a marker of lipid peroxidation were significantly decreased in the nigro-striatal dopaminergic pathway in mice drinking H2-containing water, whereas production of superoxide (O2•−) detected by intravascular injection of dihydroethidium (DHE) was not reduced significantly. Our results indicated that low concentration of H2 in drinking water can reduce oxidative stress in the brain. Thus, drinking H2-containing water may be useful in daily life to prevent or minimize the risk of life style-related oxidative stress and neurodegeneration

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

GWTC-2.1: Deep extended catalog of compact binary coalescences observed by LIGO and Virgo during the first half of the third observing run

The second Gravitational-Wave Transient Catalog, GWTC-2, reported on 39 compact binary coalescences observed by the Advanced LIGO and Advanced Virgo detectors between 1 April 2019 15 ∶ 00 UTC and 1 October 2019 15 ∶ 00 UTC. Here, we present GWTC-2.1, which reports on a deeper list of candidate events observed over the same period. We analyze the final version of the strain data over this period with improved calibration and better subtraction of excess noise, which has been publicly released. We employ three matched-filter search pipelines for candidate identification, and estimate the probability of astrophysical origin for each candidate event. While GWTC-2 used a false alarm rate threshold of 2 per year, we include in GWTC-2.1, 1201 candidates that pass a false alarm rate threshold of 2 per day. We calculate the source properties of a subset of 44 high-significance candidates that have a probability of astrophysical origin greater than 0.5. Of these candidates, 36 have been reported in GWTC-2. We also calculate updated source properties for all binary black hole events previously reported in GWTC-1. If the eight additional high-significance candidates presented here are astrophysical, the mass range of events that are unambiguously identified as binary black holes (both objects ≥ 3 M⊙ ) is increased compared to GWTC-2, with total masses from ∼ 14 M ⊙ for GW190924_021846 to ∼ 182 M⊙ for GW190426_190642. Source properties calculated using our default prior suggest that the primary components of two new candidate events (GW190403_051519 and GW190426_190642) fall in the mass gap predicted by pair-instability supernova theory. We also expand the population of binaries with significantly asymmetric mass ratios reported in GWTC-2 by an additional two events (the mass ratio is less than 0.65 and 0.44 at 90% probability for GW190403_051519 and GW190917_114630 respectively), and find that two of the eight new events have effective inspiral spins χeff > 0 (at 90% credibility), while no binary is consistent with χeff < 0 at the same significance. We provide updated estimates for rates of binary black hole and binary neutron star coalescence in the local Universe

All-sky, all-frequency directional search for persistent gravitational waves from Advanced LIGO’s and Advanced Virgo’s first three observing runs

We present the first results from an all-sky all-frequency (ASAF) search for an anisotropic stochastic gravitational-wave background using the data from the first three observing runs of the Advanced LIGO and Advanced Virgo detectors. Upper limit maps on broadband anisotropies of a persistent stochastic background were published for all observing runs of the LIGO-Virgo detectors. However, a broadband analysis is likely to miss narrowband signals as the signal-to-noise ratio of a narrowband signal can be significantly reduced when combined with detector output from other frequencies. Data folding and the computationally efficient analysis pipeline, {\tt PyStoch}, enable us to perform the radiometer map-making at every frequency bin. We perform the search at 3072 {\tt{HEALPix}} equal area pixels uniformly tiling the sky and in every frequency bin of width $1/32$~Hz in the range $20-1726$~Hz, except for bins that are likely to contain instrumental artefacts and hence are notched. We do not find any statistically significant evidence for the existence of narrowband gravitational-wave signals in the analyzed frequency bins. Therefore, we place $95\%$ confidence upper limits on the gravitational-wave strain for each pixel-frequency pair, the limits are in the range $(0.030 - 9.6) \times10^{-24}$. In addition, we outline a method to identify candidate pixel-frequency pairs that could be followed up by a more sensitive (and potentially computationally expensive) search, e.g., a matched-filtering-based analysis, to look for fainter nearly monochromatic coherent signals. The ASAF analysis is inherently independent of models describing any spectral or spatial distribution of power. We demonstrate that the ASAF results can be appropriately combined over frequencies and sky directions to successfully recover the broadband directional and isotropic results

Extreme enrichment of Se, Te, PGE and Au in Cu sulfide microdroplets: evidence from LA-ICP-MS analysis of sulfides in the Skaergaard Intrusion, east Greenland

The Platinova Reef, in the Skaergaard Intrusion, east Greenland, is an example of a magmatic Cu–PGE–Au sulfide deposit formed in the latter stages of magmatic differentiation. As is characteristic with such deposits, it contains a low volume of sulfide, displays peak metal offsets and is Cu rich but Ni poor. However, even for such deposits, the Platinova Reef contains extremely low volumes of sulfide and the highest Pd and Au tenor sulfides of any magmatic ore deposit. Here, we present the first LA-ICP-MS analyses of sulfide microdroplets from the Platinova Reef, which show that they have the highest Se concentrations (up to 1200 ppm) and lowest S/Se ratios (190–700) of any known magmatic sulfide deposit and have significant Te enrichment. In addition, where sulfide volume increases, there is a change from high Pd-tenor microdroplets trapped in situ to larger, low tenor sulfides. The transition between these two sulfide regimes is marked by sharp peaks in Au, and then Te concentration, followed by a wider peak in Se, which gradually decreases with height. Mineralogical evidence implies that there is no significant post-magmatic hydrothermal S loss and that the metal profiles are essentially a function of magmatic processes. We propose that to generate these extreme precious and semimetal contents, the sulfides must have formed from an anomalously metal-rich package of magma, possibly formed via the dissolution of a previously PGE-enriched sulfide. Other processes such as kinetic diffusion may have also occurred alongside this to produce the ultra-high tenors. The characteristic metal offset pattern observed is largely controlled by partitioning effects, producing offset peaks in the order Pt+Pd>Au>Te>Se>Cu that are entirely consistent with published D values. This study confirms that extreme enrichment in sulfide droplets can occur in closed-system layered intrusions in situ, but this will characteristically form ore deposits that are so low in sulfide that they do not conform to conventional deposit models for Cu–Ni–PGE sulfides which require very high R factors, and settling of sulfide liquids

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