Background Monocyte-derived macrophages critically perpetuate inflammatory responses after liver injury as a prerequisite for organ fibrosis. Experimental murine models identified an essential role ...for the CCR2-dependent infiltration of classical Gr1/Ly6C+ monocytes in hepatic fibrosis. Moreover, the monocyte-related chemokine receptors CCR1 and CCR5 were recently recognized as important fibrosis modulators in mice. In humans, monocytes consist of classical CD14+CD16− and non-classical CD14+CD16+ cells. We aimed at investigating the relevance of monocyte subpopulations for human liver fibrosis, and hypothesized that ‘non-classical’ monocytes critically exert inflammatory as well as profibrogenic functions in patients during liver disease progression. Methodology/Principal Findings We analyzed circulating monocyte subsets from freshly drawn blood samples of 226 patients with chronic liver disease (CLD) and 184 healthy controls by FACS analysis. Circulating monocytes were significantly expanded in CLD-patients compared to controls with a marked increase of the non-classical CD14+CD16+ subset that showed an activated phenotype in patients and correlated with proinflammatory cytokines and clinical progression. Correspondingly, CD14+CD16+ macrophages massively accumulated in fibrotic/cirrhotic livers, as evidenced by immunofluorescence and FACS. Ligands of monocyte-related chemokine receptors CCR2, CCR1 and CCR5 were expressed at higher levels in fibrotic and cirrhotic livers, while CCL3 and CCL4 were also systemically elevated in CLD-patients. Isolated monocyte/macrophage subpopulations were functionally characterized regarding cytokine/chemokine expression and interactions with primary human hepatic stellate cells (HSC) in vitro. CD14+CD16+ monocytes released abundant proinflammatory cytokines. Furthermore, CD14+CD16+, but not CD14+CD16− monocytes could directly activate collagen-producing HSC. Conclusions/Significance Our data demonstrate the expansion of CD14+CD16+ monocytes in the circulation and liver of CLD-patients upon disease progression and suggest their functional contribution to the perpetuation of intrahepatic inflammation and profibrogenic HSC activation in liver cirrhosis. The modulation of monocyte-subset recruitment into the liver via chemokines/chemokine receptors and their subsequent differentiation may represent promising approaches for therapeutic interventions in human liver fibrosis.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Insomnia is the second most prevalent mental disorder, with no sufficient treatment available. Despite substantial heritability, insight into the associated genes and neurobiological pathways remains ...limited. Here, we use a large genetic association sample (n = 1,331,010) to detect novel loci and gain insight into the pathways, tissue and cell types involved in insomnia complaints. We identify 202 loci implicating 956 genes through positional, expression quantitative trait loci, and chromatin mapping. The meta-analysis explained 2.6% of the variance. We show gene set enrichments for the axonal part of neurons, cortical and subcortical tissues, and specific cell types, including striatal, hypothalamic, and claustrum neurons. We found considerable genetic correlations with psychiatric traits and sleep duration, and modest correlations with other sleep-related traits. Mendelian randomization identified the causal effects of insomnia on depression, diabetes, and cardiovascular disease, and the protective effects of educational attainment and intracranial volume. Our findings highlight key brain areas and cell types implicated in insomnia, and provide new treatment targets.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The QCD axion is a leading dark matter candidate that emerges as part of the solution to the strong-CP problem in the Standard Model. The coupling of the axion to photons is the most common ...experimental probe, but much parameter space remains unexplored. The coupling of the QCD axion to the Standard Model scales linearly with the axion mass; therefore, the highly motivated region 0.4–120 neV, corresponding to a GUT-scale axion, is particularly difficult to reach. This paper presents the design requirements for a definitive search for GUT-scale axions and reviews the technological advances needed to enable this program.
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CMK, CTK, FMFMET, IJS, NUK, PNG, UM
We present a catalog of galaxy cluster candidates detected in 100 square degrees surveyed with the SPTpol receiver on the South Pole Telescope. The catalog contains 89 candidates detected with a ...signal-to-noise ratio greater than 4.6. The candidates are selected using the Sunyaev-Zel'dovich effect at 95 and 150 GHz. Using both space- and ground-based optical and infrared telescopes, we have confirmed 81 candidates as galaxy clusters. We use these follow-up images and archival images to estimate photometric redshifts for 66 galaxy clusters and spectroscopic observations to obtain redshifts for 13 systems. An additional two galaxy clusters are confirmed using the overdensity of near-infrared galaxies only and are presented without redshifts. We find that 15 candidates (18% of the total sample) are at redshift z ≥ 1.0, with a maximum confirmed redshift of . We expect this catalog to contain every galaxy cluster with and z > 0.25 in the survey area. The mass threshold is approximately constant above z = 0.25, and the complete catalog has a median mass of approximately . Compared to previous SPT works, the increased depth of the millimeter-wave data (11.2 and 6.5 K-arcmin at 95 and 150 GHz, respectively) makes it possible to find more galaxy clusters at high redshift and lower mass.
Proton MRS (1H MRS) provides noninvasive, quantitative metabolite profiles of tissue and has been shown to aid the clinical management of several brain diseases. Although most modern clinical MR ...scanners support MRS capabilities, routine use is largely restricted to specialized centers with good access to MR research support. Widespread adoption has been slow for several reasons, and technical challenges toward obtaining reliable good‐quality results have been identified as a contributing factor. Considerable progress has been made by the research community to address many of these challenges, and in this paper a consensus is presented on deficiencies in widely available MRS methodology and validated improvements that are currently in routine use at several clinical research institutions. In particular, the localization error for the PRESS localization sequence was found to be unacceptably high at 3 T, and use of the semi‐adiabatic localization by adiabatic selective refocusing sequence is a recommended solution. Incorporation of simulated metabolite basis sets into analysis routines is recommended for reliably capturing the full spectral detail available from short TE acquisitions. In addition, the importance of achieving a highly homogenous static magnetic field (B0) in the acquisition region is emphasized, and the limitations of current methods and hardware are discussed. Most recommendations require only software improvements, greatly enhancing the capabilities of clinical MRS on existing hardware. Implementation of these recommendations should strengthen current clinical applications and advance progress toward developing and validating new MRS biomarkers for clinical use.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Gravitational lensing of the cosmic microwave background generates a curl pattern in the observed polarization. This "B-mode" signal provides a measure of the projected mass distribution over the ...entire observable Universe and also acts as a contaminant for the measurement of primordial gravity-wave signals. In this Letter we present the first detection of gravitational lensing B modes, using first-season data from the polarization-sensitive receiver on the South Pole Telescope (SPTpol). We construct a template for the lensing B-mode signal by combining E-mode polarization measured by SPTpol with estimates of the lensing potential from a Herschel-SPIRE map of the cosmic infrared background. We compare this template to the B modes measured directly by SPTpol, finding a nonzero correlation at 7.7σ significance. The correlation has an amplitude and scale dependence consistent with theoretical expectations, is robust with respect to analysis choices, and constitutes the first measurement of a powerful cosmological observable.
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CMK, CTK, FMFMET, IJS, NUK, PNG, UM
We present a far-IR survey of the entire Mon R2 giant molecular cloud (GMC) with Herschel–Spectral and Photometric Imaging REceiver cross-calibrated with Planck-High Frequency Instrument data. We fit ...the spectral energy distributions of each pixel with a greybody function and an optimal beta value of 1.8. We find that mid-range column densities obtained from far-IR dust emission and near-IR extinction are consistent. For the entire GMC, we find that the column density histogram, or column density probability distribution function (N-PDF), is lognormal below ∼1021 cm−2. Above this value, the distribution takes a power law form with an index of −2.15. We analyse the gas geometry, N-PDF shape, and young stellar object (YSO) content of a selection of subregions in the cloud. We find no regions with pure lognormal N-PDFs. The regions with a combination of lognormal and one power-law N-PDF have a YSO cluster and a corresponding centrally concentrated gas clump. The regions with a combination of lognormal and two power-law N-PDF have significant numbers of typically younger YSOs but no prominent YSO cluster. These regions are composed of an aggregate of closely spaced gas filaments with no concentrated dense gas clump. We find that for our fixed scale regions, the YSO count roughly correlates with the N-PDF power-law index. The correlation appears steeper for single power-law regions relative to two power-law regions with a high column density cut-off, as a greater dense gas mass fraction is achieved in the former. A stronger correlation is found between embedded YSO count and the dense gas mass among our regions.
ABSTRACT We present a measurement of the B-mode polarization power spectrum (the BB spectrum) from 100 of sky observed with SPTpol, a polarization-sensitive receiver currently installed on the South ...Pole Telescope. The observations used in this work were taken during 2012 and early 2013 and include data in spectral bands centered at 95 and 150 GHz. We report the BB spectrum in five bins in multipole space, spanning the range , and for three spectral combinations: 95 GHz × 95 GHz, 95 GHz × 150 GHz, and 150 GHz × 150 GHz. We subtract small (<0.5 in units of statistical uncertainty) biases from these spectra and account for the uncertainty in those biases. The resulting power spectra are inconsistent with zero power but consistent with predictions for the BB spectrum arising from the gravitational lensing of E-mode polarization. If we assume no other source of BB power besides lensed B modes, we determine a preference for lensed B modes of 4.9 . After marginalizing over tensor power and foregrounds, namely, polarized emission from galactic dust and extragalactic sources, this significance is 4.3 . Fitting for a single parameter, , that multiplies the predicted lensed B-mode spectrum, and marginalizing over tensor power and foregrounds, we find , indicating that our measured spectra are consistent with the signal expected from gravitational lensing. The data presented here provide the best measurement to date of the B-mode power spectrum on these angular scales.
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