RORα and 25-Hydroxycholesterol Crosstalk Regulates Lipid Droplet Homeostasis in Macrophages.

Nuclear hormone receptors have important roles in the regulation of metabolic and inflammatory pathways. The retinoid-related orphan receptor alpha (Rorα)-deficient staggerer (sg/sg) mice display several phenotypes indicative of aberrant lipid metabolism, including dyslipidemia, and increased susceptibility to atherosclerosis. In this study we demonstrate that macrophages from sg/sg mice have increased ability to accumulate lipids and accordingly exhibit larger lipid droplets (LD). We have previously shown that BMMs from sg/sg mice have significantly decreased expression of cholesterol 25-hydroxylase (Ch25h) mRNA, the enzyme that produces the oxysterol, 25-hydroxycholesterol (25HC), and now confirm this at the protein level. 25HC functions as an inverse agonist for RORα. siRNA knockdown of Ch25h in macrophages up-regulates Vldlr mRNA expression and causes increased accumulation of LDs. Treatment with physiological concentrations of 25HC in sg/sg macrophages restored lipid accumulation back to normal levels. Thus, 25HC and RORα signify a new pathway involved in the regulation of lipid homeostasis in macrophages, potentially via increased uptake of lipid which is suggested by mRNA expression changes in Vldlr and other related genes

LoCuSS: A Comparison of Sunyaev-Zel'dovich Effect and Gravitational Lensing Measurements of Galaxy Clusters

We present the first measurement of the relationship between the Sunyaev-Zel'dovich effect signal and the mass of galaxy clusters that uses gravitational lensing to measure cluster mass, based on 14 X-ray luminous clusters at z~0.2 from the Local Cluster Substructure Survey. We measure the integrated Compton y-parameter, Y, and total projected mass of the clusters (M_GL) within a projected clustercentric radius of 350 kpc, corresponding to mean overdensities of 4000-8000 relative to the critical density. We find self-similar scaling between M_GL and Y, with a scatter in mass at fixed Y of 32%. This scatter exceeds that predicted from numerical cluster simulations, however, it is smaller than comparable measurements of the scatter in mass at fixed T_X. We also find no evidence of segregation in Y between disturbed and undisturbed clusters, as had been seen with T_X on the same physical scales. We compare our scaling relation to the Bonamente et al. relation based on mass measurements that assume hydrostatic equilibrium, finding no evidence for a hydrostatic mass bias in cluster cores (M_GL = 0.98+/-0.13 M_HSE), consistent with both predictions from numerical simulations and lensing/X-ray-based measurements of mass-observable scaling relations at larger radii. Overall our results suggest that the Sunyaev-Zel'dovich effect may be less sensitive than X-ray observations to the details of cluster physics in cluster cores.Comment: Minor changes to match published version: 2009 ApJL 701:114-11

Investigation on the direct and bystander effects in HeLa cells exposed to very low α-radiation using electrical impedance measurement

The impact of radiation-induced bystander effect (RIBE) is still not well understood in radiotherapy. RIBEs are biological effects expressed by nonirradiated cells near or far from the irradiated cells. Most radiological studies on cancer cells have been based on biochemical characterization. However, biophysical investigation with label-free techniques to analyze and compare the direct irradiation effect and RIBE has lagged. In this work, we employed an electrical cell-indium tin oxide (ITO) substrate impedance system (ECIIS) as a bioimpedance sensor to evaluate the HeLa cells’ response. The bioimpedance of untreated/nonirradiated HeLa (N-HeLa) cells, α-particle (Am-241)-irradiated HeLa (I-HeLa) cells, and bystander HeLa (B-HeLa) cells exposed to media from I-HeLa cells was monitored with a sampling interval of 8 s over a period of 24 h. Also, we imaged the cells at times where impedance changes were observed. Different radiation doses (0.5 cGy, 1.2 cGy, and 1.7 cGy) were used to investigate I-HeLa and B-HeLa cells’ radiation-dose-dependence. By analyzing the changes in absolute impedance and cell size/number with time, compared to N-HeLa cells, B-HeLa cells mimicked the I-HeLa cells’ damage and modification of proliferation rate. Contrary to the irradiated cells, the bystander cells’ damage rate and proliferation rate enhancements have an inverse radiation-dose-response. Also, we report multiple RIBEs in HeLa cells in a single measurement and provide crucial insights into the RIBE mechanism without any labeling procedure. Unambiguously, our results have shown that the time-dependent control of RIBE is important during α-radiation-based radiotherapy of HeLa cells

The Atacama Cosmology Telescope: Extragalactic Sources at 148 GHz in the 2008 Survey

We report on extragalactic sources detected in a 455 square-degree map of the southern sky made with data at a frequency of 148 GHz from the Atacama Cosmology Telescope 2008 observing season. We provide a catalog of 157 sources with flux densities spanning two orders of magnitude: from 15 to 1500 mJy. Comparison to other catalogs shows that 98% of the ACT detections correspond to sources detected at lower radio frequencies. Three of the sources appear to be associated with the brightest cluster galaxies of low redshift X-ray selected galaxy clusters. Estimates of the radio to mm-wave spectral indices and differential counts of the sources further bolster the hypothesis that they are nearly all radio sources, and that their emission is not dominated by re-emission from warm dust. In a bright (>50 mJy) 148 GHz-selected sample with complete cross-identifications from the Australia Telescope 20 GHz survey, we observe an average steepening of the spectra between 5, 20, and 148 GHz with median spectral indices of $\alpha_{\rm 5-20} = -0.07 \pm 0.06$, $\alpha_{\rm 20-148} = -0.39 \pm0.04$, and $\alpha_{\rm 5-148} = -0.20 \pm 0.03$. When the measured spectral indices are taken into account, the 148 GHz differential source counts are consistent with previous measurements at 30 GHz in the context of a source count model dominated by radio sources. Extrapolating with an appropriately rescaled model for the radio source counts, the Poisson contribution to the spatial power spectrum from synchrotron-dominated sources with flux density less than 20 mJy is C^{\rm Sync} = (2.8 \pm 0.3) \times 10^{-6} \micro\kelvin^2.Comment: Accepted to Ap

Detailed spectral and morphological analysis of the shell type SNR RCW 86

Aims: We aim for an understanding of the morphological and spectral properties of the supernova remnant RCW~86 and for insights into the production mechanism leading to the RCW~86 very high-energy gamma-ray emission. Methods: We analyzed High Energy Spectroscopic System data that had increased sensitivity compared to the observations presented in the RCW~86 H.E.S.S. discovery publication. Studies of the morphological correlation between the 0.5-1~keV X-ray band, the 2-5~keV X-ray band, radio, and gamma-ray emissions have been performed as well as broadband modeling of the spectral energy distribution with two different emission models. Results:We present the first conclusive evidence that the TeV gamma-ray emission region is shell-like based on our morphological studies. The comparison with 2-5~keV X-ray data reveals a correlation with the 0.4-50~TeV gamma-ray emission.The spectrum of RCW~86 is best described by a power law with an exponential cutoff at $E_{cut}=(3.5\pm 1.2_{stat})$ TeV and a spectral index of $\Gamma$~$1.6\pm 0.2$. A static leptonic one-zone model adequately describes the measured spectral energy distribution of RCW~86, with the resultant total kinetic energy of the electrons above 1 GeV being equivalent to $\sim$0.1\% of the initial kinetic energy of a Type I a supernova explosion. When using a hadronic model, a magnetic field of $B$~100$\mu$G is needed to represent the measured data. Although this is comparable to formerly published estimates, a standard E$^{-2}$ spectrum for the proton distribution cannot describe the gamma-ray data. Instead, a spectral index of $\Gamma_p$~1.7 would be required, which implies that ~$7\times 10^{49}/n_{cm^{-3}}$erg has been transferred into high-energy protons with the effective density $n_{cm^{-3}}=n/ 1$ cm^-3. This is about 10\% of the kinetic energy of a typical Type Ia supernova under the assumption of a density of 1~cm^-3.Comment: accepted for publication by A&

Characterizing the gamma-ray long-term variability of PKS 2155-304 with H.E.S.S. and Fermi-LAT

Studying the temporal variability of BL Lac objects at the highest energies provides unique insights into the extreme physical processes occurring in relativistic jets and in the vicinity of super-massive black holes. To this end, the long-term variability of the BL Lac object PKS 2155-304 is analyzed in the high (HE, 100 MeV 200 GeV) gamma-ray domain. Over the course of ~9 yr of H.E.S.S observations the VHE light curve in the quiescent state is consistent with a log-normal behavior. The VHE variability in this state is well described by flicker noise (power-spectral-density index {\ss}_VHE = 1.10 +0.10 -0.13) on time scales larger than one day. An analysis of 5.5 yr of HE Fermi LAT data gives consistent results ({\ss}_HE = 1.20 +0.21 -0.23, on time scales larger than 10 days) compatible with the VHE findings. The HE and VHE power spectral densities show a scale invariance across the probed time ranges. A direct linear correlation between the VHE and HE fluxes could neither be excluded nor firmly established. These long-term-variability properties are discussed and compared to the red noise behavior ({\ss} ~ 2) seen on shorter time scales during VHE-flaring states. The difference in power spectral noise behavior at VHE energies during quiescent and flaring states provides evidence that these states are influenced by different physical processes, while the compatibility of the HE and VHE long-term results is suggestive of a common physical link as it might be introduced by an underlying jet-disk connection.Comment: 11 pages, 16 figure

Detection of variable VHE gamma-ray emission from the extra-galactic gamma-ray binary LMC P3

Context. Recently, the high-energy (HE, 0.1-100 GeV) $\gamma$-ray emission from the object LMC P3 in the Large Magellanic Cloud (LMC) has been discovered to be modulated with a 10.3-day period, making it the first extra-galactic $\gamma$-ray binary. Aims. This work aims at the detection of very-high-energy (VHE, >100 GeV) $\gamma$-ray emission and the search for modulation of the VHE signal with the orbital period of the binary system. Methods. LMC P3 has been observed with the High Energy Stereoscopic System (H.E.S.S.); the acceptance-corrected exposure time is 100 h. The data set has been folded with the known orbital period of the system in order to test for variability of the emission. Energy spectra are obtained for the orbit-averaged data set, and for the orbital phase bin around the VHE maximum. Results. VHE $\gamma$-ray emission is detected with a statistical significance of 6.4 $\sigma$. The data clearly show variability which is phase-locked to the orbital period of the system. Periodicity cannot be deduced from the H.E.S.S. data set alone. The orbit-averaged luminosity in the $1-10$ TeV energy range is $(1.4 \pm 0.2) \times 10^{35}$ erg/s. A luminosity of $(5 \pm 1) \times 10^{35}$ erg/s is reached during 20% of the orbit. HE and VHE $\gamma$-ray emissions are anti-correlated. LMC P3 is the most luminous $\gamma$-ray binary known so far.Comment: 5 pages, 3 figures, 1 table, accepted for publication in A&

Lithium exposure during pregnancy increases fetal growth

Background: Lithium is an effective treatment in pregnancy and postpartum for the prevention of relapse in bipolar disorder, but there is a lack of knowledge about the potential adverse impact on fetal development. Aims: To investigate the impact of lithium exposure on early fetal growth. Methods: In this retrospective observational cohort study, we included all singleton pregnancies of women using lithium and referred for advanced fetal ultrasound scanning between 1994 and 2018 to the University Medical Centers in Leiden and Rotterdam, the Netherlands (n=119). The Generation R study, a population-based cohort, served as a non-exposed control population from the same geographic region (n=8184). Fetal head circumference, abdominal circumference, femur length, and transcerebellar diameter were measured by ultrasound at 18–22 weeks of gestation. Results: Lithium use during pregnancy was associated with an average increase in head circumference of 1.77 mm (95% confidence interval: 0.53, 3.01), in abdominal circumference of 5.54 mm (95% confidence interval: 3.95, 7.12) and in femur length of 0.59 mm (95% confidence interval: 0.22, 0.96) at 18–22 weeks gestation. Furthermore, lithium use during pregnancy was associated with an average increase in birth weight of 142.43 grams (95% confidence interval: 58.01, 226.89), whereas it was associated with an average decrease of 1.41 weeks in gestational duration (95% confidence interval: −1.78, −1.05). Conclusions: Lithium use during pregnancy was associated with increased fetal growth parameters at 18–22 weeks gestational age and increased birth weight. Furthe

Early Stage Alterations in White Matter and Decreased Functional Interhemispheric Hippocampal Connectivity in the 3xTg Mouse Model of Alzheimer’s Disease

Alzheimer’s disease (AD) is characterized in the late stages by amyloid-β (Aβ) plaques and neurofibrillary tangles. Nevertheless, recent evidence has indicated that early changes in cerebral connectivity could compromise cognitive functions even before the appearance of the classical neuropathological features. Diffusion tensor imaging (DTI), resting-state functional magnetic resonance imaging (rs-fMRI) and volumetry were performed in the triple transgenic mouse model of AD (3xTg-AD) at 2 months of age, prior to the development of intraneuronal plaque accumulation. We found the 3xTg-AD had significant fractional anisotropy (FA) increase and radial diffusivity (RD) decrease in the cortex compared with wild-type controls, while axial diffusivity (AD) and mean diffusivity (MD) were similar. Interhemispheric hippocampal connectivity was decreased in the 3xTg-AD while connectivity in the caudate putamen (CPu) was similar to controls. Most surprising, ventricular volume in the 3xTg-AD was four times larger than controls. The results obtained in this study characterize the early stage changes in interhemispheric hippocampal connectivity in the 3xTg-AD mouse that could represent a translational biomarker to human models in preclinical stages of the AD

Quantitative first principles calculations of protein circular dichroism in the near-ultraviolet

Vibrational structure in the near-UV circular dichroism (CD) spectra of proteins is an important source of information on protein conformation and can be exploited to study structure and folding. A fully quantitative theory of the relationship between protein conformation and optical spectroscopy would facilitate deeper interpretation and insights into biophysical and simulation studies of protein dynamics and folding. We have developed new models of the aromatic side chain chromophores toluene, p-cresol and 3-methylindole, which incorporate ab initio calculations of the Franck-Condon effect into first principles calculations of CD using an exciton approach. The near-UV CD spectra of 40 proteins are calculated with the new parameter set and the correlation between the computed and the experimental intensity from 270 to 290 nm is much improved. The contribution of individual chromophores to the CD spectra has been calculated for several mutants and in many cases helps rationalize changes in their experimental spectra. Considering conformational flexibility by using families of NMR structures leads to further improvements for some proteins and illustrates an informative level of sensitivity to side chain conformation. In several cases, the near-UV CD calculations can distinguish the native protein structure from a set of computer-generated misfolded decoy structures