Evidence for low-density lipoprotein–induced expression of connective tissue growth factor in mesangial cells

Evidence for low-density lipoprotein–induced expression of connective tissue growth factor in mesangial cells.BackgroundAlthough hyperlipidemia is a risk factor for the progression of renal damage, the relationship between increased plasma lipoproteins and glomerular injury is poorly defined. Connective tissue growth factor (CTGF) is emerging as a key determinant of progressive fibrotic diseases and its expression is up-regulated by diabetes. To define the mechanisms through which low-density lipoproteins (LDLs) promote glomerular injury, we evaluated whether LDL can modulate the expression of CTGF and collagen I.MethodsThe effects of LDL on CTGF and collagen I expression were carried out in rat mesangial cells.ResultsTreatment of mesangial cells with LDL for 24 hours produced a significant increase in the protein levels of CTGF and collagen I compared to unstimulated controls. To explore if CTGF and collagen I are downstream targets for regulation by transforming growth factor-β (TGF-β), mesangial cells were treated with various concentration of TGF-β for 24 hours. TGF-β produced a concentration-dependent increase in the protein levels of CTGF and collagen I. The increase in CTGF and collagen I induced by LDL was significantly inhibited by neutralizing anti-TGF-β antibodies. Inhibition of p38mapk or p42/44mapk activities did not affect LDL-induced TGF-β1, CTGF, and collagen I expression, whereas inhibition of c-Jun NH2-terminal kinase (JNK) suppressed LDL-induced TGF-β, CTGF, and collagen I expression.ConclusionThese findings implicate JNK pathway and TGF-β1 as key players in LDL signaling leading to CTGF and collagen I expression in mesangial cells. The data also point to a potential mechanistic pathway through which lipoproteins may promote glomerular injury

Reinforcement Learning for Sparse-Reward Object-Interaction Tasks in First-person Simulated 3D Environments

First-person object-interaction tasks in high-fidelity, 3D, simulated environments such as the AI2Thor virtual home-environment pose significant sample-efficiency challenges for reinforcement learning (RL) agents learning from sparse task rewards. To alleviate these challenges, prior work has provided extensive supervision via a combination of reward-shaping, ground-truth object-information, and expert demonstrations. In this work, we show that one can learn object-interaction tasks from scratch without supervision by learning an attentive object-model as an auxiliary task during task learning with an object-centric relational RL agent. Our key insight is that learning an object-model that incorporates object-attention into forward prediction provides a dense learning signal for unsupervised representation learning of both objects and their relationships. This, in turn, enables faster policy learning for an object-centric relational RL agent. We demonstrate our agent by introducing a set of challenging object-interaction tasks in the AI2Thor environment where learning with our attentive object-model is key to strong performance. Specifically, we compare our agent and relational RL agents with alternative auxiliary tasks to a relational RL agent equipped with ground-truth object-information, and show that learning with our object-model best closes the performance gap in terms of both learning speed and maximum success rate. Additionally, we find that incorporating object-attention into an object-model's forward predictions is key to learning representations which capture object-category and object-state

The VMC survey - XVII : The proper motions of the Small Magellanic Cloud and the Milky Way globular cluster 47 Tucanae

In this study we use multi-epoch near-infrared observations from the VISTA survey of the Magellanic Cloud system (VMC) to measure the proper motion of different stellar populations in a tile of 1.5 deg sq. in size in the direction of the Galactic globular cluster 47 Tuc. We obtain the proper motion of the cluster itself, of the Small Magellanic Cloud (SMC), and of the field Milky Way stars. Stars of the three main stellar components are selected from their spatial distribution and their distribution in colour-magnitude diagrams. Their average coordinate displacement is computed from the difference between multiple Ks-band observations for stars as faint as Ks=19 mag. Proper motions are derived from the slope of the best-fitting line among 10 VMC epochs over a time baseline of ~1 yr. Background galaxies are used to calibrate the absolute astrometric reference frame. The resulting absolute proper motion of 47 Tuc is (mu_alpha cos(delta), mu_delta)=(+7.26+/-0.03, -1.25+/-0.03) mas/yr. This measurement refers to about 35000 sources distributed between 10 and 60 arcmin from the cluster centre. For the SMC we obtain (mu_alpha cos(delta), mu_delta)=(+1.16+/-0.07, -0.81+/-0.07) mas/yr from about 5250 red clump and red giant branch stars. The absolute proper motion of the Milky Way population in the line-of-sight (l =305.9, b =-44.9) of this VISTA tile is (mu_alpha cos(delta), mu_delta)=(+10.22+/-0.14, -1.27+/-0.12) mas/yr and results from about 4000 sources. Systematic uncertainties associated to the astrometric reference system are 0.18 mas/yr. Thanks to the proper motion we detect 47 Tuc stars beyond its tidal radius.Peer reviewe

Infrared Nonlinear Optics

Contains reports on six research projects.Defense Advanced Research Projects Agency Universities Research Initiative (Contract N00014-46-K-0760)Strategic Defense Initiative/Innovative Science & Technology, managed by the U.S. Naval Research Laboratory (Contract N00014-87-K-2031)National Science Foundation (Grant EET-87-18417

The SPLASH Survey: A Spectroscopic Portrait of Andromeda's Giant Southern Stream

The giant southern stream (GSS) is the most prominent tidal debris feature in M31's stellar halo. The GSS is composed of a relatively metal-rich, high surface-brightness "core" and a lower metallicity, lower surface brightness "envelope." We present Keck/DEIMOS spectroscopy of red giant stars in six fields in the vicinity of M31's GSS and one field on Stream C, an arc-like feature on M31's SE minor axis at R=60 kpc. Several GSS-related findings and measurements are presented here. We present the innermost kinematical detection of the GSS core to date (R=17 kpc). This field also contains the continuation of a second kinematically cold component originally seen in a GSS core field at R=21 kpc. The velocity gradients of the GSS and the second component in the combined data set are parallel over a radial range of 7 kpc, suggesting a possible bifurcation in the line-of-sight velocities of GSS stars. We also present the first kinematical detection of substructure in the GSS envelope. Using kinematically identified samples, we show that the envelope debris has a ~0.7 dex lower mean photometric metallicity and possibly higher intrinsic velocity dispersion than the GSS core. The GSS is also identified in the field of the M31 dSph satellite And I; the GSS in this field has a metallicity distribution identical to that of the GSS core. We confirm the presence of two kinematically cold components in Stream C, and measure intrinsic velocity dispersions of ~10 and ~4 km/s. This compilation of the kinematical (mean velocity, intrinsic velocity dispersion) and chemical properties of stars in the GSS core and envelope, coupled with published surface brightness measurements and wide-area star-count maps, will improve constraints on the orbit and internal structure of the dwarf satellite progenitor.Comment: Accepted for publication in Ap

PEG Branched Polymer for Functionalization of Nanomaterials with Ultralong Blood Circulation

Nanomaterials have been actively pursued for biological and medical applications in recent years. Here, we report the synthesis of several new poly(ethylene glycol) grafted branched-polymers for functionalization of various nanomaterials including carbon nanotubes, gold nanoparticles (NP) and gold nanorods (NRs), affording high aqueous solubility and stability for these materials. We synthesize different surfactant polymers based upon poly-(g-glutamic acid) (gPGA) and poly(maleic anhydride-alt-1-octadecene) (PMHC18). We use the abundant free carboxylic acid groups of gPGA for attaching lipophilic species such as pyrene or phospholipid, which bind to nanomaterials via robust physisorption. Additionally, the remaining carboxylic acids on gPGA or the amine-reactive anhydrides of PMHC18 are then PEGylated, providing extended hydrophilic groups, affording polymeric amphiphiles. We show that single-walled carbon nanotubes (SWNTs), Au NPs and NRs functionalized by the polymers exhibit high stability in aqueous solutions at different pHs, at elevated temperatures and in serum. Morever, the polymer-coated SWNTs exhibit remarkably long blood circulation (t1/2 22.1 h) upon intravenous injection into mice, far exceeding the previous record of 5.4 h. The ultra-long blood circulation time suggests greatly delayed clearance of nanomaterials by the reticuloendothelial system (RES) of mice, a highly desired property for in vivo applications of nanomaterials, including imaging and drug delivery

Exploring Halo Substructure with Giant Stars XI: The Tidal Tails of the Carina Dwarf Spheroidal and the Discovery of Magellanic Cloud Stars in the Carina Foreground

A new large-area Washington M,T_2+DDO51 filter survey of more than 10 deg^2 around the Carina dSph galaxy reveals a spectroscopically confirmed power law radial density "break" population of Carina giant stars extending several degrees beyond the central King profile. Magellan telescope MIKE spectroscopy establishes the existence of Carina stars to at least 4.5 times its central King limiting radius, r_lim and primarily along Carina's major axis. To keep these stars bound to the dSph would require a global Carina mass-to-light ratio of M/L > 6,300 M/L_sun. The MIKE velocities, supplemented with ~950 additional Carina field velocities from archived VLT+GIRAFFE spectra with r<=r_lim, demonstrate a nearly constant Carina velocity dispersion to just beyond r = r_lim, and both a rising velocity dispersion and a velocity shear at still larger radii. Together, the observational evidence suggests that the discovered extended Carina population represents tidal debris from the dSph. Of 65 giant candidates at large angular radii from the Carina center for which MIKE spectra have been obtained 94% are associated either with Carina or a second, newly discovered diffuse, but strongly radial velocity-coherent (velocity dispersion of 9.8 km s^-1), foreground halo system. The fifteen stars in this second, retrograde velocity population have (1) a mean metallicity ~1 dex higher than that of Carina, and (2) colors and magnitudes consistent with the red clump of the Large Magellanic Cloud (LMC). Additional spectroscopy of giant star candidates in fields linking Carina and the LMC shows a smooth velocity gradient between the LMC and the retrograde Carina moving group. We conclude that we have found Magellanic stars almost twice as far (22 deg) from the LMC center than previously known.Comment: ApJ, in pres

Evidence that breast cancer risk at the 2q35 locus is mediated through IGFBP5 regulation.

GWAS have identified a breast cancer susceptibility locus on 2q35. Here we report the fine mapping of this locus using data from 101,943 subjects from 50 case-control studies. We genotype 276 SNPs using the 'iCOGS' genotyping array and impute genotypes for a further 1,284 using 1000 Genomes Project data. All but two, strongly correlated SNPs (rs4442975 G/T and rs6721996 G/A) are excluded as candidate causal variants at odds against &gt;100:1. The best functional candidate, rs4442975, is associated with oestrogen receptor positive (ER+) disease with an odds ratio (OR) in Europeans of 0.85 (95% confidence interval=0.84-0.87; P=1.7 × 10(-43)) per t-allele. This SNP flanks a transcriptional enhancer that physically interacts with the promoter of IGFBP5 (encoding insulin-like growth factor-binding protein 5) and displays allele-specific gene expression, FOXA1 binding and chromatin looping. Evidence suggests that the g-allele confers increased breast cancer susceptibility through relative downregulation of IGFBP5, a gene with known roles in breast cell biology

Behavior of a Metabolic Cycling Population at the Single Cell Level as Visualized by Fluorescent Gene Expression Reporters

BACKGROUND: During continuous growth in specific chemostat cultures, budding yeast undergo robust oscillations in oxygen consumption that are accompanied by highly periodic changes in transcript abundance of a majority of genes, in a phenomenon called the Yeast Metabolic Cycle (YMC). This study uses fluorescent reporters of genes specific to different YMC phases in order to visualize this phenomenon and understand the temporal regulation of gene expression at the level of individual cells within the cycling population. METHODOLOGY: Fluorescent gene expression reporters for different phases of the YMC were constructed and stably integrated into the yeast genome. Subsequently, these reporter-expressing yeast were used to visualize YMC dynamics at the individual cell level in cultures grown in a chemostat or in a microfluidics platform under varying glucose concentrations, using fluorescence microscopy and quantitative Western blots. CONCLUSIONS: The behavior of single cells within a metabolic cycling population was visualized using phase-specific fluorescent reporters. The reporters largely recapitulated genome-specified mRNA expression profiles. A significant fraction of the cell population appeared to exhibit basal expression of the reporters, supporting the hypothesis that there are at least two distinct subpopulations of cells within the cycling population. Although approximately half of the cycling population initiated cell division in each permissive window of the YMC, metabolic synchrony of the population was maintained. Using a microfluidics platform we observed that low glucose concentrations appear to be necessary for metabolic cycling. Lastly, we propose that there is a temporal window in the oxidative growth phase of the YMC where the cycling population segregates into at least two subpopulations, one which will enter the cell cycle and one which does not

COVID-19 Molecular Pathophysiology::Acetylation of Repurposing Drugs

Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces immune-mediated type 1 interferon (IFN-1) production, the pathophysiology of which involves sterile alpha motif and histidine-aspartate domain-containing protein 1 (SAMHD1) tetramerization and the cytosolic DNA sensor cyclic-GMP-AMP synthase (cGAS)–stimulator of interferon genes (STING) signaling pathway. As a result, type I interferonopathies are exacerbated. Aspirin inhibits cGAS-mediated signaling through cGAS acetylation. Acetylation contributes to cGAS activity control and activates IFN-1production and nuclear factor-κB (NF-κB) signaling via STING. Aspirin and dapsone inhibit the activation of both IFN-1 and NF-κB by targeting cGAS. We define these as anticatalytic mechanisms. It is necessary to alleviate the pathologic course and take the lag time of the odds of achieving viral clearance by day 7 to coordinate innate or adaptive immune cell reactions