The 0.5 micrometer-2.2 micrometer Scattered Light Spectrum of the Disk Around TW Hya

We present a 0.5-2.2micron scattered light spectrum of the circumstellar disk around TW Hya from a combination of spatially resolved HST STIS spectroscopy and NICMOS coronagraphic images of the disk. \Ve investigate the morphology at the disk at distances> 40 AU over this wide range of wavelengths. We measure the surface brightness, azimuthal symmetry, and spectral character of the disk as a function of radius. We find that the scattering efficiency of the dust is largely neutral to blue over the observed wavelengths. We find a good fit to the data over a wide range of distances from the star if we use a model disk with a partial gap of 30% depth at 80 AU and with steep disk truncation exterior to 100 AU. If the gap is caused by a planetary companion in the process of accreting disk gas, it must be less than 20 Solar mass

Role of endolysosomes in HIV-1 Tat-induced neurotoxicity

Combined anti-retroviral therapeutic drugs effectively increase the lifespan of HIV-1-infected individuals who then have a higher prevalence of HAND (HIV-1 associated neurocognitive disorder). Soluble factors including HIV-1 proteins released from HIV-1-infected cells have been implicated in the pathogenesis of HAND, and particular attention has been paid to the HIV-1 Tat (transactivator of transcription) protein because of its ability to directly excite neurons and cause neuronal cell death. Since HIV-1 Tat enters cells by receptor-mediated endocytosis and since endolysosomes play an important role in neuronal cell life and death, we tested here the hypothesis that HIV-1 Tat neurotoxicity is associated with changes in the endolysosome structure and function and also autophagy. Following the treatment of primary cultured rat hippocampal neurons with HIV-1 Tat or as controls mutant-Tat or PBS, neuronal viability was determined using a triple staining method. Preceding observations of HIV-1 Tat-induced neuronal cell death, we observed statistically significant changes in the structure and membrane integrity of endolysosomes, endolysosome pH and autophagy. As early as 24 h after HIV-1 Tat was applied to neurons, HIV-1 Tat accumulated in endolysosomes, endolysosome morphology was affected and their size increased, endolysosome membrane integrity was disrupted, endolysosome pH increased, specific activities of endolysosome enzymes decreased and autophagy was inhibited, as indicated by the significant changes in three markers for autophagy. In contrast, statistically significant levels of HIV-1 Tat-induced neuronal cell death were observed only after 48 h of HIV-1 Tat treatment. Our findings suggest that endolysosomes are involved in HIV-1 Tat-induced neurotoxicity and may represent a target for therapeutic intervention against HAND

New methods for analysis of oxysterols and related compounds by LC–MS

Oxysterols are oxygenated forms of cholesterol or its precursors. They are formed enzymatically and via reactive oxygen species. Oxysterols are intermediates in bile acid and steroid hormone biosynthetic pathways and are also bioactive molecules in their own right, being ligands to nuclear receptors and also regulators of the processing of steroid regulatory element-binding proteins (SREBPs) to their active forms as transcription factors regulating cholesterol and fatty acid biosynthesis. Oxysterols are implicated in the pathogenesis of multiple disease states ranging from atherosclerosis and cancer to multiple sclerosis and other neurodegenerative diseases including Alzheimer’s and Parkinson’s disease. Analysis of oxysterols is challenging on account of their low abundance in biological systems in comparison to cholesterol, and due to the propensity of cholesterol to undergo oxidation in air to generate oxysterols with the same structures as those present endogenously. In this article we review the mass spectrometry-based methods for oxysterol analysis paying particular attention to analysis by liquid chromatography – mass spectrometry (LC-MS)

Cholesterolomics: An update

Cholesterolomics can be regarded as the identification and quantification of cholesterol, its precursors post squalene, and metabolites of cholesterol and of its precursors, in a biological sample. These molecules include 1,25-dihydroxyvitamin D3, steroid hormones and bile acids and intermediates in their respective biosynthetic pathways. In this short article we will concentrate our attention on intermediates in bile acid biosynthesis pathways, in particular oxysterols and cholestenoic acids. These molecular classes are implicated in the aetiology of a diverse array of diseases including autoimmune disease, Parkinson's disease, motor neuron disease, breast cancer, the lysosomal storage disease Niemann-Pick type C and the autosomal recessive disorder Smith-Lemli-Opitz syndrome. Mass spectrometry (MS) is the dominant technology for sterol analysis including both gas-chromatography (GC)-MS and liquid chromatography (LC)-MS and more recently matrix-assisted laser desorption/ionisation (MALDI)-MS for tissue imaging studies. Here we will discuss exciting biological findings and recent analytical improvements

Effects of dog ownership in early childhood on immune development and atopic diseases

Summary Background Exposure to pets in childhood has been associated with a reduced risk of wheezing and atopy. Objective Our objective was to determine whether the effects of pet exposure on immune development and atopy in early childhood can be explained by alterations in exposure to innate immune stimuli in settled dust. Methods Two hundred and seventy-five children at increased risk of developing allergic diseases were evaluated to age 3 years for pet ownership, blood cell cytokine responses, and atopy. Can f 1, Fel d 1, endotoxin, ergosterol, and muramic acid were measured in settled dust from 101 homes. Results Dog exposure at birth was associated with decreased atopic dermatitis (AD) (12% vs. 27%; P = 0.004) and wheezing (19% vs. 36%; P = 0.005) in year 3. The rates of AD (23%) and wheezing (42%) in year 3 were relatively high in children who acquired dogs after birth. The prevalence of dog sensitization (10-12%) did not vary according to dog exposure. Can f 1 levels in bedroom dust were positively associated with IL-10 (r = 0.26; P = 0.01), IL-5 (r = 0.34, P o 0.001), and IL-13 (r = 0.28; P = 0.004) responses at age 1, and IL-5 (r = 0.24; P = 0.022) and IL-13 (r = 0.25; P = 0.015) responses at age 3. In contrast, endotoxin was associated with IFN-g (r = 0.31; P = 0.002) and IL-13 (r = 0.27; P = 0.01) responses at age 3 but not at age 1, and similar relationships were present for muramic acid. Adjustment for levels of innate immune stimuli in house dust did not significantly affect the relationships between Can f 1 and cytokine responses. Conclusions Exposure to dogs in infancy, and especially around the time of birth, is associated with changes in immune development and reductions in wheezing and atopy. These findings are not explained by exposure to endotoxin, ergosterol, or muramic acid

α-Arrestins Aly1 and Aly2 Regulate Intracellular Trafficking in Response to Nutrient Signaling

Arrestins, known regulators of endocytosis, take on novel functions in nutrient-regulated endosomal recycling. Yeast α-arrestins, Aly1 and Aly2, redistribute the Gap1 permease from endosomes to the cell surface and interact with clathrin/AP-1. Aly2 is regulated by the Npr1 kinase and acts through mechanisms distinct from Aly1

Impaired LXRa phosphorylation attenuates progression of fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) is a very common indication for liver transplantation. How fat-rich diets promote progression from fatty liver to more damaging inflammatory and fibrotic stages is poorly understood. Here, we show that disrupting phosphorylation at Ser196 (S196A) in the liver X receptor alpha (LXRα, NR1H3) retards NAFLD progression in mice on a high-fat-high-cholesterol diet. Mechanistically, this is explained by key histone acetylation (H3K27) and transcriptional changes in pro-fibrotic and pro-inflammatory genes. Furthermore, S196A-LXRα expression reveals the regulation of novel diet-specific LXRα-responsive genes, including the induction of Ces1f, implicated in the breakdown of hepatic lipids. This involves induced H3K27 acetylation and altered LXR and TBLR1 cofactor occupancy at the Ces1f gene in S196A fatty livers. Overall, impaired Ser196-LXRα phosphorylation acts as a novel nutritional molecular sensor that profoundly alters the hepatic H3K27 acetylome and transcriptome during NAFLD progression placing LXRα phosphorylation as an alternative anti-inflammatory or anti-fibrotic therapeutic target