Mercury accumulation in kidney lysosomes of proteinuric rats

Mercury accumulation in kidney lysosomes of proteinuric rats. The purpose of the present study was to determine whether lysosomal accumulation of mercury in the kidney is due to a leakage of protein-bound mercury through the glomerular filtration barrier followed by reabsorption into the lysosomal system of the proximal tubule. The subcellular distribution of mercury in the kidney was studied in four different groups of rats with and without proteinuria: normal young rats, young rats With amino-nucleoside nephrosis, old rats with spontaneous proteinuria, and old rats with chronic mercury intoxication and proteinuria. Radioactive mercuric chloride (203HgCl2) was injected s.c. into the rats 72 hours before sacrifice. Cell fractionation experiments were carried out on homogenates of the renal cortex by differential centrifugation. Determination of radioactive mercury in the subcellular fractions revealed that mercury was concentrated in the lysosomal fraction of all rats with proteinuria. In contrast, normal rats without proteinuria had the highest concentration of mercury in the supernatant, and there was no enrichment of mercury in the lysosomal fraction. Gel filtration chromatography performed on urine samples from proteinuric rats demonstrated that excreted mercury was associated with the albumin fraction. The accumulation of mercury in renal lysosomes of proteinuric rats and the demonstration of mercury bound to albumin in the urine support the hypothesis that mercury bound to plasma proteins passes the glomerular filtration barrier in proteinuric conditions and enters the lysosomal system of the proximal tubule by way of endocytosis.Accumulation de mercure dans les lysosomes rénaux de rats protéinuriques. Le but de ce travail a été de déterminer si l'accumulation lysosomale de mercure dans le rein est due à une fuite de mercure lié aux protéines à travers la barrière de filtration glomérulaire suivie d'une réabsorption dans le système lysosomal du tube proximal. La distribution subcellulaire du mercure a été étudiée dans quatre groupes de rats : des jeunes rats normaux, des jeunes rats atteints de néphropathie de l'aminonucléoside, des rats âgés avec une protéinurie spontanée et des rats âgés avec une intoxication mercurielle chronique et une proteinurie Du mercure radioactif (203HgCl2) a été injecté par voie sous-cutanée à des rats 72 heures avant le sacrifice. Le fractionnement cellulaire a été réalisé sur des homogénats de cortex rénal par centrifugation différentielle. La détermination du mercure radioactif dans les fractions subcellulaires a révélé que le mercure est concentré dans la fraction lysosomale de tous les rats protéinuriques. Les rats normaux sans protéinurie au contraire, ont une concentration de mercure plus élevée dans le surnageant et il n'y a pas d'enrichissement en mercure de la fraction lysosomale. La chromatographie par filtration sur gel réalisée sur les échantillons d'urine de rats protéinuriques a démontré que du mercure excrété est associée à la fraction albuminique. L'accumulation de mercure dans les lysosomes rénaux des rats protéinuriques et la mise en évidence de mercure lié à l'albumine dans l'urine sont en faveur de l'hypothèse selon laquelle le mercure lié à des protéines plasmatiques passe la barrière de filtration glomérulaire dans les situations où il existe une protéinurie et entre dans le système lysosomal du tube proximal par endocytose

Finite Number and Finite Size Effects in Relativistic Bose-Einstein Condensation

Bose-Einstein condensation of a relativistic ideal Bose gas in a rectangular cavity is studied. Finite size corrections to the critical temperature are obtained by the heat kernel method. Using zeta-function regularization of one-loop effective potential, lower dimensional critical temperatures are calculated. In the presence of strong anisotropy, the condensation is shown to occur in multisteps. The criteria of this behavior is that critical temperatures corresponding to lower dimensional systems are smaller than the three dimensional critical temperature.Comment: 18 pages, 9 figures, Fig.3 replaced, to appear in Physical Review

SNHG16 is regulated by the Wnt pathway in colorectal cancer and affects genes involved in lipid metabolism

It is well established that lncRNAs are aberrantly expressed in cancer where they have been shown to act as oncogenes or tumor suppressors. RNA profiling of 314 colorectal adenomas/adenocarcinomas and 292 adjacent normal colon mucosa samples using RNA‐sequencing demonstrated that the snoRNA host gene 16 (SNHG16) is significantly up‐regulated in adenomas and all stages of CRC. SNHG16 expression was positively correlated to the expression of Wnt‐regulated transcription factors, including ASCL2, ETS2, and c‐Myc. In vitro abrogation of Wnt signaling in CRC cells reduced the expression of SNHG16 indicating that SNHG16 is regulated by the Wnt pathway. Silencing of SNHG16 resulted in reduced viability, increased apoptotic cell death and impaired cell migration. The SNHG16 silencing particularly affected expression of genes involved in lipid metabolism. A connection between SNHG16 and genes involved in lipid metabolism was also observed in clinical tumors. Argonaute CrossLinking and ImmunoPrecipitation (AGO‐CLIP) demonstrated that SNHG16 heavily binds AGO and has 27 AGO/miRNA target sites along its length, indicating that SNHG16 may act as a competing endogenous RNA (ceRNA) “sponging” miRNAs off their cognate targets. Most interestingly, half of the miRNA families with high confidence targets on SNHG16 also target the 3′UTR of Stearoyl‐CoA Desaturase (SCD). SCD is involved in lipid metabolism and is down‐regulated upon SNHG16 silencing. In conclusion, up‐regulation of SNHG16 is a frequent event in CRC, likely caused by deregulated Wnt signaling. In vitro analyses demonstrate that SNHG16 may play an oncogenic role in CRC and that it affects genes involved in lipid metabolism, possible through ceRNA related mechanisms

Efficient Transduction of Vascular Endothelial Cells with Recombinant Adeno-Associated Virus Serotype 1 and 5 Vectors

Recombinant adeno-associated virus (rAAV) has become an attractive tool for gene therapy because of its ability to transduce both dividing and nondividing cells, elicit a limited immune response, and the capacity for imparting long-term transgene expression. Previous studies have utilized rAAV serotype 2 predominantly and found that transduction of vascular cells is relatively inefficient. The purpose of the present study was to evaluate the transduction efficiency of rAAV serotypes 1 through 5 in human and rat aortic endothelial cells (HAEC and RAEC). rAAV vectors with AAV2 inverted terminal repeats containing the human α1-antitrypsin (hAAT) gene were transcapsidated using helper plasmids to provide viral capsids for the AAV1 through 5 serotypes. True type rAAV2 and 5 vectors encoding β-galactosidase or green fluorescence protein were also studied. Infection with rAAV1 resulted in the most efficient transduction in both HAEC and RAEC compared to other serotypes (p < 0.001) at 7 days posttransduction. Interestingly, expression was increased in cells transduced with rAAV5 to levels surpassing rAAV1 by day 14 and 21. Transduction with rAAV1 was completely inhibited by removal of sialic acid with sialidase, while heparin had no effect. These studies are the first demonstration that sialic acid residues are required for rAAV1 transduction in endothelial cells. Transduction of rat aortic segments ex vivo and in vivo demonstrated significant transgene expression in endothelial and smooth muscle cells with rAAV1 and 5 serotype vectors, in comparison to rAAV2. These results suggest the unique potential of rAAV1 and rAAV5-based vectors for vascular-targeted gene-based therapeutic strategies

Measuring the Neutrino Cross Section Using 8 years of Upgoing Muon Neutrinos Observed with IceCube

The IceCube Neutrino Observatory detects neutrinos at energies orders of magnitude higher than those available to current accelerators. Above 40 TeV, neutrinos traveling through the Earth will be absorbed as they interact via charged current interactions with nuclei, creating a deficit of Earth-crossing neutrinos detected at IceCube. The previous published results showed the cross section to be consistent with Standard Model predictions for 1 year of IceCube data. We present a new analysis that uses 8 years of IceCube data to fit the ν$_{μ}$ absorption in the Earth, with statistics an order of magnitude better than previous analyses, and with an improved treatment of systematic uncertainties. It will measure the cross section in three energy bins that span the range 1 TeV to 100 PeV. We will present Monte Carlo studies that demonstrate its sensitivity