75 research outputs found
An Architecture of Small-scaled Neuro-hardware Using Probabilistically-coded Pulse Neurons
PROCEEDINGS OF 2000 IEEE INTERNATIONAL CONFERENCE ON INDUSTRIAL ELECTRONICS, CONTROL AND INSTRUMENTATIO
CFTR Functions as a Bicarbonate Channel in Pancreatic Duct Cells
Pancreatic duct epithelium secretes a HCO3β-rich fluid by a mechanism dependent on cystic fibrosis transmembrane conductance regulator (CFTR) in the apical membrane. However, the exact role of CFTR remains unclear. One possibility is that the HCO3β permeability of CFTR provides a pathway for apical HCO3β efflux during maximal secretion. We have therefore attempted to measure electrodiffusive fluxes of HCO3β induced by changes in membrane potential across the apical membrane of interlobular ducts isolated from the guinea pig pancreas. This was done by recording the changes in intracellular pH (pHi) that occurred in luminally perfused ducts when membrane potential was altered by manipulation of bath K+ concentration. Apical HCO3β fluxes activated by cyclic AMP were independent of Clβ and luminal Na+, and substantially inhibited by the CFTR blocker, CFTRinh-172. Furthermore, comparable HCO3β fluxes observed in ducts isolated from wild-type mice were absent in ducts from cystic fibrosis (ΞF) mice. To estimate the HCO3β permeability of the apical membrane under physiological conditions, guinea pig ducts were luminally perfused with a solution containing 125 mM HCO3β and 24 mM Clβ in the presence of 5% CO2. From the changes in pHi, membrane potential, and buffering capacity, the flux and electrochemical gradient of HCO3β across the apical membrane were determined and used to calculate the HCO3β permeability. Our estimate of βΌ0.1 Β΅m secβ1 for the apical HCO3β permeability of guinea pig duct cells under these conditions is close to the value required to account for observed rates of HCO3β secretion. This suggests that CFTR functions as a HCO3β channel in pancreatic duct cells, and that it provides a significant pathway for HCO3β transport across the apical membrane
Analysis of the anti-tumor mechanism of BRD4 inhibition in hepatocellular carcinoma
Bromodomain and extra terminal (BET) family proteins, which include BRD4, are readers of histone acetyl-lysines and key regulators of gene transcription. BRD4 inhibitors exert anti-tumor effects in various cancers, including hepatocellular carcinoma (HCC). We investigated the mechanism underlying the antitumor effects of BRD4 inhibition in HCC. We first tested the effects of the BRD4 inhibitor JQ1 in a series of 9 HCC cell lines and found that it strongly suppressed HCC cell proliferation by inducing cell cycle arrest and apoptosis. Gene expression microarray analysis revealed that JQ1 also induced marked changes in the gene expression profiles of HCC cells, and genes associated with cell cycle and apoptosis were significantly enriched among the affected genes. Notably, a number of cancer-related genes, including BCAT1, DDR1, GDF15, FANCD2, SENP1 and TYRO3, were strongly suppressed by JQ1 in HCC cells. We also confirmed BRD4 bound within the promoter regions of these genes, which suggests they are targets of BRD4 in HCC cells. JQ1 thus appears to exert its anti-tumor effects in HCC by suppressing multiple BRD4 target genes
Glucose transport in interlobular ducts isolated from rat pancreas
Pancreatic duct cells express Na+-dependent glucose transporter, SGLT1 and Na+-independent glucose transporters, GLUT1, GLUT2, and GLUT8. We examined transepithelial glucose transport by pancreatic duct. Interlobular ducts were isolated from rat pancreas. During overnight culture both ends of the duct segments sealed spontaneously. The lumen of the sealed duct was micropunctured and the luminal fluid was replaced by HEPES-buffered solution containing 10.0 mM or 44.4 mM glucose. The bath was perfused with HEPES-buffered solution at 37β containing 10.0 or 44.4 mM glucose. Transepithelial differences in osmolality were balanced with mannitol. Glucose transport across ductal epithelium was measured by monitoring changes in luminal volume. When the lumen was filled with 44.4 mM glucose, with either 10.0 or 44.4 mM glucose in the bath, the luminal volume decreased to 65ο½70% of the initial volume in 15 min. Luminally-injected phlorizin, an inhibitor of SGLT1, abolished the decrease in luminal volume. With 10.0 mM glucose in the lumen and 44.4 mM glucose in the bath, the luminal volume did not change significantly. Luminal application of phlorizin under identical condition led to an increase in luminal volume. The data suggest that both active and passive transport mechanisms of glucose are present in pancreatic ductal epithelium
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