Aberrant HCO(3)(-) transport is a hallmark of cystic fibrosis (CF) and is associated with aberrant Cl(-)-dependent HCO(3)(-) transport by the cystic fibrosis transmembrane conductance regulator (CFTR). We show here that HCO(3)(-) current by CFTR cannot account for CFTR-activated HCO(3)(-) transport and that CFTR does not activate AE1-AE4. In contrast, CFTR markedly activates Cl(-) and OH(-)/HCO(3)(-) transport by members of the SLC26 family DRA, SLC26A6 and pendrin. Most notably, the SLC26s are electrogenic transporters with isoform-specific stoichiometries. DRA activity occurred at a Cl(-)/HCO(3)(-) ratio > or =2. SLC26A6 activity is voltage regulated and occurred at HCO(3)(-)/Cl(-) > or =2. The physiological significance of these findings is demonstrated by interaction of CFTR and DRA in the mouse pancreas and an altered activation of DRA by the R117H and G551D mutants of CFTR. These findings provide a molecular mechanism for epithelial HCO(3)(-) transport (one SLC26 transporter-electrogenic transport; two SLC26 transporters with opposite stoichiometry in the same membrane domain-electroneutral transport), the CF-associated aberrant HCO(3)(-) transport, and reveal a new function of CFTR with clinical implications for CF and congenital chloride diarrhea.

Serious complications have occurred in a considerable proportion of living donors of liver transplants, but data from a single high-volume center has rarely been available. We analyzed the medical records of donors and recipients of the first 1,000 living donor liver transplants, performed at Asan Medical Center from December 1994 to June 2005, with a focus on donor safety. There were 107 pediatric and 893 adult transplants. The most common diagnoses were biliary atresia in pediatric recipients (63%) and hepatitis B-associated liver cirrhosis (80%) in adult recipients. Right lobe donors were strictly selected based on liver resection rate and steatosis. From 1,162 living donors, 588 right lobes, 6 extended right lobes, 7 right posterior segments, 464 left lobes, and 107 left lateral segments were obtained. Of these, 837 grafts were implanted singly, whereas 325, along with 1 cadaveric split graft, were implanted as dual grafts into 163 recipients. The 5-yr survival rates were 84.8% in pediatric recipients and 83.2% in adult recipients. There was no donor mortality, but 3.2% of donors experienced major complications. Until the end of 2001, the major donor complication rate was 6.7%, with most occurring in right liver donors. Since 2002, liver resection exceeding 65% of whole liver volume were avoided except for young donors with no hepatic steatosis, and the donor complication rate has been reduced to 1.3%. In conclusion, a majority of major living donor complications appear to be avoidable through the strict selection of living donor and graft type, intensive postoperative surveillance, and timely feedback of surgical techniques. Selection of right lobe graft should be very prudently considered if the donor right liver appears to be larger than 65% of the whole liver volume. Liver Transpl 12: 920-927, 2006.

The pretreatment of cultured cortical neurons with neurotrophic factors markedly potentiates the cytotoxicity induced by low concentrations of Zn(2+) or excitotoxins. In the current study, we investigated the mechanism underlying the insulin-like growth factor-I (IGF-I)-induced Zn(2+) toxicity potentiation. The pretreatment of primary cortical cultures for more than 12 h with 100 ng/ml of IGF-I increased the cytotoxicity induced by 80 microM Zn(2+) by more than 2-fold. The IGF-I-enhanced cell death was blocked by the COX-2-specific inhibitors N-[2-(cyclohexyloxyl)-4-nitrophenyl]-methane sulfonamide (NS-398; 10-100 microM) and 1-[(4-methylsulfonyl)phenyl]-3-trifluoro-methyl-5-[(4-fluoro)phenyl]pyrazole (SC58125; 10 microM) and by the antioxidant trolox (30 microM). In addition, it was observed that COX-2 expression was increased 12 to 24 h after IGF-I treatment. Preincubation of cortical cultures with IGF-I increased arachidonic acid (AA)-induced cytotoxicity, and AA increased Zn(2+) toxicity, which suggested the involvement of COX activity in these cellular responses. Moreover, enhanced COX-2 activity led to a decrease in the cell's reducing power, as indicated by a gradual depletion of intracellular GSH. Cortical neurons pretreated with IGF-I and then Zn(2+) showed consistently enhanced reactive oxygen species production, which was repressed by NS-398 and SC58125. Cortical neurons treated with Zn(2+) and then AA displayed the increased ROS production, which was also suppressed by NS-398 and SC58125. These results suggest that COX-2 is an endogenous factor responsible for the IGF-I-induced potentiation of Zn(2+) toxicity and that enhanced COX-2 activity leads to a decrease in the cell's reducing power and an increase in ROS accumulation in primary cortical cultures.

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We have developed a three-dimensional (3D) liver-on-a-chip to investigate the interaction of hepatocytes and hepatic stellate cells (HSCs) in which primary 3D hepatocyte spheroids and HSCs are co-cultured without direct cell-cell contact. Here, we show that the 3D liver chip offers substantial advantages for the formation and harvesting of spheroids. The most important feature of this liver chip is that it enables continuous flow of medium to the cells through osmotic pumping, and thus requires only minimal handling and no external power source. We also demonstrate that flow assists the formation and long-term maintenance of spheroids. Additionally, we quantitatively and qualitatively investigated the paracrine effects of HSCs, demonstrating that HSCs assist in the maintenance of hepatocyte spheroids and play an important role in the formation of tight cell-cell contacts, thereby improving liver-specific function. Spheroids derived from co-cultures exhibited improved albumin and urea secretion rates compared to mono-cultured spheroids after 9 days. Immunostaining for cytochrome P450 revealed that the enzymatic activity of spheroids co-cultured for 8 days was greater than that of mono-cultured spheroids. These results indicate that this system has the potential for further development as a unique model for studying cellular interactions or as a tool that can be incorporated into other models aimed at creating hepatic structure and prolonging hepatocyte function in culture.

The ability to control the molecular organization of electronically active liquid-crystalline polymer semiconductors on surfaces provides opportunities to develop easy-to-process yet highly ordered supramolecular systems and, in particular, to optimize their electrical and environmental reliability in applications in the field of large-area printed electronics and photovoltaics. Understanding the relationship between liquid-crystalline nanostructure and electrical stability on appropriate molecular surfaces is the key to enhancing the performance of organic field-effect transistors (OFETs) to a degree comparable to that of amorphous silicon (a-Si). Here, we report a novel donor-acceptor type liquid-crystalline semiconducting copolymer, poly(didodecylquaterthiophene-alt-didodecylbithiazole), which contains both electron-donating quaterthiophene and electron-accepting 5,5'-bithiazole units. This copolymer exhibits excellent electrical characteristics such as field-effect mobilities as high as 0.33 cm(2)/V.s and good bias-stress stability comparable to that of amorphous silicon (a-Si). Liquid-crystalline thin films with structural anisotropy form spontaneously through self-organization of individual polymer chains as a result of intermolecular interactions in the liquid-crystalline mesophase. These thin films adopt preferential well-ordered intermolecular pi-pi stacking parallel to the substrate surface. This bottom-up assembly of the liquid-crystalline semiconducting copolymer enables facile fabrication of highly ordered channel layers with remarkable electrical stability.

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