The transcription factor NFB is activated by phosphorylation and acetylation and plays important roles in inflammatory and immune responses in the cell. Additionally, posttranslational modification of the NFB p65 subunit by O-linked N-acetylglucosamine (OGlcNAc) has been reported, but the modification site of O-GlcNAc on NFB p65 and its exact function have not been elucidated. In this work, we show that O-GlcNAcylation of NFB p65 decreases binding to IB␣ and increases transcriptional activity under hyperglycemic conditions. Also, we demonstrate that both Thr-322 and Thr-352 of NFB p65 can be modified with O-GlcNAc, but modification on Thr-352, not Thr-322, is important for transcriptional activation. Our findings suggest that site-specific O-GlcNAcylation may be a reason why NFB activity increases continuously under hyperglycemic conditions.T ranscription factor NFB plays important roles in inflammatory, immune, and antiapoptotic responses (1-3). In mammals, NFB is present as a dimer composed of various combinations of Rel proteins such as p65 (RelA), RelB, c-Rel, p50/p105, and p52/p100. In most cell types, NFB is composed of p65 and p50 and is localized in the cytosol where it binds inhibitor (IB). Treatment with NFB-activating agents such as tumor necrosis factor ␣ (TNF␣) activates IB kinase (IKK) complexes, inducing phosphorylation in the N terminus of IB. The phosphorylation event induces IB degradation via a ubiquitin-dependent proteolysis. Free NFB translocates to the nucleus and activates the expression of target genes (1, 2).Posttranslational modifications such as phosphorylation (4-9) and acetylation (10, 11) regulate the transcriptional activity of NFB. The activity of NFB is influenced also by the hexosamine biosynthetic pathway, which produces a substrate of O-GlcNAcylation, UDP-GlcNAc (12). Many nucleocytoplasmic proteins are known to be dynamically modified with O-GlcNAc. This modification is modulated by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) (13-18). O-GlcNAcylation levels play an important role in transcription, translation, nuclear transport, protein stability, and protein-protein interactions and can be increased under hyperglycemic conditions caused by diabetes (16 -18). Although it is known that O-GlcNAcylation of NFB is involved in hyperglycemia-induced NFB activation (12) and is required for lymphocyte activation (19), the specific sites and the function of O-GlcNAcylation on NFB are not well understood.In this work, we show that OGA overexpression downregulates O-GlcNAcylation and inhibits hyperglycemia-induced NFB activation in rat vascular smooth muscle cells (VSMCs). In contrast, up-regulation of O-GlcNAcylation after OGT overexpression and treatment of cells with the O-GlcNAcase inhibitors streptozotocin (STZ) (20) and O-(2-acetamido-2-deoxy-Dglucopyranosylidene)amino-N-phenylcarbamate (PUGNAc)(21) increase NFB transcriptional activity. Additionally, we identify Thr-322 and Thr-352 as O-GlcNAcylation sites in a mutation study and with mass spectrometry analysis. Our data sho...

Background: Despite the potential importance of pulmonary artery hypertension (PAH) in preterm infants with bronchopulmonary dysplasia (BPD), little is known about the risk factors for PAH. Objectives: To investigate the risk factors for PAH in preterm infants with BPD. Methods: Infants diagnosed with BPD were assigned to the PAH group or non-PAH group except for infants with mild BPD who had no PAH. PAH was diagnosed on the basis of echocardiograms demonstrating elevated right ventricle pressure beyond the postnatal age of 2 months. Logistic regression analysis was done for the multivariate assessment of the risk factors for PAH in preterm infants with moderate or severe BPD. Results: A total of 98 infants among 145 infants with BPD were divided into a PAH group (n = 25) or non-PAH group (n = 73), while the remaining 47 infants had mild BPD with no PAH. Among the study patients, survival rate of the PAH group was significantly lower than that of the non-PAH group. Infants with PAH had more severe cases of BPD and underwent longer durations of oxygen therapy, conventional or high-frequency ventilation, and hospitalization compared to those without PAH. Low 5-min Apgar scores (≤6; relative risk (RR) 6.2; 95% confidence interval (CI) 1.4–28.0; p = 0.017) and oligohydramnios (RR 7.7; 95% CI 2.0–29.6; p = 0.030) were found to be significant risk factors for PAH according to multivariate analysis. Conclusions: The present study shows that oligohydramnios is a specific risk factor for PAH in preterm infants with moderate or severe BPD.

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Direct 3d printing for functional modules and their assembly into an integrated microfluidic device.