Phosphorylation of ARD1 by IKK beta contributes to its destabilization and degradation

[[abstract]]I kappa B kinase beta (IKK beta), a major kinase downstream of various proinflammatory signals, mediates multiple cellular functions through phosphorylation and regulation of its substrates. On the basis of protein sequence analysis, we identified arrest-defective protein 1 (ARD1), a protein involved in apoptosis and cell proliferation processes in many human cancer cells, as a new IKK beta substrate. We provided evidence showing that ARD1 is indeed a bona. de substrate of IKK beta. IKK beta physically associated with ARD1 and phosphorylated it at Ser209. Phosphorylation by IKK beta destabilized ARD1 and induced its proteasome-mediated degradation. Impaired growth suppression was observed in ARD1 phosphorylation-mimic mutant (S209E)-transfected cells as compared with ARD1 non-phosphorylatable mutant (S209A)-transfected cells. Our findings of molecular interactions between ARD1 and IKK beta may enable further understanding of the upstream regulation mechanisms of ARD1 and of the diverse functions of IKK beta. (C) 2009 Elsevier Inc. All rights reserved

TNF alpha induces HIF-1 alpha expression through activation of IKK beta

[[abstract]]The transcription factor hypoxia-inducible factor 1 alpha (HIF-1 alpha) is regulated by oxygen availability as well as various inflammatory mediators, including tumor necrosis factor alpha (TNF alpha). Early work suggested that the phosphatidylinositol-3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) signaling pathways are involved in TNF alpha-mediated HIF-1 alpha accumulation and activation under normoxic conditions. Here, we provide evidence showing that I kappa B kinase beta (IKK beta) is required for HIF-1 alpha regulation by TNF alpha. We found that TNF alpha enhances HIF-1 alpha protein expression in various breast cancer cell lines under either normoxic or hypoxia-mimicking conditions, but has little effect on the HIF-1 alpha mRNA level. Increased HIF-1 alpha expression was found in IKK beta stable clones and transient transfectants, and depletion of IKK beta consistently reduced the amount of HIF-1 alpha protein. Treatment of cells with the IKK beta inhibitor Bay 11-7082 reduced the TNF alpha-induced HIF-1 alpha expression, suggesting that IKK beta is required in this signaling pathway. Decreased expression of vascular endothelial growth factor (VEGF), a direct target of HIF-1 alpha, was shown in IKK beta-knockout mouse embryonic fibroblast cells. We further demonstrated a positive correlation between IKK beta and VEGF expression in primary human breast cancer specimens. Our findings indicate that TNF alpha-induced HIF-1 alpha accumulation is IKK beta dependent, and may enable further understanding of the HIF-1 alpha regulation by inflammatory signals. (C) 2009 Elsevier Inc. All rights reserved

Partially hydrolyzed guar gum supplement reduces high-fat diet increased blood lipids and oxidative stress and ameliorates FeCl3-induced acute arterial injury in hamsters

Increased reactive oxygen species (ROS) and hyperlipidemia can promote arterial thrombus. We evaluated the potential of a partially hydrolyzed guar gum (PHGG) as dietary fiber on lipid profiles and FeCl3-induced arterial thrombosis in the high fat-diet fed hamsters. Our in vitro results found that PHGG is efficient to scavenge O2-•, H2O2, and HOCl. High fat-diet increased plasma triglyceride, total cholesterol, LDL, VLDL, methylguanidine and dityrosine level and accelerated FeCl3-induced arterial thrombosis formation (from 463 ± 51 to 303 ± 45 sec). Low dose PHGG supplement significantly decreased the total cholesterol, LDL, methylguanidine and dityrosine level and delayed the time for arterial thrombosis formation (528 ± 75 sec). High dose PHGG supplement decreased the level in triglyceride, total cholesterol, LDL and VLDL and further delayed the time for arterial thrombus (671 ± 36 sec). The increased Bax protein and decreased Bcl-2 and HSP-70 protein expression was found in the carotid and femoral arteries of high fat-diet hamsters. Low and high dose of PHGG supplement decreased Bax expression and increased Bcl-2 and HSP-70 protein expression. We found that FeCl3 significantly enhanced intercellular adhesion molecule-1 and 4-hydroxynonenal expression in the endothelial site of damaged artery after 150-sec FeCl3 stimulation. PHGG supplement decreased the endothelial ICAM-1 and 4-hydroxynonenal expression after 150-sec FeCl3 stimulation. Based on these results, we conclude that PHGG supplement can increase antioxidant protein expression and thus decrease oxidative stress induced arterial injury

Assessment of Changes in Knowledge and Stigmatization Following Tuberculosis Training Workshops in Taiwan

Background/PurposeThere is little understanding of the depth of knowledge of health workers involved in tuberculosis (TB) control programs, and even less is known about health workers attaching stigma to TB patients. This study surveyed health workers enrolled in TB training workshops prior to the execution of the directly observed treatment, short course (DOTS) program.MethodsAll participants attended the training course and completed structured questionnaires before (pre-test) and after training (post-test). The questionnaires were collected immediately following completion and the scores were analyzed.ResultsPair comparison of knowledge scores revealed that all participants made statistically significant improvements in level of TB knowledge, except those who had a history of TB (p = 0.331). Pair comparison of stigmatization scores revealed a reduction in stigmatization, with the DOTS workers attaching less stigma to TB patients. After training, caregivers, including women (p = 0.012), public health workers (p = 0.028), 40–49-year-old subjects (p = 0.035), those with an education of < 12 years (p = 0.024), those who had been a volunteer (p = 0.018), and those who had a history of TB and those who did not (p = 0.034, p = 0.036), were significantly less likely to stigmatize patients. TB knowledge was not found to be significantly correlated with stigmatization (pre-test, p = 0.298; post-test, p = 0.821).ConclusionTraining workshops in TB control were effective for promotion of knowledge and elimination of stigmatization in first-line caregivers. DOTS workers attached less stigma to TB patients than public health workers, and older workers who had been volunteers attached the least stigma

An Integrated Edge and Fog System for Future Communication Networks

Put together, the edge and fog form a large diverse pool of computing and networking resources from different owners that can be leveraged towards low latency applications as well as for alleviating high traffic volume in future networks including 5G and beyond. This paper sets out a framework for the integration of edge and fog computing and networking leveraging on ongoing specifications by ETSI MEC ISG and the OpenFog Consortium. It also presents the technological gaps that need to be addressed before such an integrated solution can be developed. These noticeably include challenges relating to the volatility of resources, heterogeneity of underlying technologies, virtualization of devices, and security issues. The framework presented is a Launchpad for a complete solution under development by the 5G-CORAL consortium.This work has been partially funded by the H2020 collaborative Europe/Taiwan research project 5G-CORAL (grant num. 761586

Prompting and Adapter Tuning for Self-supervised Encoder-Decoder Speech Model

Prompting and adapter tuning have emerged as efficient alternatives to fine-tuning (FT) methods. However, existing studies on speech prompting focused on classification tasks and failed on more complex sequence generation tasks. Besides, adapter tuning is primarily applied with a focus on encoder-only self-supervised models. Our experiments show that prompting on Wav2Seq, a self-supervised encoder-decoder model, surpasses previous works in sequence generation tasks. It achieves a remarkable 53% relative improvement in word error rate for ASR and a 27% in F1 score for slot filling. Additionally, prompting competes with the FT method in the low-resource scenario. Moreover, we show the transferability of prompting and adapter tuning on Wav2Seq in cross-lingual ASR. When limited trainable parameters are involved, prompting and adapter tuning consistently outperform conventional FT across 7 languages. Notably, in the low-resource scenario, prompting consistently outperforms adapter tuning.Comment: Accepted to IEEE ASRU 202

Equivalent efficacies of reverse hybrid and concomitant therapies in first- line treatment of Helicobacter pylori infection

Background and AimConcomitant therapy is a recommended first- line treatment for Helicobacter pylori infection in most national or international consensuses. Reverse hybrid therapy is a modified 14- day concomitant therapy without clarithromycin and metronidazole in the final 7 days. This study aims to test whether 14- day reverse hybrid therapy is non- inferior to 14- day concomitant therapy in the first- line treatment of H. pylori infection.MethodsHelicobacter pylori- infected adult patients were randomly assigned to receive either reverse hybrid therapy (dexlansoprazole 60 mg o.d. plus amoxicillin 1 g b.d. for 14 days, and clarithromycin 500 mg plus metronidazole 500 mg b.d. for initial 7 days) or concomitant therapy (dexlansoprazole 60 mg once o.d. plus amoxicillin 1 g, clarithromycin 500 mg, and metronidazole 500 mg b.d. for 14 days). H. pylori status was assessed 6 weeks after the end of treatment.ResultsHelicobacter pylori- infected participants (n = 248) were randomized to receive either 14- day reverse hybrid therapy (n = 124) or 14- day concomitant therapy (n = 124). Intention- to- treat analysis demonstrated that the two therapies had comparable eradication rate (95.2% vs 93.5%; 95% confidence interval, - 4.0% to 7.4%; P = 0.582). However, reverse hybrid therapy had a much lower frequency of adverse events than concomitant therapy (20.2% vs 38.7%, P = 0.001). The two therapies exhibited comparable drug adherence (93.5% vs 87.9%, P = 0.125).ConclusionsFourteen- day reverse hybrid therapy and 14- day concomitant therapy are equivalent in efficacy for the first- line treatment of H. pylori infection. However, reverse hybrid therapy has fewer adverse events compared with concomitant therapy.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/163472/2/jgh15034_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/163472/1/jgh15034.pd

Transcriptome analysis of Dnmt3l knock-out mice derived multipotent mesenchymal stem/stromal cells during osteogenic differentiation

Multipotent mesenchymal stem/stromal cells (MSCs) exhibit great potential for cell-based therapy. Proper epigenomic signatures in MSCs are important for the maintenance and the subsequent differentiation potential. The DNA methyltransferase 3-like (DNMT3L) that was mainly expressed in the embryonic stem (ES) cells and the developing germ cells plays an important role in shaping the epigenetic landscape. Here, we report the reduced colony forming ability and impaire