Global gene expression during muscle hypertrophy induced by myostatin suppression and/or beta-adrenergic agonist

Ph.D. University of Hawaii at Manoa 2011.Includes bibliographical references.Skeletal muscle growth is important for animal agriculture, particularly for meat-producing animals, and for human health as well. A better understanding of the mechanisms regulating skeletal muscle growth is expected to contribute to improving the efficiency of meat animal production and alleviating human suffereings caused by muscle atrorphic conditions. Currently, two molecules have been shown to have dramatic effects on skeletal muscle mass: myostatin and β-adrenergic agonists. Myostatin (Mstn), a member of the TGF-β superfamily proteins, acts as a potent negative regulator of skeletal muscle growth. Suppression of Mstn by varying means has shown to increase skeletal muscle mass of animals. Administration of β-adrenergic agonist (BAA) such as clenbuterol (CL) induces dramatic increase in skeletal muscle mass or inhibits muscle atrophy. Although there have been numerous demonstrations of the muscle growth--promoting effect of BAA administration or Mstn suppression, the effect of a combination of BAA administration and Mstn inhibition on skeletal muscle growth has not been investigated. Similarly, very little is known about the molecular signaling pathways leading to muscle hypertrophy induced by the two stimuli and the genes that are commonly regulated by both Mstn and BAA administration. Therefore, the objectives of this study were 1) to investigate the combined effect of Mstn-suppression and BAA administration on skeletal muscle growth, 2) to examine the role of the Akt/mTOR pathway in the two muscle hypertrophic models, 3) to examine global changes in gene expression in skeletal muscle undergoing hypertrophy induced by chronic suppression of Mstn or BAA administration , and 4) to compare the changes in gene expression between these two muscle hypertrophic models. We used a transgenic mouse strain that overexpresses the Mstn-prodomain (Mstn-pro) and exhibits a significant increase in skeletal muscle mass regardless of age and sex. Clenbuterol (CL) was used as a BAA compound. Heterozygous Mstn-pro and wild-type littermates were produced and were given 0 or 20 ppm of CL in their drinking water. Phosphorylation of molecules involved in the Akt/mTOR pathway was examined by using the Western blot analysis. RNA samples of the gastrocnemius muscle in each group were subjected to microarray analysis using the Affymetrix GeneChip Mouse 430-2.0 platform. CL increased body and muscle mass of male and female mice in both genotypes, indincating that the muscle-hypertrophic effect of CL is additive to the effect of Mstn suppression. Levels of phosphorylated muscle 4E-BP1 and p70S6k, two downstream effectors of the mTOR pathway, were higher in Mstn-pro mice than in wild type mice. Levels of phosphorylated muscle Akt, an upstream effector of the mTOR pathway, were also higher in Mstn-pro mice than in wild type mice, indicating that the Akt/mTOR anabolic pathway is involved in the regulation of muscle mass by Mstn. CL increased the phosphorylation of Akt, 4E-BP1 and p70S6k in both genotypes, resulting in the highest phosphorylation levels of Akt, 4E-BP1 and p70S6k in CL-fed Mstn-pro mice. This result suggests that like Mstn, BAA also regulates muscle hypertrophy through the Akt/mTOR pathway, and the pathways of Mstn and CL signaling converge to the Akt/mTOR anabolic pathway to regulate skeletal muscle hypertrophy. Microarray analysis of global gene expression showed that Mstn suppression and CL administration induced significant changes in the mRNA abundance of various genes associated with muscle contraction, initiation of translation, transcription, and muscle hypertrophic signal pathway, suggesting that increased protein synthesis is partly responsible for the hypetrophy induced by Mstn and CL. Additionally, the alteration of Igf2 obsderved in Mstn suppressed mice, and the alterations of eIF4e, Acvr2b, FoxO and PTEN observed in mice treated with CL indicate that the pathways of Mstn and CL signaling converge to the Akt/mTOR anabolic pathway to regulate skeletal muscle hypertrophy

Epoxyketone-Based Immunoproteasome Inhibitors

An efficient new route for the preparation of dihydroeponemycin, an active eponemycin derivative, is provided, which includes the synthesis of the intermediate compound, a hydroxymethyl-substituted enone. In addition, a method is provided for synthesizing inhibitors, which includes PI′-modified analogues. These analogues selectively bind to a major immunoproteasome catalytic subunit LMP2 and inactivate its proteolytic activity in a method of treating diseases, including myeloma and other cancers, Huntington\u27s disease and Alzheimer\u27s disease

DeepStory: Video Story QA by Deep Embedded Memory Networks

Question-answering (QA) on video contents is a significant challenge for achieving human-level intelligence as it involves both vision and language in real-world settings. Here we demonstrate the possibility of an AI agent performing video story QA by learning from a large amount of cartoon videos. We develop a video-story learning model, i.e. Deep Embedded Memory Networks (DEMN), to reconstruct stories from a joint scene-dialogue video stream using a latent embedding space of observed data. The video stories are stored in a long-term memory component. For a given question, an LSTM-based attention model uses the long-term memory to recall the best question-story-answer triplet by focusing on specific words containing key information. We trained the DEMN on a novel QA dataset of children's cartoon video series, Pororo. The dataset contains 16,066 scene-dialogue pairs of 20.5-hour videos, 27,328 fine-grained sentences for scene description, and 8,913 story-related QA pairs. Our experimental results show that the DEMN outperforms other QA models. This is mainly due to 1) the reconstruction of video stories in a scene-dialogue combined form that utilize the latent embedding and 2) attention. DEMN also achieved state-of-the-art results on the MovieQA benchmark.Comment: 7 pages, accepted for IJCAI 201

Vulnerability assessment for the hazards of crosswinds when vehicles cross a bridge deck

AbstractA new procedure to assess the crosswind hazard of operating a vehicle over a bridge deck has been developed using a probabilistic approach that utilizes long-term wind data at bridge sites as well as the aerodynamic properties of bridge decks and vehicles. The proposed procedure for safety assessment considers the probabilities of two accident types: sideslip and overturning. The vulnerability of vehicles to crosswinds is represented by the number of days for traffic control that would be required to secure vehicle safety over a period of one year. The distribution of wind speed over a bridge deck was estimated from a section model wind tunnel test. A sea-crossing bridge was selected as an example, and a series of case studies were performed to identify the influential factors affecting vehicle vulnerability to crosswinds: vehicle type and loaded weight, the position of a running vehicle over a bridge deck, the bridge alignment relative to the dominant wind direction, and vehicle speed

Past, Present and Future Molecular Approaches to Improve Yield in Wheat

This chapter addresses the development and use of molecular markers for yield enhancement in wheat. Since their key goal for breeding is to maximize yield, extensive efforts have been made toward the improvement of yield. Agronomic traits related to yield, yield-related, disease resistance, and abiotic stresses are considered to be quantitative traits (QTLs), also known as complex traits, because they are controlled by numerous genes and are affected by environmental factors. Researchers have been studying such traits in the past decades for the development of molecular markers which can be used in various wheat breeding studies mainly involving restriction fragment length polymorphism (RFLP), simple sequence repeat (SSR), single nucleotide polymorphism (SNP), random amplified polymorphic DNA (RAPD), and amplified fragment length polymorphism (AFLP). Furthermore, the advent of next-generation sequencing (NGS) has accelerated the discovery of agronomically important genes. All of the technologies have enabled great advances for increasing the productivity of wheat. Here, the past history of first-generation sequencing, present status of second-generation sequencing, and future potential of translational genomics linked to the yield will be discussed

The Biblical Approach to Church Growth Through Personal Evangelism

The greatest commandment of the Lord is preaching the gospel all over the world. It is the duty of all Christians to preach the gospel to the world. If we are negligent about it, we may lose God\u27s blessings. When we study the way Jesus preached the gospel, we see that He personally met people individually and called them to become His disciples. Those who met Jesus personally became evangelists themselves, proclaimed God\u27s Word, and expanded the church. Jesus built the church so that it would do His work after He left this earth. Therefore, it is the mission of the church to go out and preach the gospel. To carry out this mission the author\u27s church held Evangelism Mobilization Sunday, through which every church member could participate in evangelism and realize the importance of training. With the example of Sung Dong church members, this thesis shows the close relationship between personal evangelism and church growth

Attitude after a mild aortic valve lesion during rheumatic mitral valve surgery

ObjectiveWe evaluated whether rheumatic aortic valve disease of mild degree should be treated in patients undergoing mitral valve surgery.MethodsFrom 1992 to 2010, 197 patients (aged 52 [19-82] years, male:female = 60:137) who had rheumatic mitral valve disease and mild aortic valve disease were enrolled. The aortic valve was untreated in 114 patients (no treatment group), repaired in 40 patients (aortic valvuloplasty group), and replaced in 43 patients (aortic valve replacement group).ResultsOperative mortality occurred in 4 patients (2.0%). There were no differences in early mortality and postoperative complications among the 3 groups. Overall survival at 5, 10, and 15 years was 96.3%, 92.1%, and 85.7%, respectively. In the no treatment group, progression-free survival in significant aortic valve disease at 5, 10, and 15 years was 98.7%, 91.3%, and 81.1%, respectively. This was not superior in the aortic valvuloplasty group (85.9%, 77.6%, and 69.8%, respectively) than in the no treatment group. Freedom from aortic valve disease was lower in patients with aortic stenosis than in those with aortic regurgitation in univariate and multivariable analyses (P < .001). Reoperation was performed in 19 patients, including 2 aortic valve reoperations. Aortic valve–related event-free survival was similar among the 3 groups.ConclusionsMild aortic valve disease in patients undergoing rheumatic mitral valve surgery could be left untreated, because preventive aortic valve operation does not result in better clinical and echocardiographic outcomes