An Integrated Network of Androgen Receptor, Polycomb, and TMPRSS2-ERG Gene Fusions in Prostate Cancer Progression

Forkhead transcription factor FKHR (Foxo1) is a key regulator of glucose homeostasis, cell-cycle progression, and apoptosis. It has been shown that FKHR is phosphorylated via insulin or growth factor signaling cascades, resulting in its cytoplasmic retention and the repression of target gene expression. Here, we investigate the fate of FKHR after cells are stimulated by insulin. We show that insulin treatment decreases endogenous FKHR proteins in HepG2 cells, which is inhibited by proteasome inhibitors. FKHR is ubiquitinated in vivo and in vitro, and insulin enhances the ubiquitination in the cells. In addition, the signal to FKHR degradation from insulin is mediated by the phosphatidylinositol 3-kinase pathway, and the mutation of FKHR at the serine or threonine residues phosphorylated by protein kinase B, a downstream target of phosphatidylinositol 3-kinase, inhibits the ubiquitination in vivo and in vitro. Finally, efficient ubiquitination of FKHR requires both phosphorylation and cytoplasmic retention in the cells. These results demonstrate that the insulin-induced phosphorylation of FKHR leads to the multistep negative regulation, not only by the nuclear exclusion but also the ubiquitination-mediated degradation.

https://www.pnas.org/content/pnas/100/20/11285.full.pdf

Insulin-induced phosphorylation of FKHR (Foxo1) targets to proteasomal degradation

Oxidative stress inhibits osteoblastic differentiation of bone cells by ERK and NF-kappaB.

Teeth move through alveolar bone, whether through the normal process of tooth eruption or by strains generated by orthodontic appliances. Both eruption and orthodontics accomplish this feat through similar fundamental biological processes, osteoclastogenesis and osteogenesis, but there are differences that make their mechanisms unique. A better appreciation of the molecular and cellular events that regulate osteoclastogenesis and osteogenesis in eruption and orthodontics is not only central to our understanding of how these processes occur, but also is needed for ultimate development of the means to control them. Possible future studies in these areas are also discussed, with particular emphasis on translation of fundamental knowledge to improve dental treatments.

Mechanisms of Tooth Eruption and Orthodontic Tooth Movement

The FOXO family of forkhead transcription factors plays a key role in a variety of biological processes, including metabolism, cell proliferation, and oxidative stress response. We previously reported that Foxo1, a member of the FOXO family, is regulated through reversible acetylation catalyzed by histone acetyltransferase cAMP-response element-binding protein (CREB)-binding protein (CBP) and NAD-dependent histone deacetylase silent information regulator 2, and that the acetylation at Lys-242, Lys-245, and Lys-262 of Foxo1 attenuates its transcriptional activity. However, the molecular mechanism by which acetylation modulates Foxo1 activity remains unknown. Here, we show that the positive charge of these lysines in Foxo1 contributes to its DNA-binding, and acetylation at these residues by CBP attenuates its ability to bind cognate DNA sequence. Remarkably, we also show that acetylation of Foxo1 increases the levels of its phosphorylation at Ser-253 through the phosphatidylinositol 3-kinase–protein kinase B signaling pathway, and this effect was overridden on the acetylation-deficient Foxo1 mutant. Furthermore, in in vitro kinase reactions, the association of wild-type Foxo1 and its target DNA sequence inhibits the protein kinase B-dependent phosphorylation of Foxo1, whereas mutated Foxo1 proteins, which mimic constitutively acetylated states, are efficiently phosphorylated even in the presence of the DNA. These results suggest that acetylation regulates the function of Foxo1 through altering the affinity with the target DNA and the sensitivity for phosphorylation.

https://www.pnas.org/content/pnas/102/32/11278.full.pdf

Acetylation of Foxo1 alters its DNA-binding ability and sensitivity to phosphorylation

Transportation and transit systems draw upon broad spectra of research fields due to the diversity and interconnectivity of transport modes, including road, rail, aviation, pipeline, maritime, or even aerospace. These systems have evolved over centuries to be considerably more efficient and environment-friendly for a wide range of customers. The fundamental principle "safety first" is still the key priority in most research today. However, thanks to extensive interface with various customers; research and innovation in practices have shifted from optimizing functional purposes and targets through each stage of life cycle toward modernization, reliability, resilience, and better quality of life. These initiatives additionally coincide with the grand challenges for engineering proposed by the National Academy of Engineering and the United Nations' Millennium Development Goals (National Academy of Engineering, 2015). Language: en

/pdf/grand-challenges-in-transportation-and-transit-systems-gu0h6fawju.pdf

Grand Challenges in Transportation and Transit Systems

The receptor activator of NF-kappa B ligand (RANKL) and its decoy receptor, osteoprotegerin (OPG), are the important proteins implicated in osteoclastogenesis. In this study, we investigated the expressions of RANKL and OPG in cultured human periodontal ligament (PDL) cells and their roles in osteoclastogenesis. Northern blotting revealed that the OPG mRNA was down-regulated remarkably by application of 10-8 m one-alpha, 25-dihydroxyvitamin D3[1,25-(OH)2D3] and 10-7 m dexamethasone (Dex). In contrast, RANKL mRNA was up-regulated by the same treatment. Western blotting demonstrated decrease of OPG by the application of 1,25-(OH)2D3 and Dex. Tartrate-resistant acid phosphatase-positive multinuclear cells were markedly induced when the PDL cells were cocultured with mouse bone marrow cells in the presence of an anti-OPG antibody together with 1,25-(OH)2D3 and Dex. These results indicate that PDL cells synthesize both RANKL and OPG and that inactivation of OPG may play a key role in the differentiation of osteoclasts.

Expression of receptor activator of NF-kappa B ligand and osteoprotegerin in culture of human periodontal ligament cells

This paper summarizes the development of a portable track-condition-monitoring system for easy installation on in-service vehicles. In this system, rail irregularities are estimated from the vertical and lateral acceleration of the car body. The roll angle of the car body, calculated using a rate gyroscope, is used to distinguish line irregularities from level irregularities. Rail corrugation is detected from cabin noise with spectral peak calculation. A GPS system and a map-matching algorithm are used to pinpoint the location of faults on tracks. Field test using in-service vehicle was carried out to evaluate the developed system. The results show that the condition of rail irregularity and rail corrugation can be estimated effectively.

/pdf/condition-monitoring-of-railway-track-using-in-service-3p3l798r5r.pdf

Akira Matsumoto

Papers

Grand Challenges in Transportation and Transit Systems

Expression of receptor activator of NF-kappa B ligand and osteoprotegerin in culture of human periodontal ligament cells

Condition Monitoring of Railway Track Using In-Service Vehicle

Formation mechanism and countermeasures of rail corrugation on curved track

A new measuring method of wheel–rail contact forces and related considerations