The novel heart-specific RING finger protein 207 is involved in energy metabolism in cardiomyocytes

A failing heart shows severe energy insufficiency, and it is presumed that this energy shortage plays a critical role in the development of cardiac dysfunction. However, little is known about the mechanisms that cause energy metabolic alterations in the failing heart. Here, we show that the novel RING-finger protein 207 (RNF207), which is specifically expressed in the heart, plays a role in cardiac energy metabolism. Depletion of RNF207 in neonatal rat cardiomyocytes (NRCs) leads to a reduced cellular concentration of adenosine triphosphate (ATP) and mitochondrial dysfunction. Consistent with this result, we observed here that the expression of RNF207 was significantly reduced in mice with common cardiac diseases including heart failure. Intriguingly, proteomic approaches revealed that RNF207 interacts with the voltage-dependent anion channel (VDAC), which is considered to be a key regulator of mitochondria function, as an RNF207-interacting protein. Our findings indicate that RNF207 is involved in ATP production by cardiomyocytes, suggesting that RNF207 plays an important role in the development of heart failure

A phospho-switch controls RNF43-mediated degradation of Wnt receptors to suppress tumorigenesis.

Funder: Japan Foundation for Applied Enzymology; doi: https://doi.org/10.13039/100008695Funder: Pancreas Research Foundation of Japan Collaborative Research Project Program of the Medical Institute of Bioregulation, Kyushu University, Japan Joint Research Program of the Institute for Molecular and Cellular Regulation, Gunma University, Japan Grant for Joint Research Project of the Research Institute for Microbial Diseases Osaka UniversityFunder: European Research Council (ERC (639050) and the Interpark Bio-Convergence Center Grant Program.Frequent mutation of the tumour suppressor RNF43 is observed in many cancers, particularly colon malignancies. RNF43, an E3 ubiquitin ligase, negatively regulates Wnt signalling by inducing degradation of the Wnt receptor Frizzled. In this study, we discover that RNF43 activity requires phosphorylation at a triplet of conserved serines. This phospho-regulation of RNF43 is required for zebrafish development and growth of mouse intestinal organoids. Cancer-associated mutations that abrogate RNF43 phosphorylation cooperate with active Ras to promote tumorigenesis by abolishing the inhibitory function of RNF43 in Wnt signalling while maintaining its inhibitory function in p53 signalling. Our data suggest that RNF43 mutations cooperate with KRAS mutations to promote multi-step tumorigenesis via the Wnt-Ras-p53 axis in human colon cancers. Lastly, phosphomimetic substitutions of the serine trio restored the tumour suppressive activity of extracellular oncogenic mutants. Therefore, harnessing phospho-regulation of RNF43 might be a potential therapeutic strategy for tumours with RNF43 mutations

A Potent Inhibitor of SIK2, 3, 3′, 7-Trihydroxy-4′-Methoxyflavon (4′-O-Methylfisetin), Promotes Melanogenesis in B16F10 Melanoma Cells

Flavonoids, which are plant polyphenols, are now widely used in supplements and cosmetics. Here, we report that 4′-methylflavonoids are potent inducers of melanogenesis in B16F10 melanoma cells and in mice. We recently identified salt inducible kinase 2 (SIK2) as an inhibitor of melanogenesis via the suppression of the cAMP-response element binding protein (CREB)-specific coactivator 1 (TORC1). Using an in vitro kinase assay targeting SIK2, we identified fisetin as a candidate inhibitor, possibly being capable of promoting melanogenesis. However, fisetin neither inhibited the CREB-inhibitory activity of SIK2 nor promoted melanogenesis in B16F10 melanoma cells. Conversely, mono-methyl-flavonoids, such as diosmetin (4′-O-metlylluteolin), efficiently inhibited SIK2 and promoted melanogenesis in this cell line. The cAMP-CREB system is impaired in Ay/a mice and these mice have yellow hair as a result of pheomelanogenesis, while Sik2+/−; Ay/a mice also have yellow hair, but activate eumelanogenesis when they are exposed to CREB stimulators. Feeding Sik2+/−; Ay/a mice with diets supplemented with fisetin resulted in their hair color changing to brown, and metabolite analysis suggested the presence of mono-methylfisetin in their feces. Thus, we decided to synthesize 4′-O-methylfisetin (4′MF) and found that 4′MF strongly induced melanogenesis in B16F10 melanoma cells, which was accompanied by the nuclear translocation of TORC1, and the 4′-O-methylfisetin-induced melanogenic programs were inhibited by the overexpression of dominant negative TORC1. In conclusion, compounds that modulate SIK2 cascades are helpful to regulate melanogenesis via TORC1 without affecting cAMP levels, and the combined analysis of Sik2+/− mice and metabolites from these mice is an effective strategy to identify beneficial compounds to regulate CREB activity in vivo

Network-based traitor-tracing technique using traffic pattern

Today, with the rapid advance in broadband technology, streaming technology is applied to many applications, such as content delivery systems and web conference systems. On the other hand, we must implement digital rights management (DRM) to control content spreading and to avoid unintended content use. Traitor tracing is one of the key technologies that constructs DRM systems, and enables content distributors to observe and control content reception. General methods make use of watermarking to provide users' individual information unique to each user. However, these methods need to produce many individual contents. Especially, this is not realistic for real-time streaming systems. Furthermore, watermarking, which is a key technology adopted by contemporary methods, has known limitations and attacks against it. This is why the authors have proposed a method to monitor the content stream using traffic patterns constructed from only traffic volume information obtained from routers. The proposed method can determine who is watching the streaming content and whether or not a secondary content delivery exists. This information can be also used with general methods to construct a more practical traitor-tracing system. A method to cope with random errors and burst errors has also been investigated. Finally, the results of simulation and practical experiment are provided demonstrating the effectiveness of the proposed approach.14 page(s

Handwritten Japanese Address Recognition Technique Based on Improved Phased Search of Candidate Rectangle Lattice

In the field of handwritten Japanese address recognition, it is common to recognize place-name strings from place-name images. However, in practice, it is necessary to recognize the place-name strings from address images. Therefore, we have proposed the post-processing system, which checks the list of the place-name strings in two-stages for recognizing the place-name images. In this paper, we propose a new technique based on phased search of candidate rectangle lattice, and improve the technique with the detection of key-characters for final output. Applying our proposal to the IPTP 1840 image data of address strings, the results of experiments clearly show the efficiency of our system in handwritten Japanese address recognition

Role of the UBL-UBA Protein KPC2 in Degradation of p27 at G(1) Phase of the Cell Cycle

KPC2 (Kip1 ubiquitylation-promoting complex 2) together with KPC1 forms the ubiquitin ligase KPC, which regulates degradation of the cyclin-dependent kinase inhibitor p27 at the G(1) phase of the cell cycle. KPC2 contains a ubiquitin-like (UBL) domain, two ubiquitin-associated (UBA) domains, and a heat shock chaperonin-binding (STI1) domain. We now show that KPC2 interacts with KPC1 through its UBL domain, with the 26S proteasome through its UBL and NH(2)-terminal UBA domains, and with polyubiquitylated proteins through its UBA domains. The association of KPC2 with KPC1 was found to stabilize KPC1 in a manner dependent on the STI1 domain of KPC2. KPC2 mutants that lacked either the NH(2)-terminal or the COOH-terminal UBA domain supported the polyubiquitylation of p27 in vitro, whereas a KPC2 derivative lacking the STI1 domain was greatly impaired in this regard. Depletion of KPC2 by RNA interference resulted in inhibition of p27 degradation at the G(1) phase, and introduction of KPC2 derivatives into the KPC2-depleted cells revealed that the NH(2)-terminal UBA domain of KPC2 is essential for p27 degradation. These observations suggest that KPC2 cooperatively regulates p27 degradation with KPC1 and that the STI1 domain as well as the UBL and UBA domains of KPC2 are indispensable for its function

A Dynamic Anomaly Detection Scheme for AODV-Based Mobile Ad Hoc Networks

Abstract-Mobile ad hoc networks (MANETs) are usually formed without any major infrastructure. As a result, they are relatively vulnerable to malicious network attacks, and therefore, security is a more significant issue than infrastructure-based wireless networks. In MANETs, it is difficult to identify malicious hosts as the topology of the network dynamically changes. A malicious host can easily interrupt a route for which it is one of the forming nodes in the communication path. In the literature, there are several proposals to detect such malicious hosts inside the network. In those methods, a baseline profile, which is defined as per static training data, is usually used to verify the identity and the topology of the network, thus preventing any malicious host from joining the network. Since the topology of a MANET dynamically changes, the mere use of a static baseline profile is not efficient. In this paper, we propose a new anomaly-detection scheme based on a dynamic learning process that allows the training data to be updated at particular time intervals. Our dynamic learning process involves calculating the projection distances based on multidimensional statistics using weighted coefficients and a forgetting curve. We use the network simulator 2 (ns-2) system to conduct the MANET simulations and consider scenarios for detecting five types of attacks. The simulation results involving two different networks in size show the effectiveness of the proposed techniques. Index Terms-Ad hoc on-demand distance vector (AODV), anomaly detection, dynamic learning, forgetting curve, malicious attacks, mobile ad hoc networks (MANETs), projection distance