Domain flexibility in retroviral proteases: structural implications for drug resistant mutations

Rigid body rotation of five domains and movements within their interfacial joints provide a rational context for understanding why HIV protease mutations that arise in drug resistant strains are often spatially removed from the drug or substrate binding sites. Domain motions associated with substrate binding in the retroviral HIV-1 and SIV proteases are identified and characterized. These motions are in addition to closure of the flaps and result from rotations of approximately 6-7 degrees at primarily hydrophobic interfaces. A crystal structure of unliganded SIV protease (incorporating the point mutation Ser 4 His to stabilize the protease against autolysis) was determined to 2.0 A resolution in a new space group, P3221. The structure is in the most "open" conformation of any retroviral protease so far examined, with six residues of the flaps disordered. Comparison of this and unliganded HIV structures, with their respective liganded structures by difference distance matrixes identifies five domains of the protease dimer that move as rigid bodies against one another: one terminal domain encompassing the N- and C-terminal beta sheet of the dimer, two core domains containing the catalytic aspartic acids, and two flap domains. The two core domains rotate toward each other on substrate binding, reshaping the binding pocket. We therefore show that, for enzymes, mutations at interdomain interfaces that favor the unliganded form of the target active site will increase the off-rate of the inhibitor, allowing the substrate greater access for catalysis. This offers a mechanism of resistance to competitive inhibitors, especially when the forward enzymatic reaction rate exceeds the rate of substrate dissociation.     

Unkeito Suppresses RANKL-Mediated Osteoclastogenesis via the Blimp1–Bcl6 and NF-κB Signaling Pathways and Enhancing Osteoclast Apoptosis

Osteoporosis is a common bone disease, particularly in menopausal women. Herein, we screened four Kampo medicines (Unkeito (UKT), Kamishoyosan (KSS), Kamikihito (KKT), and Ninjinyoeito (NYT)), frequently used to treat menopausal syndromes, for their effects on receptor activator of nuclear factor-kappaB ligand (RANKL)-induced osteoclast differentiation in RAW 264 cells. Considering that UKT exhibited the most potent effect, we examined its effect on RANKL-induced osteoclastogenesis, the induction of osteoclast apoptosis, and the mechanisms underlying its effects. UKT inhibits RANKL-induced osteoclast differentiation in the early stage and decreases osteoclast-related genes, including tartrate-resistant acid phosphatase (Trap), dendritic cell-specific transmembrane protein (Dcstamp), matrix metalloproteinase-9 (Mmp9), and cathepsin K (Ctsk). Specifically, UKT inhibits the nuclear factor of activated T cells 1 (NFATc1), which is essential for osteoclastogenesis. UKT increases Bcl6, which antagonizes NFATc1 and Dc-stamp, thereby blocking the progression of osteoclasts to maturation. UKT also decreased nuclear translocation by downregulating the activity of p65/NF-κB. In addition, UKT enhances mononuclear osteoclast apoptosis via activation of caspase-3. Herein, we demonstrate that UKT suppresses RANKL-mediated osteoclastogenesis via the Blimp1–Bcl6 and NF-κB signaling pathways and enhances mononuclear osteoclast apoptosis. Furthermore, UKT prevents bone loss in OVX mice. Thus, UKT might be a potential therapeutic agent for postmenopausal osteoporosis.     

SrCaO Protective Layer for High-Efficiency PDPs

The sustain pulse voltage of the panel for 66-kPa Ne + Xe (5%-30%) is 20%-40% lower with a Sr_0.62Ca_0.38O protective layer than with a MgO protective layer. At a normal sustain voltage of 160-200 V, the luminous efficiency of the panel with the Sr_0.62 Ca_0.38O protective layer for Xe (30%) is about twice as high as with the MgO protective layer for Xe (10%). The luminances of these panels are almost the same. This high efficiency at normal sustain pulse voltage and normal luminance is obtained through the combined use of the Sr_0.62Ca_0.38O protective layer and high Xe content. With regard to ion bombardment, the Sr_0.62Ca_0.38O film has a 4.5 times longer life than SrO film and nearly 80% of the life of MgO film. We also calculated the values of theoretical secondary electron emission yield gamma_imin of MgO, SrO, and CaO without energy bands in the band gap for rare gas ions and found that [ gamma_imin of MgO] les [gamma_imin of CaO] < [gamma_imin of SrO] except for the one case with He. The breakdown voltage decreases with higher gamma_imin values. As expected, the discharge voltage of the panel is much lower with the SrO protective layer than with the MgO protective layer. The discharge voltages of the panels with Sr_0.62Ca_0.38O and SrO protective layers are almost the same. These findings show that the life of the SrO protective layer can be made 4.5 times longer without any increase in the discharge voltage by adding CaO (40 at.%)     

Effect of Oxygen Adsorbates on Terahertz Emission Properties of Various Semiconductor Surfaces Covered with Graphene

We have studied coherent terahertz (THz) emission from graphene-coated surfaces of three different semiconductors—InP, GaAs, and InAs—to provide insight into the influence of O₂ adsorption on charge states and dynamics at the graphene/semiconductor interface. The amplitude of emitted THz radiation from graphene-coated InP was found to change significantly upon desorption of O₂ molecules by thermal annealing, while THz emission from bare InP was nearly uninfluenced by O₂ desorption. In contrast, the amount of change in the amplitude of emitted THz radiation due to O₂ desorption was essentially the same for graphene-coated GaAs and bare GaAs. However, in InAs, neither graphene coating nor O₂ adsorption/desorption affected the properties of its THz emission. These results can be explained in terms of the effects of adsorbed O₂ molecules on the different THz generation mechanisms in these semiconductors. Furthermore, these observations suggest that THz emission from graphene-coated semiconductors can be used for probing surface chemical reactions (e.g., oxidation) as well as for developing O₂ gas sensor devices.     

Controlled levitation of bulk superconductors

Levitation of bulk Y-Ba-Cu-O superconductors could successfully be controlled using a Bi-Sr-Ca-Cu-O superconducting electromagnet. It was found that stable levitation without tilting was obtained only when the sample trapped a certain amount of field, the minimum of which depended on the external field and the sample dimensions. We also employed a novel analysis method for levitation based on the total energy balance, which is much simpler than the force method and could be applied to the understanding of general levitation behavior. Numerical analyzes thus developed suggested that stable levitation of superconductors with large dimensions can only be achieved when the induced currents can flow with three dimensional freedom     

Characterization of interfacial reaction and chemical bonding features of LaOx/HfO2 stack structure formed on thermally-grown SiO2/Si(1 0 0)

A stack structure consisting of ～1.5 nm-thick LaO_x and ～4.0 nm-thick HfO₂ was formed on thermally grown SiO₂ on Si(1 0 0) by MOCVD using dipivaloymethanato precursors, and the influence of N₂ annealing on interfacial reaction for this stack structure was examined by using X-ray photoelectron spectroscopy and Fourier transform infrared attenuated total reflection. We found that compositional mixing between LaO_x and HfO₂ becomes significant from 600 °C upwards and that interfacial reaction between HfLa_yO_z and SiO₂ proceeds consistently at 1000 °C in N₂ ambience.     

Context-Based Network and Application Management on Seamless Networking Platform

A context-based adaptive communication system is introduced for use in heterogeneous networks. Context includes the user's presence, location, available network interfaces, network availability, network priority, communication status, terminal features, and installed applications. An experimental system was developed to clarify the feasibility of using context information to flexibly control networks and applications. The system operates on a seamless networking platform we developed for heterogeneous networks. By using contexts, the system can inform the caller and callee of applications they can access, which are available through the network before communication occurs. Changes in contexts can switch an on-going application to another during actual communication. These functions provide unprecedented styles of communication. A business scenario for a seamless networking provider is also presented. Dr. Morikawa has also been in charge of NICT's Mobile Networking Group. Masugi Inoue received his B.E. from Kyoto University in 1992 and his M.E. and D.E. from the University of Tokyo in 1994 and 1997, all in the field of Electrical Engineering. He is currently a senior researcher at the Yokosuka Radio Communications Research Center under the National Institute of Information and Communications Technology (NICT), Japan, and has been engaged in R&D on ultrahigh-speed WLANs and mobile networking. He joined the Communications Research Laboratory (CRL) of the Ministry of Posts and Telecommunications, Japan, in 1997, which was reorganized as NICT in April 2004. He was a visiting researcher at Polytechnic University in Brooklyn, New York in 2000. Khaled Mahmud received his B.Sc. (Eng.) in Electrical and Electronics Engineering from the Bangladesh University of Engineering and Technology in Dhaka in 1991. He received his M.E. and Ph.D. in the same field from Shizuoka University in Japan, in 1997 and 2000, respectively. He was a research fellow at NICT, Japan, from 2000 to 2004. He is currently an Assistant Professor in the Department of Computer Science and Engineering at North South University, Bangladesh. His research interests include modulation-demodulation techniques, software radio, mobile communication systems, wireless Internet, and IP mobility technologies. Homare Murakami received his B.E. and M.E. in Electronic Engineering from Hokkaido University in 1997 and 1999. In 2004, he received the Young Investigators Award from IEICE. He is currently a researcher at NICT's Mobile Networking Group. He is also an industrial PhD student in Aalborg University since 2003. His interest areas are naming scheme, wireless TCP and new transport protocol, IP mobility, fast handover method, and location management. Mikio Hasegawa received his B. Eng, M. Eng., and Dr. Eng. in 1995, 1997, and 2000 from Science University of Tokyo. From 1997 to 2000, he was a Research Fellow of the Japan Society for the Promotion of Science (JSPS). He is currently a senior researcher in Mobile Networking Group, National Institute of Information and Communications Technology, and a technical advisor in ChaosWare Inc. His research interests include applications of chaotic dynamical theory, combinatorial optimization, mobile networks, and ubiquitous computing. Hiroyuki Morikawa received his B.E., M.E., and D.E. in Electrical Engineering from the University of Tokyo in 1987, 1989, and 1992. He is currently an Associate Professor in the Department of Frontier Informatics at the University of Tokyo and is in charge of NICT's Mobile Networking Group. His research interests are in the areas of computer networks, mobile computing/networks, ubiquitous computing, and network services. He serves as Editor of Transactions of the IEICE and has been on the technical program committees of IEEE/ACM conferences and workshops. He sits on numerous telecommunications advisory committees and frequently serves as a consultant to the government.     

FIR system identification based on a nonparametric Bayesian model using the Indian buffet process

In this paper, we propose a nonparametric Bayesian model combined with the Indian buffet process (IBP) for a finite impulse response (FIR) system. We develop an FIR system identification method that can simultaneously estimate the number of FIR taps and coefficients. In the proposed model, each FIR tap consists of a coefficient and a gain, and the gain is a binary value. An infinite-dimensional binary vector is composed of binary values, and we assume that this binary vector is generated by the IBP. To identify the FIR system, we specify the likelihood function and prior distributions of the parameters and derive their posterior distributions. We can simultaneously estimate the number of FIR taps and coefficients by sampling from posterior distributions using the Gibbs sampler. Our simulations demonstrate that although the number of FIR taps is unknown, the identification performance of the proposed method in a high signal-to-noise ratio environment is similar to or better than that of the conventional least square solution.