A touch of history and a peep into the future of the lipid-quinone known as coenzyme Q and ubiquinone

Coenzyme Q (ubiquinone), a fully substituted benzoquinone with polyprenyl side chain, participates in many cellular redox activities. Paradoxically it was discovered only in 1957, albeit being ubiquitous. It required a person, F. L. Crane, a place, Enzyme Institute, Madison, USA, and a time when D. E. Green was directing vigorous research on mitochondria. Located at the transition of 2-electron flavoproteins and 1-electron cytochrome carriers, it facilitates electron transfer through the elegant Q-cycle in mitochondria to reduce O-2 to H2O, and to H2O2, now a significant signal-transducing agent, as a minor activity in shunt pathway (animals) and alternative oxidase (plants). The ability to form Q-radical by losing an electron and a proton was ingeniously used by Mitchell to explain the formation of the proton gradient, considered the core of energy transduction, and also in acidification in vacuoles. Known to be a mobile membrane constituent (microsomes, plasma membrane and Golgi apparatus), allowing it to reach multiple sites, coenzyme Q is expected to have other activities. Coenzyme Q protects circulating lipoproteins being a better lipid antioxidant than even vitamin E. Binding to proteins such as QPS, QPN, QPC and uncoupling protein in mitochondria, QA and QB in the reaction centre in R. sphaeroides, and disulfide bond-forming protein in E. coli (possibly also in Golgi), coenzyme Q acquires selective functions. A characteristic of orally dosed coenzyme Q is its exclusive absorption into the liver, but not the other tissues. This enrichment of Q is accompanied by significant decrease of blood pressure and of serum cholesterol. Inhibition of formation of mevalonate, the common precursor in the branched isoprene pathway, by the minor product, coenzyme Q, decreases the major product, cholesterol. Relaxation of contracted arterial smooth muscle by a side-chain truncated product of coenzyme Q explains its effect of decreasing blood pressure. Extensive clinical studies carried out on oral supplements of coenzyine Q, initially by K. Folkers and Y. Yamamura and followed many others, revealed a large number of beneficial effects, significantly in cardiovascular diseases. Such a variety of effects by this lipid quinone cannot depend on redox activity alone. The fat-soluble vitamins (A, D, E and K) that bear structural relationship with coenzyme Q are known to be active in their polar forms. A vignette of modified forms of coenzyme Q taking active role in its multiple effects is emerging.

Polymorphism and tautomeric preference in fenobam and the utility of NLO response to detect polymorphic impurities

Crystal structures of polymorphs and solvatomorphs of the potential anxiolytic drug fenobam exhibit an exclusive preference for one of the two possible tautomeric structures. A novel methodology based on nonlinear optical response has been successfully employed to detect the presence of a polymorphic impurity in a mixture of polymorphs.

Oncogenic MicroRNA-155 Down-regulates Tumor Suppressor CDC73 and Promotes Oral Squamous Cell Carcinoma Cell Proliferation IMPLICATIONS FOR CANCER THERAPEUTICS

The CDC73 gene is mutationally inactivated in hereditary and sporadic parathyroid tumors. It negatively regulates beta-catenin, cyclin D1, and c-MYC. Down-regulation of CDC73 has been reported in breast, renal, and gastric carcinomas. However, the reports regarding the role of CDC73 in oral squamous cell carcinoma (OSCC) are lacking. In this study we show that CDC73 is down-regulated in a majority of OSCC samples. We further show that oncogenic microRNA-155 (miR-155) negatively regulates CDC73 expression. Our experiments show that the dramatic up-regulation of miR-155 is an exclusive mechanism for down-regulation of CDC73 in a panel of human cell lines and a subset of OSCC patient samples in the absence of loss of heterozygosity, mutations, and promoter methylation. Ectopic expression of miR-155 in HEK293 cells dramatically reduced CDC73 levels, enhanced cell viability, and decreased apoptosis. Conversely, the delivery of a miR-155 antagonist (antagomir-155) to KB cells overexpressing miR-155 resulted in increased CDC73 levels, decreased cell viability, increased apoptosis, and marked regression of xenografts in nude mice. Cotransfection of miR-155 with CDC73 in HEK293 cells abrogated its pro-oncogenic effect. Reduced cell proliferation and increased apoptosis of KB cells were dependent on the presence or absence of the 3'-UTR in CDC73. In summary, knockdown of CDC73 expression due to overexpression of miR-155 not only adds a novelty to the list of mechanisms responsible for its down-regulation in different tumors, but the restoration of CDC73 levels by the use of antagomir-155 may also have an important role in therapeutic intervention of cancers, including OSCC.

Distributed Space Time Coding for Wireless Two-Way Relaying

We consider the wireless two-way relay channel, in which two-way data transfer takes place between the end nodes with the help of a relay. For the Denoise-And-Forward (DNF) protocol, it was shown by Koike-Akino et al. that adaptively changing the network coding map used at the relay greatly reduces the impact of Multiple Access Interference at the relay. The harmful effect of the deep channel fade conditions can be effectively mitigated by proper choice of these network coding maps at the relay. Alternatively, in this paper we propose a Distributed Space Time Coding (DSTC) scheme, which effectively removes most of the deep fade channel conditions at the transmitting nodes itself without any CSIT and without any need to adaptively change the network coding map used at the relay. It is shown that the deep fades occur when the channel fade coefficient vector falls in a finite number of vector subspaces of, which are referred to as the singular fade subspaces. DSTC design criterion referred to as the singularity minimization criterion under which the number of such vector subspaces are minimized is obtained. Also, a criterion to maximize the coding gain of the DSTC is obtained. Explicit low decoding complexity DSTC designs which satisfy the singularity minimization criterion and maximize the coding gain for QAM and PSK signal sets are provided. Simulation results show that at high Signal to Noise Ratio, the DSTC scheme provides large gains when compared to the conventional Exclusive OR network code and performs better than the adaptive network coding scheme.

Dramatic Structural Changes Resulting from the Loss of a Crucial Hydrogen Bond in the Hinge Region Involved in C-Terminal Helix Swapping in SurE: A Survival Protein from Salmonella typhimurium

Domain swapping is an interesting feature of some oligomeric proteins in which each protomer of the oligomer provides an identical surface for exclusive interaction with a segment or domain belonging to another protomer. Here we report results of mutagenesis experiments on the structure of C-terminal helix swapped dimer of a stationary phase survival protein from Salmonella typhimurium (StSurE). Wild type StSurE is a dimer in which a large helical segment at the C-terminus and a tetramerization loop comprising two beta strands are swapped between the protomers. Key residues in StSurE that might promote C-terminal helix swapping were identified by sequence and structural comparisons. Three mutants in which the helix swapping is likely to be avoided were constructed and expressed in E. coli. Three-dimensional X-ray crystal structures of the mutants H234A and D230A/H234A could be determined at 2.1 angstrom and 2.35 angstrom resolutions, respectively. Contrary to expectations, helix swapping was mostly retained in both the mutants. The loss of the crucial D230 OD2- H234 NE2 hydrogen bond (2.89 angstrom in the wild type structure) in the hinge region was compensated by new inter and intra-chain interactions. However, the two fold molecular symmetry was lost and there were large conformational changes throughout the polypeptide. In spite of these changes, the dimeric structure and an approximate tetrameric organization were retained, probably due to the interactions involving the tetramerization loop. Mutants were mostly functionally inactive, highlighting the importance of precise inter-subunit interactions for the symmetry and function of StSurE.

Probing p300/CBP associated Factor (PCAF)-dependent pathways with a small molecule inhibitor

PCAF (KAT2B) belongs to the GNAT family of lysine acetyltransferases (KAT) and specifically acetylates the histone H3K9 residue and several nonhistone proteins. PCAF is also a transcriptional coactivator. Due to the lack of a PCAF KAT-specific small molecule inhibitor, the exclusive role of the acetyltransferase activity of PCAF is not well understood. Here, we report that a natural compound of the hydroxybenzoquinone class, embelin, specifically inhibits H3Lys9 acetylation in mice and inhibits recombinant PCAF-mediated acetylation with near complete specificity in vitro. Furthermore, using embelin, we have identified the gene networks that are regulated by PCAF during muscle differentiation, further highlighting the broader regulatory functions of PCAF in muscle differentiation in addition to the regulation via MyoD acetylation.

Wireless Network Coding for MIMO Two-Way Relaying

The design of modulation schemes for the physical layer network-coded two-way MIMO relaying scenario is considered, with the denoise-and-forward protocol which employs two phases: Multiple Access phase and Broadcast phase. It is shown that for MIMO two-way relaying, the minimum distance of the effective constellation at the relay becomes zero when all the rows of the channel fade coefficient matrix belong to a finite number of vector subspaces referred to as the singular fade subspaces. The singular fade subspaces can be classified into two kinds based on whether their harmful effects can be removed or not: (i) the removable and (ii) the non-removable singular fade subspaces. It is shown that network coding maps obtained by the completion of appropriate partially filled Latin Rectangles can remove the harmful effects of all the removable singular fade subspaces. For 2(lambda)-PSK signal set, the removable and non-removable singular fade subspaces are characterized and, it is shown that the number of non-removable singular fade subspaces is a small fraction of the total number of singular fade subspaces and this fraction tends to zero as the constellation size tends to infinity. The Latin Rectangles for the case when the end nodes use different number of antennas are shown to be obtainable from the Latin Squares for the case when they use the same number of antennas. Also, the network coding maps which remove all the removable singular singular fade subspaces are shown to be obtainable from a small set of Latin Squares. The removal of all the singular fade subspaces by properly choosing the network coding map, provides a gain of 5.5 dB over the conventional Exclusive-OR network coding, in a Rayleigh fading scenario with 2 antennas at the end nodes and one antenna at the relay node, for 4-PSK signal set.

Wireless Network-Coded Bidirectional Relaying Using Latin Squares for M-PSK Modulation

The design of modulation schemes for the physical layer network-coded two-way relaying scenario is considered with a protocol which employs two phases: multiple access (MA) phase and broadcast (BC) phase. It was observed by Koike-Akino et al. that adaptively changing the network coding map used at the relay according to the channel conditions greatly reduces the impact of MA interference which occurs at the relay during the MA phase and all these network coding maps should satisfy a requirement called the exclusive law. We show that every network coding map that satisfies the exclusive law is representable by a Latin Square and conversely, that this relationship can be used to get the network coding maps satisfying the exclusive law. The channel fade states for which the minimum distance of the effective constellation at the relay become zero are referred to as the singular fade states. For M - PSK modulation (M any power of 2), it is shown that there are (M-2/4 - M/2 + 1) M singular fade states. Also, it is shown that the constraints which the network coding maps should satisfy so that the harmful effects of the singular fade states are removed, can be viewed equivalently as partially filled Latin Squares (PFLS). The problem of finding all the required maps is reduced to finding a small set of maps for M - PSK constellations (any power of 2), obtained by the completion of PFLS. Even though the completability of M x M PFLS using M symbols is an open problem, specific cases where such a completion is always possible are identified and explicit construction procedures are provided. Having obtained the network coding maps, the set of all possible channel realizations (the complex plane) is quantized into a finite number of regions, with a specific network coding map chosen in a particular region. It is shown that the complex plane can be partitioned into two regions: a region in which any network coding map which satisfies the exclusive law gives the same best performance and a region in which the choice of the network coding map affects the performance. The quantization thus obtained analytically, leads to the same as the one obtained using computer search for M = 4-PSK signal set by Koike-Akino et al., when specialized for Simulation results show that the proposed scheme performs better than the conventional exclusive-OR (XOR) network coding and in some cases outperforms the scheme proposed by Koike-Akino et al.

Physical layer network coding for two-way relaying with QAM and latin squares

In the design of modulation schemes for the physical layer network-coded two way relaying scenario with two phases (Multiple access (MA) Phase and Broadcast (BC) Phase), it was observed by Koike-Akino et al. that adaptively changing the network coding map used at the relay according to the channel conditions greatly reduces the impact of multiple access interference and all these network coding maps should satisfy a requirement called the exclusive law. In [11] the case in which the end nodes use M-PSK signal sets is extensively studied using Latin Squares. This paper deals with the case in which the end nodes use square M-QAM signal sets. In a fading scenario, for certain channel conditions, termed singular fade states, the MA phase performance is greatly reduced. We show that the square QAM signal sets lead to lesser number of singular fade states compared to PSK signal sets. Because of this, the complexity at the relay is enormously reduced. Moreover lesser number of overhead bits are required in the BC phase. We find the number of singular fade states for PAM and QAM signal sets used at the end nodes. The fade state γejθ = 1 is a singular fade state for M-QAM for all values of M and it is shown that certain block circulant Latin Squares remove this singular fade state. Simulation results are presented to show that QAM signal set perform better than PSK.

Wireless network-coded accumulate-compute and forward two-way relaying

The design of modulation schemes for the physical layer network-coded two way wireless relaying scenario is considered. It was observed by Koike-Akino et al. for the two way relaying scenario, that adaptively changing the network coding map used at the relay according to the channel conditions greatly reduces the impact of multiple access interference which occurs at the relay during the MA Phase and all these network coding maps should satisfy a requirement called exclusive law. We extend this approach to an Accumulate-Compute and Forward protocol which employs two phases: Multiple Access (MA) phase consisting of two channel uses with independent messages in each channel use, and Broadcast (BC) phase having one channel use. Assuming that the two users transmit points from the same 4-PSK constellation, every such network coding map that satisfies the exclusive law can be represented by a Latin Square with side 16, and conversely, this relationship can be used to get the network coding maps satisfying the exclusive law. Two methods of obtaining this network coding map to be used at the relay are discussed. Using the structural properties of the Latin Squares for a given set of parameters, the problem of finding all the required maps is reduced to finding a small set of maps. Having obtained all the Latin Squares, the set of all possible channel realizations is quantized, depending on which one of the Latin Squares obtained optimizes the performance. The quantization thus obtained, is shown to be the same as the one obtained in [7] for the 2-stage bidirectional relaying.

Wireless network-coded three-way relaying using Latin Cubes

The design of modulation schemes for the physical layer network-coded three-way wireless relaying scenario is considered. The protocol employs two phases: Multiple Access (MA) phase and Broadcast (BC) phase with each phase utilizing one channel use. For the two-way relaying scenario, it was observed by Koike-Akino et al. [4], that adaptively changing the network coding map used at the relay according to the channel conditions greatly reduces the impact of multiple access interference which occurs at the relay during the MA phase and all these network coding maps should satisfy a requirement called exclusive law. This paper does the equivalent for the three-way relaying scenario. We show that when the three users transmit points from the same 4-PSK constellation, every such network coding map that satisfies the exclusive law can be represented by a Latin Cube of Second Order. The network code map used by the relay for the BC phase is explicitly obtained and is aimed at reducing the effect of interference at the MA stage.

Game theoretic analysis of collusions in nonneutral networks

This paper studies the impact of exclusive contracts between a content provider (CP) and an internet service provider (ISP) in a nonneutral network. We consider a simple linear demand function for the CPs. We studywhen an exclusive contract is benefcial to the colluding pair and evaluate its impact on the noncolluding players at equilibrium. For the case of two CPs and one ISP we show that collusion may not always be benefcial. We derive an explicit condition in terms of the advertisement revenues of the CPs that tells when a collusion is proftable to the colluding entities.

Channel quantization for physical layer network-coded two-way relaying

The design of modulation schemes for the physical layer network-coded two way relaying scenario is considered with the protocol which employs two phases: Multiple access (MA) Phase and Broadcast (BC) phase. It was observed by Koike-Akino et al. that adaptively changing the network coding map used at the relay according to the channel conditions greatly reduces the impact of multiple access interference which occurs at the relay during the MA phase. In other words, the set of all possible channel realizations (the complex plane) is quantized into a finite number of regions, with a specific network coding map giving the best performance in a particular region. We obtain such a quantization analytically for the case when M-PSK (for M any power of 2) is the signal set used during the MA phase. We show that the complex plane can be classified into two regions: a region in which any network coding map which satisfies the so called exclusive law gives the same best performance and a region in which the choice of the network coding map affects the performance, which is further quantized based on the choice of the network coding map which optimizes the performance. The quantization thus obtained analytically, leads to the same as the one obtained using computer search for 4-PSK signal set by Koike-Akino et al., for the specific value of M = 4.

Wireless bidirectional relaying and Latin squares

The design of modulation schemes for the physical layer network-coded two way relaying scenario is considered with the protocol which employs two phases: Multiple access (MA) Phase and Broadcast (BC) Phase. It was observed by Koike-Akino et al. that adaptively changing the network coding map used at the relay according to the channel conditions greatly reduces the impact of multiple access interference which occurs at the relay during the MA Phase and all these network coding maps should satisfy a requirement called the exclusive law. We show that every network coding map that satisfies the exclusive law is representable by a Latin Square and conversely, and this relationship can be used to get the network coding maps satisfying the exclusive law. Using the structural properties of the Latin Squares for a given set of parameters, the problem of finding all the required maps is reduced to finding a small set of maps for M-PSK constellations. This is achieved using the notions of isotopic and transposed Latin Squares. Furthermore, the channel conditions for which the bit-wise XOR will perform well is analytically obtained which holds for all values of M (for M any power of 2). We illustrate these results for the case where both the end users use QPSK constellation.

External support and innovation performance of SMEs in Bangalore: Role of firm level factors

This paper probes the role of internal factors in SMEs in obtaining external support and achieving innovation performance in the context of auto component, electronics and machine tool industries of Bangalore in India. Using step-wise logistic regression analysis, the study found that only if SMEs have internal technical competence in terms of technically qualified entrepreneur, an exclusive design centre, and innovate more frequently, they will be able to obtain external support. Further using step-wise multiple regression the study concluded that SMEs which have come up to implement innovative ideas or exploit market opportunities and which have obtained external support with technically qualified entrepreneurs are able to exhibit better innovation performance.