In the Sense of Transcription Regulation by G-Quadruplexes: Asymmetric Effects in Sense and Antisense Strands

G-Quadruplexes occupy important regulatory regions in the genome. DNA G-quadruplexes in the promoter regions and RNA quadruplexes in the UTRs (untranslated regions) have been individually studied and variously implicated at different regulatory levels of gene expression. However, the formation of G-quadruplexes in the sense and antisense strands and their corresponding roles in gene regulation have not been studied in much detail. In the present study, we have elucidated the effect of strand asymmetry in this context. Using biophysical methods, we have demonstrated the formation of stable G-quadruplex structure in vitro using CD and UV melting. Additionally, ITC was employed to demonstrate that a previously reported selective G-quadruplex ligand was able to bind and stabilize the G-quadruplex in the present sequence. Further, we have shown using reporter constructs that although the DNA G-quadruplex in either strand can reduce translation efficiency, transcriptional regulation differs when G-quadruplex is present in the sense or antisense strand. We demonstrate that the G-quadruplex motif in the antisense strand substantially inhibits transcription, while when in the sense strand, it does not affect transcription, although it does ultimately reduce translation. Further, it is also shown that the G-quadruplex stabilizing ligand can enhance this asymmetric transcription regulation as a result of the increased stabilization of the G-quadruplex.

Optimal Trajectory Generation for Convergence to a Rectilinear Path

This paper presents a strategy to determine the shortest path of a fixed-wing Miniature Air Vehicle (MAV), constrained by a bounded turning rate, to eventually fly along a given straight line, starting from an arbitrary but known initial position and orientation. Unlike the work available in the literature that solves the problem using the Pontryagin's Minimum Principle (PMP) the trajectory generation algorithm presented here considers a geometrical approach which is intuitive and easy to understand. This also computes the explicit solution for the length of the optimal path as a function of the initial configuration. Further, using a 6-DOF model of a MAV the generated optimal path is tracked by an autopilot consisting of proportional-integral-derivative (PID) controllers. The simulation results show the path generation and tracking for different cases.

Incoherence-based optimal selection of independent measurements in diffuse optical tomography

An optimal measurement selection strategy based on incoherence among rows (corresponding to measurements) of the sensitivity (or weight) matrix for the near infrared diffuse optical tomography is proposed. As incoherence among the measurements can be seen as providing maximum independent information into the estimation of optical properties, this provides high level of optimization required for knowing the independency of a particular measurement on its counterparts. The proposed method was compared with the recently established data-resolution matrix-based approach for optimal choice of independent measurements and shown, using simulated and experimental gelatin phantom data sets, to be superior as it does not require an optimal regularization parameter for providing the same information. (C) 2014 Society of Photo-Optical Instrumentation Engineers (SPIE)

Optimal control of information epidemics modeled as Maki Thompson rumors

We model the spread of information in a homogeneously mixed population using the Maki Thompson rumor model. We formulate an optimal control problem, from the perspective of single campaigner, to maximize the spread of information when the campaign budget is fixed. Control signals, such as advertising in the mass media, attempt to convert ignorants and stiflers into spreaders. We show the existence of a solution to the optimal control problem when the campaigning incurs non-linear costs under the isoperimetric budget constraint. The solution employs Pontryagin's Minimum Principle and a modified version of forward backward sweep technique for numerical computation to accommodate the isoperimetric budget constraint. The techniques developed in this paper are general and can be applied to similar optimal control problems in other areas. We have allowed the spreading rate of the information epidemic to vary over the campaign duration to model practical situations when the interest level of the population in the subject of the campaign changes with time. The shape of the optimal control signal is studied for different model parameters and spreading rate profiles. We have also studied the variation of the optimal campaigning costs with respect to various model parameters. Results indicate that, for some model parameters, significant improvements can be achieved by the optimal strategy compared to the static control strategy. The static strategy respects the same budget constraint as the optimal strategy and has a constant value throughout the campaign horizon. This work finds application in election and social awareness campaigns, product advertising, movie promotion and crowdfunding campaigns. (C) 2014 Elsevier B.V. All rights reserved.

Optimal sequential wireless relay placement on a random lattice path

Our work is motivated by impromptu (or ``as-you-go'') deployment of wireless relay nodes along a path, a need that arises in many situations. In this paper, the path is modeled as starting at the origin (where there is the data sink, e.g., the control center), and evolving randomly over a lattice in the positive quadrant. A person walks along the path deploying relay nodes as he goes. At each step, the path can, randomly, either continue in the same direction or take a turn, or come to an end, at which point a data source (e.g., a sensor) has to be placed, that will send packets to the data sink. A decision has to be made at each step whether or not to place a wireless relay node. Assuming that the packet generation rate by the source is very low, and simple link-by-link scheduling, we consider the problem of sequential relay placement so as to minimize the expectation of an end-to-end cost metric (a linear combination of the sum of convex hop costs and the number of relays placed). This impromptu relay placement problem is formulated as a total cost Markov decision process. First, we derive the optimal policy in terms of an optimal placement set and show that this set is characterized by a boundary (with respect to the position of the last placed relay) beyond which it is optimal to place the next relay. Next, based on a simpler one-step-look-ahead characterization of the optimal policy, we propose an algorithm which is proved to converge to the optimal placement set in a finite number of steps and which is faster than value iteration. We show by simulations that the distance threshold based heuristic, usually assumed in the literature, is close to the optimal, provided that the threshold distance is carefully chosen. (C) 2014 Elsevier B.V. All rights reserved.

Role of the loop L-4,L-5 in allosteric regulation in mtHsp70s: in vivo significance of domain communication and its implications in protein translocation

Mitochondrial Hsp70 (mtHsp70) is essential for a vast repertoire of functions, including protein import, and requires effective interdomain communication for efficient partner-protein interactions. However, the in vivo functional significance of allosteric regulation in eukaryotes is poorly defined. Using integrated biochemical and yeast genetic approaches, we provide compelling evidence that a conserved substrate-binding domain (SBD) loop, L-4,L-5, plays a critical role in allosteric communication governing mtHsp70 chaperone functions across species. In yeast, a temperature-sensitive L-4,L-5 mutation (E467A) disrupts bidirectional domain communication, leading to compromised protein import and mitochondrial function. Loop L-4,L-5 functions synergistically with the linker in modulating the allosteric interface and conformational transitions between SBD and the nucleotide-binding domain (NBD), thus regulating interdomain communication. Second-site intragenic suppressors of E467A isolated within the SBD suppress domain communication defects by conformationally altering the allosteric interface, thereby restoring import and growth phenotypes. Strikingly, the suppressor mutations highlight that restoration of communication from NBD to SBD alone is the minimum essential requirement for effective in vivo function when primed at higher basal ATPase activity, mimicking the J-protein-bound state. Together these findings provide the first mechanistic insights into critical regions within the SBD of mtHsp70s regulating interdomain communication, thus highlighting its importance in protein translocation and mitochondrial biogenesis.

Multimodal therapy for complete regression of malignant melanoma using constrained nonlinear optimal dynamic inversion

Using a realistic nonlinear mathematical model for melanoma dynamics and the technique of optimal dynamic inversion (exact feedback linearization with static optimization), a multimodal automatic drug dosage strategy is proposed in this paper for complete regression of melanoma cancer in humans. The proposed strategy computes different drug dosages and gives a nonlinear state feedback solution for driving the number of cancer cells to zero. However, it is observed that when tumor is regressed to certain value, then there is no need of external drug dosages as immune system and other therapeutic states are able to regress tumor at a sufficiently fast rate which is more than exponential rate. As model has three different drug dosages, after applying dynamic inversion philosophy, drug dosages can be selected in optimized manner without crossing their toxicity limits. The combination of drug dosages is decided by appropriately selecting the control design parameter values based on physical constraints. The process is automated for all possible combinations of the chemotherapy and immunotherapy drug dosages with preferential emphasis of having maximum possible variety of drug inputs at any given point of time. Simulation study with a standard patient model shows that tumor cells are regressed from 2 x 107 to order of 105 cells because of external drug dosages in 36.93 days. After this no external drug dosages are required as immune system and other therapeutic states are able to regress tumor at greater than exponential rate and hence, tumor goes to zero (less than 0.01) in 48.77 days and healthy immune system of the patient is restored. Study with different chemotherapy drug resistance value is also carried out. (C) 2014 Elsevier Ltd. All rights reserved.

A simulation-based algorithm for optimal pricing policy under demand uncertainty

We propose a simulation-based algorithm for computing the optimal pricing policy for a product under uncertain demand dynamics. We consider a parameterized stochastic differential equation (SDE) model for the uncertain demand dynamics of the product over the planning horizon. In particular, we consider a dynamic model that is an extension of the Bass model. The performance of our algorithm is compared to that of a myopic pricing policy and is shown to give better results. Two significant advantages with our algorithm are as follows: (a) it does not require information on the system model parameters if the SDE system state is known via either a simulation device or real data, and (b) as it works efficiently even for high-dimensional parameters, it uses the efficient smoothed functional gradient estimator.

Interference-Constrained Optimal Power-Adaptive Amplify-and-Forward Relaying and Selection for Underlay Cognitive Radios

In an underlay cognitive radio (CR) system, a secondary user can transmit when the primary is transmitting but is subject to tight constraints on the interference it causes to the primary receiver. Amplify-and-forward (AF) relaying is an effective technique that significantly improves the performance of a CR by providing an alternate path for the secondary transmitter's signal to reach the secondary receiver. We present and analyze a novel optimal relay gain adaptation policy (ORGAP) in which the relay is interference aware and optimally adapts both its gain and transmit power as a function of its local channel gains. ORGAP minimizes the symbol error probability at the secondary receiver subject to constraints on the average relay transmit power and on the average interference caused to the primary. It is different from ad hoc AF relaying policies and serves as a new and fundamental theoretical benchmark for relaying in an underlay CR. We also develop a near-optimal and simpler relay gain adaptation policy that is easy to implement. An extension to a multirelay scenario with selection is also developed. Our extensive numerical results for single and multiple relay systems quantify the power savings achieved over several ad hoc policies for both MPSK and MQAM constellations.

Interferon-gamma induced cell death: Regulation and contributions of nitric oxide, cJun N-terminal kinase, reactive oxygen species and peroxynitrite

Interferon-gamma (Ifn gamma), a known immunomodulatory cytokine, regulates cell proliferation and survival. In this study, the mechanisms leading to the selective susceptibility of some tumor cells to Ifn gamma were deciphered. Seven different mouse tumor cell lines tested demonstrated upregulation of MHC class I to variable extents with Ifn gamma; however, only the cell lines, H6 hepatoma and L929 fibrosarcoma, that produce higher amounts of nitric oxide (NO) and reactive oxygen species (ROS) are sensitive to Ifn gamma-induced cell death. NO inhibitors greatly reduce Ifn gamma-induced ROS; however, ROS inhibitors did not affect the levels of Ifn gamma-induced NO, demonstrating that NO regulates ROS. Consequently, NO inhibitors are more effective, compared to ROS inhibitors, in reducing Ifn gamma-induced cell death. Further analysis revealed that Ifn gamma induces peroxynitrite and 3-nitrotyrosine amounts and a peroxynitrite scavenger, FeTPPS, reduces cell death. Ifn gamma treatment induces the phosphorylation of c-jun N-terminal kinase (Jnk) in H6 and L929 but not CT26, a colon carcinoma cell line, which is resistant to Ifn gamma-mediated death. Jnk activation downstream to NO leads to induction of ROS, peroxynitrite and cell death in response to Ifn gamma. Importantly, three cell lines tested, i.e. CT26, EL4 and Neuro2a, that are resistant to cell death with Ifn gamma alone become sensitive to the combination of Ifn gamma and NO donor or ROS inducer in a peroxynitrite-dependent manner. Overall, this study delineates the key roles of NO as the initiator and Jnk, ROS, and peroxynitrite as the effectors during Ifn gamma-mediated cell death. The implications of these findings in the Ifn gamma-mediated treatment of malignancies are discussed. (C) 2014 Elsevier B.V. All rights reserved.

Interferon-gamma induced cell death: Regulation and contributions of nitric oxide, cJun N-terminal kinase, reactive oxygen species and peroxynitrite

Interferon-gamma (Ifn gamma), a known immunomodulatory cytokine, regulates cell proliferation and survival. In this study, the mechanisms leading to the selective susceptibility of some tumor cells to Ifn gamma were deciphered. Seven different mouse tumor cell lines tested demonstrated upregulation of MHC class I to variable extents with Ifn gamma; however, only the cell lines, H6 hepatoma and L929 fibrosarcoma, that produce higher amounts of nitric oxide (NO) and reactive oxygen species (ROS) are sensitive to Ifn gamma-induced cell death. NO inhibitors greatly reduce Ifn gamma-induced ROS; however, ROS inhibitors did not affect the levels of Ifn gamma-induced NO, demonstrating that NO regulates ROS. Consequently, NO inhibitors are more effective, compared to ROS inhibitors, in reducing Ifn gamma-induced cell death. Further analysis revealed that Ifn gamma induces peroxynitrite and 3-nitrotyrosine amounts and a peroxynitrite scavenger, FeTPPS, reduces cell death. Ifn gamma treatment induces the phosphorylation of c-jun N-terminal kinase (Jnk) in H6 and L929 but not CT26, a colon carcinoma cell line, which is resistant to Ifn gamma-mediated death. Jnk activation downstream to NO leads to induction of ROS, peroxynitrite and cell death in response to Ifn gamma. Importantly, three cell lines tested, i.e. CT26, EL4 and Neuro2a, that are resistant to cell death with Ifn gamma alone become sensitive to the combination of Ifn gamma and NO donor or ROS inducer in a peroxynitrite-dependent manner. Overall, this study delineates the key roles of NO as the initiator and Jnk, ROS, and peroxynitrite as the effectors during Ifn gamma-mediated cell death. The implications of these findings in the Ifn gamma-mediated treatment of malignancies are discussed. (C) 2014 Elsevier B.V. All rights reserved.

BELIEF PROPAGATION FOR OPTIMAL EDGE COVER IN THE RANDOM COMPLETE GRAPH

We apply the objective method of Aldous to the problem of finding the minimum-cost edge cover of the complete graph with random independent and identically distributed edge costs. The limit, as the number of vertices goes to infinity, of the expected minimum cost for this problem is known via a combinatorial approach of Hessler and Wastlund. We provide a proof of this result using the machinery of the objective method and local weak convergence, which was used to prove the (2) limit of the random assignment problem. A proof via the objective method is useful because it provides us with more information on the nature of the edge's incident on a typical root in the minimum-cost edge cover. We further show that a belief propagation algorithm converges asymptotically to the optimal solution. This can be applied in a computational linguistics problem of semantic projection. The belief propagation algorithm yields a near optimal solution with lesser complexity than the known best algorithms designed for optimality in worst-case settings.

Regulation of Off-Network Pricing in a Nonneutral Network

Representatives of several Internet service providers (ISPs) have expressed their wish to see a substantial change in the pricing policies of the Internet. In particular, they would like to see content providers (CPs) pay for use of the network, given the large amount of resources they use. This would be in clear violation of the ``network neutrality'' principle that had characterized the development of the wireline Internet. Our first goal in this article is to propose and study possible ways of implementing such payments and of regulating their amount. We introduce a model that includes the users' behavior, the utilities of the ISP and of the CPs, and, the monetary flow that involves the content users, the ISP and CP, and, in pUrticular, the CP's revenues from advertisements. We consider various game models and study the resulting equilibria; they are all combinations of a noncooperative game (in which the ISPs and CPs determine how much they will charge the users) with a ``cooperative'' one on how the CP and the ISP share the payments. We include in our model a possible asymmetric weighting parameter (that varies between zero to one). We also study equilibria that arise when one of the CPs colludes with the TSP. We also study two dynamic game models as well as the convergence of prices to the equilibrium values.

Optimal Binary Power Control for Underlay CR With Different Interference Constraints and Impact of Channel Estimation Errors

Adapting the power of secondary users (SUs) while adhering to constraints on the interference caused to primary receivers (PRxs) is a critical issue in underlay cognitive radio (CR). This adaptation is driven by the interference and transmit power constraints imposed on the secondary transmitter (STx). Its performance also depends on the quality of channel state information (CSI) available at the STx of the links from the STx to the secondary receiver and to the PRxs. For a system in which an STx is subject to an average interference constraint or an interference outage probability constraint at each of the PRxs, we derive novel symbol error probability (SEP)-optimal, practically motivated binary transmit power control policies. As a reference, we also present the corresponding SEP-optimal continuous transmit power control policies for one PRx. We then analyze the robustness of the optimal policies when the STx knows noisy channel estimates of the links between the SU and the PRxs. Altogether, our work develops a holistic understanding of the critical role played by different transmit and interference constraints in driving power control in underlay CR and the impact of CSI on its performance.

Optimal error estimate using mesh equidistribution technique for singularly perturbed system of reaction-diffusion boundary-value problems

In this article, we study the problem of determining an appropriate grading of meshes for a system of coupled singularly perturbed reaction-diffusion problems having diffusion parameters with different magnitudes. The central difference scheme is used to discretize the problem on adaptively generated mesh where the mesh equation is derived using an equidistribution principle. An a priori monitor function is obtained from the error estimate. A suitable a posteriori analogue of this monitor function is also derived for the mesh construction which will lead to an optimal second-order parameter uniform convergence. We present the results of numerical experiments for linear and semilinear reaction-diffusion systems to support the effectiveness of our preferred monitor function obtained from theoretical analysis. (C) 2014 Elsevier Inc. All rights reserved.