The antibodies against the computationally designed mimic of the glycoprotein hormone receptor transmembrane domain provide insights into receptor activation and suppress the constitutively activated receptor Mutants

The exoloops of glycoprotein hormone receptors (GpHRs) transduce the signal generated by the ligand-ectodomain interactions to the transmembrane helices either through direct hormonal contact and/or by modulating the interdomain interactions between the hinge region (HinR) and the transmembrane domain (TMD). The ligand-induced conformational alterations in the HinRs and the interhelical loops of luteinizing hormone receptor/follicle stimulating hormone receptor/thyroid stimulating hormone receptor were mapped using exoloop-specific antibodies generated against a mini-TMD protein designed to mimic the native exoloop conformations that were created by joining the thyroid stimulating hormone receptor exoloops constrained through helical tethers and library-derived linkers. The antibody against the mini-TMD specifically recognized all three GpHRs and inhibited the basal and hormone-stimulated cAMP production without affecting hormone binding. Interestingly, binding of the antibody to all three receptors was abolished by prior incubation of the receptors with the respective hormones, suggesting that the exoloops are buried in the hormone-receptor complexes. The antibody also suppressed the high basal activities of gain-of-function mutations in the HinRs, exoloops, and TMDs such as those involved in precocious puberty and thyroid toxic adenomas. Using the antibody and point/deletion/chimeric receptor mutants, we demonstrate that changes in the HinR-exoloop interactions play an important role in receptor activation. Computational analysis suggests that the mini-TMD antibodies act by conformationally locking the transmembrane helices by means of restraining the exoloops and the juxta-membrane regions. Using GpHRs as a model, we describe a novel computational approach of generating soluble TMD mimics that can be used to explain the role of exoloops during receptor activation and their interplay with TMDs.

A finite population model of mlecular evolution: theory and computation

This article is concerned with the evolution of haploid organisms that reproduce asexually. In a seminal piece of work, Eigen and coauthors proposed the quasispecies model in an attempt to understand such an evolutionary process. Their work has impacted antiviral treatment and vaccine design strategies. Yet, predictions of the quasispecies model are at best viewed as a guideline, primarily because it assumes an infinite population size, whereas realistic population sizes can be quite small. In this paper we consider a population genetics-based model aimed at understanding the evolution of such organisms with finite population sizes and present a rigorous study of the convergence and computational issues that arise therein. Our first result is structural and shows that, at any time during the evolution, as the population size tends to infinity, the distribution of genomes predicted by our model converges to that predicted by the quasispecies model. This justifies the continued use of the quasispecies model to derive guidelines for intervention. While the stationary state in the quasispecies model is readily obtained, due to the explosion of the state space in our model, exact computations are prohibitive. Our second set of results are computational in nature and address this issue. We derive conditions on the parameters of evolution under which our stochastic model mixes rapidly. Further, for a class of widely used fitness landscapes we give a fast deterministic algorithm which computes the stationary distribution of our model. These computational tools are expected to serve as a framework for the modeling of strategies for the deployment of mutagenic drugs.

Highly luminescent and thermally stable lanthanide coordination polymers designed from 4-(dipyridin-2-yl)aminobenzoate: efficient energy transfer from Tb3+ to Eu3+ in a mixed lanthanide coordination compound

Herein, a new aromatic carboxylate ligand, namely, 4-(dipyridin-2-yl)aminobenzoic acid (HL), has been designed and employed for the construction of a series of lanthanide complexes (Eu3+ = 1, Tb3+ = 2, and Gd3+ = 3). Complexes of 1 and 2 were structurally authenticated by single-crystal X-ray diffraction and were found to exist as infinite 1D coordination polymers with the general formulas {Eu(L)(3)(H2O)(2)]}(n) (1) and {Tb(L)(3)(H2O)]center dot(H2O)}(n) (2). Both compounds crystallize in monoclinic space group C2/c. The photophysical properties demonstrated that the developed 4-(dipyridin-2-yl)aminobenzoate ligand is well suited for the sensitization of Tb3+ emission (Phi(overall) = 64%) thanks to the favorable position of the triplet state ((3)pi pi*) of the ligand the energy difference between the triplet state of the ligand and the excited state of Tb3+ (Delta E) = (3)pi pi* - D-5(4) = 3197 cm(-1)], as investigated in the Gd3+ complex. On the other hand, the corresponding Eu3+ complex shows weak luminescence efficiency (Phi(overall) = 7%) due to poor matching of the triplet state of the ligand with that of the emissive excited states of the metal ion (Delta E = (3)pi pi* - D-5(0) = 6447 cm(-1)). Furthermore, in the present work, a mixed lanthanide system featuring Eu3+ and Tb3+ ions with the general formula {Eu0.5Tb0.5(L)(3)(H2O)(2)]}(n) (4) was also synthesized, and the luminescent properties were evaluated and compared with those of the analogous single-lanthanide-ion systems (1 and 2). The lifetime measurements for 4 strongly support the premise that efficient energy transfer occurs between Tb3+ and Eu3+ in a mixed lanthanide system (eta = 86%).

Study of terahertz wave propagation properties in nanoplates with surface and small-scale effects

In macroscopic and even microscopic structural elements, surface effects can be neglected and classical theories are sufficient. As the structural size decreases towards the nanoscale regime, the surface-to-bulk energy ratio increases and surface effects must be taken into account. In the present work, the terahertz wave dispersion characteristics of a nanoplate are studied with consideration of the surface effects as well as the nonlocal small-scale effects. Nonlocal elasticity theory of plate is used to derive the general differential equation based on equilibrium approach to include those scale effects. Scale and surface property dependent wave characteristic equations are obtained via spectral analysis. For the present study the material properties of an anodic alumina with crystallographic of < 111 > direction are considered. The present analysis shows that the effect of surface properties on the flexural waves of nanoplates is more significant. It can be found that the flexural wavenumbers with surface effects are high as compared to that without surface effects. The scale effects show that the wavenumbers of the flexural wave become highly non-linear and tend to infinite at certain frequency. After that frequency the wave will not propagate and the corresponding wave velocities tend to zero at that frequency (escape frequency). The effects of surface stresses on the wave propagation properties of nanoplate are also captured in the present work. (C) 2012 Elsevier Ltd. All rights reserved.

Synthon Modularity in 4-Hydroxybenzamide-Dicarboxylic Acid Cocrystals

A family of 4-hydroxybenzamide-dicarboxylic acid cocrystals has been designed and subsequently isolated and characterized. The design strategy follows from an understanding of synthon modularity in crystal structures of monocomponent crystals such as gamma-quinol, 4,4'-biphenol and 4-hydroxybenzoic acid. These monocomponent structures contain infinite O-H center dot center dot center dot O-H center dot center dot center dot O-H center dot center dot center dot cooperative synthons linked with molecular connectors such as phenyl and biphenyl, and supramolecular connectors such as the acid dimer in 4-hydroxybenzoic acid. The cocrystal design was influenced by the anticipation that dicarboxylic acids can form a supramolecular connector mediated by acid-amide synthons with 4-hydroxybenzamide, which can then form the phenol O-H center dot center dot center dot O-H center dot center dot center dot O-H center dot center dot center dot infinite synthon. Effectively, the acid-amide and phenol synthons are insulated. The short axis of such a structure will be around 5.12 angstrom and this is borne out in 2:1 cocrystals of 4-hydroxybenzamide with oxalic, succinic, fumaric, glutaric (two forms) and pimelic acids. Hydrated variations of this structure type are seen in the cocrystals obtained with adipic and sebacic acids.

Minimum power consumption for drag reduction on a circular cylinder by tangential surface motion

We investigate the effect of a prescribed tangential velocity on the drag force on a circular cylinder in a spanwise uniform cross flow. Using a combination of theoretical and numerical techniques we make an attempt at determining the optimal tangential velocity profiles which will reduce the drag force acting on the cylindrical body while minimizing the net power consumption characterized through a non-dimensional power loss coefficient (C-PL). A striking conclusion of our analysis is that the tangential velocity associated with the potential flow, which completely suppresses the drag force, is not optimal for both small and large, but finite Reynolds number. When inertial effects are negligible (R e << 1), theoretical analysis based on two-dimensional Oseen equations gives us the optimal tangential velocity profile which leads to energetically efficient drag reduction. Furthermore, in the limit of zero Reynolds number (Re -> 0), minimum power loss is achieved for a tangential velocity profile corresponding to a shear-free perfect slip boundary. At finite Re, results from numerical simulations indicate that perfect slip is not optimum and a further reduction in drag can be achieved for reduced power consumption. A gradual increase in the strength of a tangential velocity which involves only the first reflectionally symmetric mode leads to a monotonic reduction in drag and eventual thrust production. Simulations reveal the existence of an optimal strength for which the power consumption attains a minima. At a Reynolds number of 100, minimum value of the power loss coefficient (C-PL = 0.37) is obtained when the maximum in tangential surface velocity is about one and a half times the free stream uniform velocity corresponding to a percentage drag reduction of approximately 77 %; C-PL = 0.42 and 0.50 for perfect slip and potential flow cases, respectively. Our results suggest that potential flow tangential velocity enables energetically efficient propulsion at all Reynolds numbers but optimal drag reduction only for Re -> infinity. The two-dimensional strategy of reducing drag while minimizing net power consumption is shown to be effective in three dimensions via numerical simulation of flow past an infinite circular cylinder at a Reynolds number of 300. Finally a strategy of reducing drag, suitable for practical implementation and amenable to experimental testing, through piecewise constant tangential velocities distributed along the cylinder periphery is proposed and analysed.

Reuse, recycle to de-bloat software

Most Java programmers would agree that Java is a language that promotes a philosophy of “create and go forth”. By design, temporary objects are meant to be created on the heap, possibly used and then abandoned to be collected by the garbage collector. Excessive generation of temporary objects is termed “object churn” and is a form of software bloat that often leads to performance and memory problems. To mitigate this problem, many compiler optimizations aim at identifying objects that may be allocated on the stack. However, most such optimizations miss large opportunities for memory reuse when dealing with objects inside loops or when dealing with container objects. In this paper, we describe a novel algorithm that detects bloat caused by the creation of temporary container and String objects within a loop. Our analysis determines which objects created within a loop can be reused. Then we describe a source-to-source transformation that efficiently reuses such objects. Empirical evaluation indicates that our solution can reduce upto 40% of temporary object allocations in large programs, resulting in a performance improvement that can be as high as a 20% reduction in the run time, specifically when a program has a high churn rate or when the program is memory intensive and needs to run the GC often.

Electron rich supramolecular polymers as fluorescent sensors for nitroaromatics

Three pi-electron rich fluorescent supramolecular polymers (1-3) have been synthesized incorporating 2-methyl-3-butyn-2-ol groups in reasonable yield by employing Sonagashira coupling. They were characterized by multinuclear NMR (H-1, C-13), ESI-MS and single crystal X-ray diffraction analyses 1 = 1( 2-methyl-3-butyn-2-ol) pyrene; 2 = 9,10-bis(2-methyl-3-butyn-2-ol) anthracene; 3 = 1,3,6,8-tetrakis(2methyl- 3-butyn-2-ol) pyrene]. Single crystal structures of 1-3 indicated that the incorporation of hydroxy (-OH) groups on the peripheral of the fluorophores helps them to self-associate into an infinite supramolecular polymeric network via intermolecular hydrogen bonding interactions between the adjacent discrete fluorophore units. All these compounds showed fluorescence characteristics in chloroform solution due to the extended pi-conjugation and were used as selective fluorescent sensors for the detection of electron deficient nitroaromatics. The changes in photophysical properties of fluorophores (1-3) upon complex formation with electron deficient nitroaromatic explosives were studied in chloroform solution by using fluorescence spectroscopy. All these fluorophores showed the largest quenching response with moderate selectivity for nitroaromatics over various other electron deficient/ rich aromatic compounds tested (Chart 1). Analysis of the fluorescence titration profile of 9,10-bis(2-methyl-3butyn- 2-ol) anthracene fluorophore (2) with 1,3,5-trinitrotoluene/ 2,4-dinitrotoluene provided evidence that this particular fluorophore detects nitroaromatics in the nanomolar range 2.0 ppb for TNT, 13.7 ppb for DNT]. Moreover, sharp visual color change was observed upon mixing nitroaromatic (DNT) with fluorophores (1-3) both in solution as well as in solid phase. Furthermore, the vapor-phase sensing study of thin film of fluorophores (1-3) showed efficient quenching responses for DNT and this sensing process is reproducible. Selective fluorescence quenching response including a sharp visual color change for nitroaromatics make these tested fluorophores (1-3) as potential sensors for nitroaromatic compounds with a detection limit of ppb level.

Jet meandering by a foil pitching in quiescent fluid

The flow produced by a rigid symmetric NACA0015 airfoil purely pitching at a fixed location in quiescent fluid (the limiting case of infinite Strouhal number) is studied using visualizations and particle image velocimetry. A weak jet is generated whose inclination changes continually with time. This meandering is observed to be random and independent of the initial conditions, over a wide range of pitching parameters. (C) 2013 American Institute of Physics.

Nonlinear dielectric response of BaBi4Ti4O15 ceramics

Nonlinear dielectric response of BaBi4Ti4O15 ceramics synthesized via the conventional solid-state reaction route has been monitored over a wide range of electric field strengths (E-0 = 0.5 - 5 kV/cm). Dielectric permittivity was found to increase linearly within the range of applied field. Rayleigh relations were employed to interpret the nonlinear dielectric response and the contribution of irreversible domain wall motion to the macroscopic permittivity was separated. The values of room temperature Rayleigh dielectric coefficient (alpha) and relative initial permittivity (epsilon'(init)) were found to be 2.28 +/- 0.02 cm/kV and 146.10 +/- 0.07, respectively. A reasonable agreement between the simulated and measured polarization-electric field (P-E) hysteresis loops was observed at an applied electric field of 5 kV/cm.

Characterization and magnetic response of multiwall carbon nanotubes filled with iron nanoparticles of different aspect ratios

Three samples of multiwall carbon nanotubes (MWCNT) TF200, TF150 and TF100, where T and F stand for toluene and ferrocene respectively, and numeral denotes the amount (mg) of ferrocene] filled with iron-nanoparticles (Fe-NPs) of different aspect ratios are grown by chemical vapor deposition of toluene-ferrocene mixture. Energy dispersive X-ray analysis shows a systematic variation in the intensities of peak corresponding to Fe, indicating that Fe is present in different amounts in the three MWCNT samples. The lengths of Fe-NPs lie in the range of 200-250; 80-120; and 30-40 nm for TF200, TF150 and TF100, respectively, as estimated statistically from transmission electron microscopy micrographs. However, the diameter of the encapsulated Fe-NPs does not vary significantly for different samples and is 20-30 nm for all samples. Hysteresis loop measurements on these MWCNT samples were done at 10, 150 and 300 K up to an applied field of 1.5 T. At 10 K, values of coercivity are 2584, 2315, and 2251 Oe for TF200, TF150 and TF100 respectively. This is attributed to the strong shape anisotropy of the Fe-NPs and significant dipolar interactions between them. Further, M-H loops reveal that saturation magnetization of TF200 is almost four times that of TF100 at all temperatures.

Minimum uncertainty and entanglement

We address the question, does a system A being entangled with another system B, put any constraints on the Heisenberg uncertainty relation (or the Schrodinger-Robertson inequality)? We find that the equality of the uncertainty relation cannot be reached for any two noncommuting observables, for finite dimensional Hilbert spaces if the Schmidt rank of the entangled state is maximal. One consequence is that the lower bound of the uncertainty relation can never be attained for any two observables for qubits, if the state is entangled. For infinite-dimensional Hilbert space too, we show that there is a class of physically interesting entangled states for which no two noncommuting observables can attain the minimum uncertainty equality.

Exchange-spring mechanism of soft and hard ferrite nanocomposites

The paper reports exchange-spring soft and hard ferrite nanocomposites synthesized by chemical co-precipitation with or without the application of ultrasonic vibration. The composites contained BaFe12O19 as the hard phase and CoFe2O4/MgFe2O4 as the soft phase. X-ray diffraction patterns of the samples in the optimum calcined condition indicated the presence of soft ferrites as face-centred cubic (fcc) and hard ferrites as hexagonal close packed (hcp) structure respectively. Temperature dependence of magnetization in the range of 20-700 degrees C demonstrated distinct presence of soft and hard ferrites as magnetic phases which are characterized by wide difference in magnetic anisotropy and coercivity. Exchange-spring mechanism led these nanocomposite systems to exchange-coupled, which ultimately produced convex hysteresis loops characteristic of a single-phase permanent magnet. Fairly high value of coercivity and maximum energy product were observed for the samples in the optimum calcined conditions with a maximum applied field of 1600 kA/m (2 T).

A relational contract for water demand management

For necessary goods like water, under supply constraints, fairness considerations lead to negative externalities. The objective of this paper is to design an infinite horizon contract or relational contract (a type of long-term contract) that ensures self-enforcing (instead of court-enforced) behaviour by the agents to mitigate the externality due to fairness issues. In this contract, the consumer is induced to consume at firm-supply level using the threat of higher fair price for future time periods. The pricing mechanism, computed in this paper, internalizes the externality and is shown to be economically efficient and provides revenue sufficiency.

Analysis of Bandwidth-Unit-Vector-Distortion Tradeoff in PLL During Abnormal Grid Conditions

Phase-locked loops (PLLs) are necessary in applications which require grid synchronization. Presence of unbalance or harmonics in the grid voltage creates errors in the estimated frequency and angle of a PLL. The error in estimated angle has the effect of distorting the unit vectors generated by the PLL. In this paper, analytical expressions are derived which determine the error in the phase angle estimated by a PLL when there is unbalance and harmonics in the grid voltage. By using the derived expressions, the total harmonic distortion (THD) and the fundamental phase error of the unit vectors can be determined for a given PLL topology and a given level of unbalance and distortion in the grid voltage. The accuracy of the results obtained from the analytical expressions is validated with the simulation and experimental results for synchronous reference frame PLL (SRF-PLL). Based on these expressions, a new tuning method for the SRF-PLL is proposed which quantifies the tradeoff between the unit vector THD and the bandwidth of the SRF-PLL. Using this method, the exact value of the bandwidth of the SRF-PLL can be obtained for a given worst case grid voltage unbalance and distortion to have an acceptable level of unit vector THD. The tuning method for SRF-PLL is also validated experimentally.