For establishment of the structure-activity relationship, 19 heterobicycle-coumarin conjugated compounds with the -SCH(2)- linker were synthesized and found to possess significant antiviral activities. Prominent examples included imidazopyridine-coumarin 12c, purine-coumarin 12d, and benzoxazole-coumarin 14c, which inhibited HCV replication at an EC(50) of 6.8, 2.0, and 12 microM, respectively. The heteroatoms in bicycles and the substituent effect on coumarin played essential roles.

Reactive oxygen species (ROS) are believed to play a major role in the proinflammatory, M1-polarized form of neuroinflammation. However, it has been difficult to assess the role of ROS and their role in neuroinflammation in animal models of disease because of the absence of probes capable of measuring their presence with the functional imaging technique positron emission tomography (PET). This study describes the synthesis and in vivo evaluation of [18F]ROStrace, a radiotracer for imaging superoxide in vivo with PET, in an LPS model of neuroinflammation. [18F]ROStrace was found to rapidly cross the blood–brain barrier (BBB) and was trapped in the brain of LPS-treated animals but not the control group. [18F]ox-ROStrace, the oxidized form of [18F]ROStrace, did not cross the BBB. These data suggest that [18F]ROStrace is a suitable radiotracer for imaging superoxide levels in the central nervous system with PET.

Cholera toxin subunit B (CTB)--quantum dot conjugates were developed for labeling mammalian cells. The conjugates were internalized by all tested cell lines into small vesicles dispersed throughout the cytoplasm, while commercially available polyarginine conjugates rapidly accumulated in large perinuclear endosomes. Although a large proportion of CTB conjugates eventually also accumulated in perinuclear endosomes, this accumulation required several days, and even then many CTB conjugated quantum dots remained in small vesicles dispersed throughout the cytoplasm. Thus CTB conjugates are a practical alternative to polyarginine conjugates for the general labeling of mammalian cells.

Two-dimensional graphene plasmon-based technologies will enable the development of fast, compact and inexpensive active photonic elements because, unlike plasmons in other materials, graphene plasmons can be tuned via the doping level. Such tuning is harnessed within terahertz quantum cascade lasers to reversibly alter their emission. This is achieved in two key steps: First by exciting graphene plasmons within an aperiodic lattice laser and, second, by engineering photon lifetimes, linking graphene's Fermi energy with the round-trip gain. Modal gain and hence laser spectra are highly sensitive to the doping of an integrated, electrically controllable, graphene layer. Demonstration of the integrated graphene plasmon laser principle lays the foundation for a new generation of active, programmable plasmonic metamaterials with major implications across photonics, material sciences and nanotechnology.Among the many intriguing properties of graphene, its plasmonic characteristics are some of the most fascinating and potentially useful [1,2]. Long-lived, tunable intrinsic graphene surface plasmons (SP) have already been demonstrated in a number of experiments [3][4][5][6][7][8][9], including optical modulators [10,11], providing the potential for applications [12,13]. In contrast to the noble metals that are usually used in SP devices [13,14], graphene's Fermi energy, E F , and carrier concentration, n s (and therefore its conductivity and SP mode properties), can be altered, for example by electrical gating and surface doping [3,15,16]. Consequently, the behavior of graphene SP-based structures can be modified in situ, without the need for structural device changes. In particular, graphene's optical and plasmonic properties are tunable in the terahertz (THz) spectral region [3,17], giving rise to the possibility of compact electrically controllable THz optical components [18]. We incorporated graphene into a plasmonic THz laser microcavity to dynamically modulate round-trip modal gain values and therefore laser emission via E F . In this way gated graphene becomes a powerful tool with which to control the fundamental properties of a laser -a tool that is potentially extremely fast and all electrical in nature, with negligible electrical power requirements.The interaction between light and matter can be altered by manipulating the electromagnetic density-of-states (DOS) using a micro resonator [19,20]. By incorporating a photonic lattice or plasmonic structure into a laser, one can control the frequency and amplification of resonant modes and hence manipulate the properties of lasing emission [21][22][23]. Furthermore, by breaking the regularity of these structures it is possible to modulate the photon DOS and hence light-matter interaction at several frequencies simultaneously. This technique was used recently to develop an aperiodic distributed feedback (ADFB) cavity laser with a lattice which is in essence a computergenerated hologram [24,25]. The hologram digitally encodes the Fourier transform of a desired optica...

A transverse computer-generated hologram (CGH) diffracts and provides flexible control of incident light by steering it to any point in the projected image plane -i.e.CGHs are able to direct the light to where it is needed and away from where it is not 1 .In addition, the number of resolvable points in the image projection plane is a function of the CGH's pixel count 2 . Here we report a longitudinal CGH (LCGH), a photonic structure, which swaps the ability to steer light toward fixed spatial points for digital control in the frequency domain. This is of particular interest in the context of tunable lasers. In this regard, an LCGH offers two important degrees-of-freedom (DOFs): 1) provides high-resolution wavevector or k-space resolution within the Brillouin zone; 2) enables full control to define or modify the reflectivity at each resolvable k-point, so attaining a target spectral response. We demonstrate the flexibility of our LCGH approach by achieving purely electronic tuning between six digitally-selected operating frequencies in a single-section terahertz (THz) quantum cascade laser (QCL) 3 . These switchable single-frequency devices will simplify combining the power and flexibility of (Fig. 1d) enabling switching between these modes, i.e.electronically-controlled discrete tuning.In order to understand the first DOF, consider an LCGH of 2N pixels in the form of a spatial relative permittivity distribution ε(z), where L = NΛ is the total length and Λ the 3 minimum hologram-element separation. There exists an approximate FT relationship between ε(z) and the spectral reflectivity response ρ(k)18-20 :Due to the pixelated nature of the spatial domain z, the wavevector k is unique only over the interval (0,k B ), with a maximum N number of resolvable k-points resulting in a density of states Δk = (k B /N)(n eff /n g ) 21, 22 , where k B = π/n eff Λ is the wavevector corresponding to the edge of Brillouin zone, n eff is the effective modal refractive index, n g is the group refractive index All QCLs were fabricated from a molecular beam epitaxially grown GaAs/Al 0.15 Ga 0.85 As wafer, V557, with an 11.4 µm-thick active region based on reference 25. V557 was processed (Fig. 2 caption) into SP waveguides and cleaved into ~6 mm-long Fabry-Perot (FP) cavities.All devices displayed similar performance characteristics − as a typical example Fig. 2a shows the FP spectra of device A, recorded at four driving current densities. As expected, In order to generate the real-space lattice structure (i.e. the LCGH) satisfying ρ target , we exploit equation 1. The pixelated nature of the real-space allows this design to be implemented using a discrete FT, specifically a fast Fourier transform (FFT). Identifying an "optimised" LCGH architecture is computationally non-trivial, particularly when N is large.An FFT-based simulated annealing (SA) inverse optimisation algorithm was chosen, details 5 of which, including the number of optimisation parameters, are described in references 26and 27. The choice of algorithm is not critica...

BackgroundMembrane proteins regulate a diversity of physiological processes and are the most successful class of targets in drug discovery. However, the number of targets adequately explored in chemical space and the limited resources available for screening are significant problems shared by drug-discovery centers and small laboratories. Therefore, a low-cost and universally applicable screen for membrane protein trafficking was developed.ResultsThis high-throughput screen (HTS), termed IRFAP-HTS, utilizes the recently described MarsCy1-fluorogen activating protein and the near-infrared and membrane impermeant fluorogen SCi1. The cell surface expression of MarsCy1 epitope-tagged receptors can be visualized by simple addition of SCi1. User-friendly, rapid, and quantitative detection occurs on a standard infrared western-blotting scanner. The reliability and robustness of IRFAP-HTS was validated by confirming human vasopressin-2 receptor and dopamine receptor-2 trafficking in response to agonist or antagonist. The IRFAP-HTS screen was deployed against the leucine-rich G protein-coupled receptor-5 (Lgr5). Lgr5 is expressed in stem cells, modulates Wnt/ß-catenin signaling, and is therefore a promising drug target. However, small molecule modulators have yet to be reported. The constitutive internalization of Lgr5 appears to be one primary mode through which its function is regulated. Therefore, IRFAP-HTS was utilized to screen 11,258 FDA-approved and drug-like small molecules for those that antagonize Lgr5 internalization. Glucocorticoids were found to potently increase Lgr5 expression at the plasma membrane.ConclusionThe IRFAP-HTS platform provides a versatile solution for screening more targets with fewer resources. Using only a standard western-blotting scanner, we were able to screen 5,000 compounds per hour in a robust and quantitative assay. Multi-purposing standardly available laboratory equipment eliminates the need for idiosyncratic and more expensive high-content imaging systems. The modular and user-friendly IRFAP-HTS is a significant departure from current screening platforms. Small laboratories will have unprecedented access to a robust and reliable screening platform and will no longer be limited by the esoteric nature of assay development, data acquisition, and post-screening analysis. The discovery of glucocorticoids as modulators for Lgr5 trafficking confirms that IRFAP-HTS can accelerate drug-discovery and drug-repurposing for even the most obscure targets.Electronic supplementary materialThe online version of this article (doi:10.1186/s12915-015-0216-3) contains supplementary material, which is available to authorized users.

A holographically designed, aperiodic distributed feedback grating is used as a multi-resonance filter and embedded within an existing Fabry-Pérot (FP) terahertz (THz) quantum cascade laser (QCL) cavity. Balancing the feedback strengths of the filter resonances and the FP cavity creates a system capable of a high degree of single-mode selectivity, which is sensitive to changes in driving current. Multi-moded QCLs operating around 2.9 THz are thus modified to achieve purely electronic discrete tuning spanning over 160 GHz with an average tuning resolution of 30 GHz. Applying the same multi-resonance filter to QCLs with gain peaks around 2.65 and 2.9 THz leads to dual-mode lasing with an electrically controlled frequency separation of between 190 and 267 GHz. A phase sensitive mode selection mechanism is experimentally confirmed by the observation of divergent fine-tuning of the lasing modes.

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