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In order to identify anti-tubercular agents with a novel scaffold, commercial libraries of small organic compounds were screened against a fluorescent strain of Mycobacterium tuberculosis H37Rv, using a dual phenotypic assay. Compounds were assessed against bacteria replicating in broth medium, as well as inside macrophages, and thienothiazolocarboxamide (TTCA) scaffold was identified as hit in both assays, with submicromolar inhibitory concentrations. Derivatives of TTCA were further synthesized and evaluated for their inhibitory effects on M. tuberculosis H37Rv. In the present study we report the structure–activity relationship of these TTCA derivatives. Compounds 28, 32 and 42 displayed good anti-tubercular activities, as well as favorable ADME and PK properties. Compound 42 exhibited excellent oral bioavailability in mice with high distribution to lungs, within 1 h. It was found to be efficacious in a dose dependent manner in a murine model of M. tuberculosis infection. Hence, compound 42 is now under evaluation as a potential lead candidate for treatment of tuberculosis.

Hepatitis C virus (HCV) infection is a major worldwide problem that has emerged as one of the most significant diseases affecting humans. There are currently no vaccines or efficient therapies without side effects, despite today's advanced medical technology. Currently, the common therapy for most patients (i.e. genotype 1) is combination of HCV-specific direct-acting antivirals (DAAs). Up to 2011, the standard of care (SOC) was a combination of peg-IFNα with ribavirin (RBV). After approval of NS3/4A protease inhibitor, SOC was peg-IFNα and RBV with either the first-generation DAAs boceprevir or telaprevir. In the past several years, various novel small molecules have been discovered and some of them (i.e., HCV polymerase, protease, helicase and entry inhibitors) have undergone clinical trials. Between 2013 and 2016, the second-generation DAA drugs simeprevir, asunaprevir, daclatasvir, dasabuvir, sofosbuvir, and elbasvir were approved, as well as the combinational drugs Harvoni®, Zepatier®, Technivie®, and Epclusa®. A number of reviews have been recently published describing the structure-activity relationship (SAR) in the development of HCV inhibitors and outlining current therapeutic approaches to hepatitis C infection. Target identification involves studying a drug's mechanism of action (MOA), and a variety of target identification methods have been developed in the past few years. Chemical biology has emerged as a powerful tool for studying biological processes using small molecules. The use of chemical genetic methods is a valuable strategy for studying the molecular mechanisms of the viral lifecycle and screening for anti-viral agents. Two general screening approaches have been employed: forward and reverse chemical genetics. This review reveals information on the small molecules in HCV drug discovery by using chemical genetics for targeting the HCV protein and describes successful examples of targets identified with these methods.

This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Science, ICT and Future Planning (NRF-2013R1A1A2010008, to BJP; 2009-0093815, to GYS; 2014R1A2A2A01005455, to KL; and NRF-2013R1A1A2063077, to SJL); the Progeria Research Foundation; the Ministerio de Economia y Competitividad of Spain; and the Red Tematica de investigacion cooperativa en cancer -Institute de Salud. The Institute Universitario de Oncologia is supported by Obra Social Cajastur-Asturias. CLO is an Investigator of the Botin Foundation., Lee, S.-J., Jung, Y.-S., Yoon, M.-H., Kang, S.-M., Oh, A.-Y., Lee, J.-H., Jun, S.-Y., Woo, T.-G., Chun, H.-Y., Kim, S.K., Chung, K.J., Lee, H.-Y., Lee, K., Jin, G., Na, M.-K., Ha, N.C., Bárcena, C., Freije, J.M.P., López-Otín, C., Song, G.Y., Park, B.-J

We report that phytosphingosine, a sphingolipid found in many organisms and implicated in cellular signaling, promotes megakaryocytic differentiation of myeloid leukemia cells. Specifically, phytosphingosine induced several hallmark changes associated with megakaryopoiesis from K562 and HEL cells including cell cycle arrest, cell size increase and polyploidization. We also confirmed that cell type specific markers of megakaryocytes, CD41a and CD42b are induced by phytosphingosine. Phospholipids with highly similar structures were unable to induce similar changes, indicating that the activity of phytosphingosine is highly specific. Although phytosphingosine is known to activate p38 mitogen-activated protein kinase (MAPK)-mediated apoptosis, the signaling mechanisms involved in megakaryopoiesis appear to be distinct. In sum, we present another model for dissecting molecular details of megakaryocytic differentiation which in large part remains obscure. [BMB Reports 2015; 48(12): 691-695]

A series of indole acrylamide derivatives were synthesized and evaluated for their inhibitory effects on hepatitis C virus (HCV) replication. Previously, we have identified (E)-N-(4-tert-butylphenyl)-3-(5-cyano-1H-indol-3-yl)-2-methylacrylamide (6c) as one of the promising leads for anti-HCV chemotherapy. Based on the structural features of indole acrylamide, we have explored extended structure–activity relationship study using analogs with substituted indoles, various amides, and N-substitution at the indole ring. Among the newly synthesized series, 5-cyanoindole acrylamide analog with N-acetyl substitution (13c) (EC50 = 0.98 μM, CC50 = 40.74 μM, and SI = 41.6) exhibited the most potent antiviral activity with reasonable cytotoxicity in a cell-based J6/JFH1 reporter assay using Huh7.5 cells. In addition, improved water solubility of 13c compared to 6c further merits consideration of 13c as a valuable candidate for anti-HCV therapeutics development.

Thin amorphous silicon (a-Si) films were crystallized into polycrystalline silicon (poly-Si) by combining solid phase crystallization (SPC) and subsequent excimer laser annealing (ELA). Then thin film transistors (TFTs) were fabricated by using the poly-Si formed in the single and double excimer laser scanned area. The device performance of the TFTs fabricated with the excimer laser energy density of 230 mJ/cm 2 is almost equal for the single and double scanned area. This observation indicates that the overlapping laser irradiation with the laser energy density below 230 mJ/cm 2 does not change the characteristics of TFTs. Based on this result, we discuss the correlation between performance of active matrix organic light emitting display (AMOLED) panels and excimer laser energy density during ELA for SPC treated and non-treated poly-Si films.

In this work, we investigated the correlation between the spacing of primary grain boundaries in sequential lateral solidification (SLS) polycrystalline silicon and the brightness non-uniformity of active matrix organic light emitting diode panels. The oblique line is attributed both to the SLS method and the thin film transistor fabrication process. We found that the oblique line type of brightness non-uniformity disappeared when the spacing of primary grain boundaries is exactly the same in the individual transistor channel or when the non-uniform size is between 2.7 and 3.3 μ m( � Lg < ±10%) in active patterns. © 2014 The Electrochemical Society. [DOI: 10.1149/2.0071408ssl] All rights reserved.

We have fabricated two kinds of thin film transistors (TFTs) on the glass substrates using polycrystalline silicon (poly-Si) thin films with small and large grain sizes processed by Excimer Laser Annealing (ELA) and carried out a comparative analysis. The grain size was controlled by nickel atom content in amorphous silicon (a-Si) thin films. With increasing grain size of poly-Si thin films, the carrier mobility increased from 40.8 to 54.4 cm2/V s and the absolute value of threshold voltage reduced from 2.1 to 1.5 V. The observed improvements in the electrical characteristics of poly-Si TFTs are attributed mainly to the reduction of defect density rendered by large grain size. These observations indicate that the sputtered nickel atom content in a-Si layer is a key parameter in determining the characteristics of ELA processed TFTs fabricated on the glass substrates.

Booster of pluripotency: RSC133, a new synthetic derivative of indoleacrylic acid/indolepropionic acid, exhibits dual activity by inhibiting histone deacetylase and DNA methyltransferase. Furthermore it potently improves the reprogramming of human somatic cells into a pluripotent state and aids the growth and maintenance of human pluripotent stem cells (hPSCs).

Active matrix organic light-emitting diode (AMOLED) displays are fabricated from polycrystalline silicon, which is formed in the single and double (overlap) scanned area during the excimer laser annealing (ELA) process. A redundant pixel line (RPL) design is proposed to remove the overlapping mura and, as a result, a 5-in AMOLED display is successfully fabricated without any non-uniform line image on the overlapping scanned area. This result indicates that the fabrication of a large-sized AMOLED panel is possible using ELA crystallization through an RPL design.

A six-day static-renewal toxicity test was performed to determine the influences of cadmium on the development of embryos of soldatov's catfish (Silurus soldatovi). The median lethal concentration (LC50) value and median effective concentration (EC50, i.e., the total adverse effects, including developmental defects and mortality) were calculated to be 2740 and 133 μg/L, respectively, when cadmium was prepared in dilution water. The LC50 decreased to 266 μg/L in a subsequent test one month later, thereby suggesting that the sensitivity of this fish to cadmium in the early life stage(1) was largely influenced by the quality of fertilized eggs, which is known to be dependent on the season. The mortality and total adverse effects showed a concentration-dependent relationship at dosages greater than 1000 or 10 μg/L (p

We have successfully fabricated a novel 3-D vertically stacked complementary metal-oxide-semiconductor hybrid inverter using a lower p-type poly-Si thin-film transistor (TFT) and an upper n-type amorphous Ga-In-Zn-O (a-GIZO) TFT. The device was fabricated step by step, starting from the fabrication of the lower poly-Si TFT via a high-temperature process to the fabrication of the upper a-GIZO TFT via a low-temperature process; this was done to prevent damage to the TFTs and to optimize their characteristics. The entire process was further simplified by the coplane gate structure that allows successive formation of the a-GIZO TFT on the poly-Si TFT. The transfer characteristics show clear inverter actions, indicating high performances of the TFTs.

A series of (E)-phenoxyacrylic amide derivatives were synthesized and evaluated as hypoxia inducible factor (HIF) 1α inhibitors. The present structure-activity relationship study on this series identified the morpholinoethyl containing ester 4p as a potent inhibitor of HIF-1α under hypoxic conditions (IC50=0.12 μM in a cell-based HRE reporter assay) in HCT116 cells. The representative compound 4p suppressed hypoxia-induced HIF-1α accumulation and targeted gene expression in a dose-dependent manner. The effect of HIF-1α inhibition by 4p was further demonstrated by its inhibitory activity on in vitro tube formation and migration of cells, which may be valuable for development of novel therapeutics for cancer and tumor angiogenesis.

A six-day static-renewal toxicity test was performed to determine the influences of cadmium on the development of embryos of soldatov's catfish (Silurus soldatovi). The median lethal concentration (LC50) value and median effective concentration (EC50, i.e., the total adverse effects, including developmental defects and mortality) were calculated to be 2740 and 133 μg/L, respectively, when cadmium was prepared in dilution water. The LC50 decreased to 266 μg/L in a subsequent test one month later, thereby suggesting that the sensitivity of this fish to cadmium in the early life stage(1) was largely influenced by the quality of fertilized eggs, which is known to be dependent on the season. The mortality and total adverse effects showed a concentration-dependent relationship at dosages greater than 1000 or 10 μg/L (p0.05), respectively, at pro-larva stage (i.e., 144 hpf) with dilution water. To compare the toxic effects of cadmium under field and experimental conditions, filtered river water was adopted as a solvent simultaneously compared with dilution water. No significant differences were observed in mortality rate, hatching rate and adverse effect prevalence between the two solvents. In comparison to previously published toxicity data for other fish, the pro-larva of soldatov's catfish were less sensitive than established test fish in the early life stage. Therefore, the environmental risks would be overestimated when considering only existing toxicity data for other test fish.

This paper presents a photonics based multi-beam RF beamformer for phased array antenna systems. This RF beamformer uses fiber optic WDM-Mux/DeMux and photonic true time delay techniques, independently and simultaneously enabling multi-beam operation in wide RF frequency range. A four-antennas of RF beamforming breadboard is built to operate two-beam for verifying its functionalities. The simultaneously steering of two beams over +/− 50° and 4GHz bandwidth have been demonstrated experimentally.

A 1.28GSPS 12-bits optoelectronic analog-to-digital converter is presented. The ADC architecture consists of an optical circuit that optically samples an analog input signal, and optoelectronic circuits that demultiplex different phases of the sampled signal (polyphase) to yield low data rate for electronic quantization. Electrical-in to electrical-out data format is maintained through the sampling, demultiplexing and quantization stages of the architecture thereby avoiding the need for electrical-to-optical and optical-to-electrical signal conversions. The ADC architecture encodes and multiplexes four 320MSPS 12-bits time interleaves quantized data into an aggregated 1.28GSPS 12-bits digital signal in real time. All clock signals at frequencies of 1.28GHz, 640MHz, and 320MHz are generated from a single 320MHz femtosecond laser source, thus eliminating the need for external synchronization and control signals. A Spurious Free Dynamic Range (SFDR) of value 80.6dB, and Effective number of bits (ENOB) of value 8.8 bits, were measured for the system.

The structural and quadratic electro-optic properties in lead magnesium niobate titanate thin films have been systematically studied as a function of the fraction x of lead titanate. (110)-oriented, pyrochlore-free PMN–PT films with PT contents around morphotropic phase boundary compositions, which have a propagation loss as low as 3 dB/cm and a high electro-optical (EO) coefficient of 1.32×10−16 (m/V)2, have been fabricated on (1012)-cut sapphire substrates. The EO measurements show that the PMN–PT is a highly promising electro-optic material.

Agiltron has demonstrated an uncooled dual-band MWIR/LWIR imager based on our previously reported photomechanical sensor technology. The readout from two separate MWIR and LWIR photomechanical sensor arrays were fused together, permitting either dual-band, MWIR-only, or LWIR-only operation of the imager. Results of the dual-band imager in response to a wide-dynamic range infrared scene are described. With the dual-band MWIR/LWIR capability, the full dynamic range of the scene was successfully captured, yet good sensitivity was still maintained when imaging near-room temperature objects. Extensive comparative performance analysis was performed for the photomechanical thermal imager and HgCdTe and InSb photon imagers. A noise model for the optical readout photomechanical thermal imager is presented. It is shown that the photomechanical pixel can be engineered to nullify the contribution of shot noise to NETD without affecting the thermal properties of the pixel. In this regime, the performance of the uncooled photomechanical imager will approach that of cooled photon imagers.

Highly (110)-oriented and (100) nearly epitaxial 0.7PMN-0.3PT thin films were deposited on (1012) sapphire and (100) LaAlO3 substrates, respectively, using a dip-coating method. Optical waveguide characterization and electro-optic effect measurements of the film on sapphire substrate were demonstrated. Low propagation loss of 4.1 dB/cm and high quadratic electro-optic coefficient of 0.75×10−16 (m/V)2 were obtained at wavelength of 632.8 nm. Epitaxial PMN-PT thin films will be suitable for integrated optic devices.

We report here a novel photonic infrared scene generator based on integration of IR fiber with MEMS attenuation technologies. We employed an infrared transmission fiber image bundles with one end coupled to an IR light source and the other end for display. A robust electromagnetic actuated MEMS attenuator array is incorporated into each fiber to individually modulate the IR light intensity, forming a 2D and high grayscale scene. The design is versatile, promising to realize the desirable performance specification for IR scene generator. Using an IR lamp as the broadband light source, our scene generator covers the wavelength range from 2~14μm, and provides the sufficient IR power for the high apparent temperature. We reported here a 4×4 format array demonstration unit. This performances achieved to date include: high apparent temperature of 1700°C, high dynamic range over 40dB, high pixel isolation over 40dB, cool ambient background, and the moderate response speed of a few ms as well as continuous gray-scale without flick-ness.

This article conducted a comparative analysis on thin film transistors (TFTs) fabricated by using the excimer laser annealed (ELA) polycrystalline silicon (poly-Si) and those fabricated by using the Ni-sputtered ELA poly-Si. The grain size of the Ni-sputtered ELA poly-Si is 3 times greater than that of the ELA poly-Si. The Ni-sputtered ELA poly-Si TFTs showed a higher drain current, lower threshold voltage, smaller subthreshold swing, and higher electron mobility than the ELA poly-Si TFTs. This improvement is attributed mainly to the reduction of the defect density rendered by the large grain size.

The oxidizing ambient was built using high pressure H2O vapor at 550 °C. For the solid phase crystallization (SPC) polycrystalline silicon (poly-Si) that is annealed for 1 h at 2 MPa, the oxide thickness is about 150 A. The oxide layer is approximately 90 A above the original surface of the poly-Si and 60 A below the original surface. The oxide layer is used as the first gate insulator layer of thin-film transistors (TFTs). The heating at 550 °C with 2 MPa H2O vapor increased the carrier mobility from 17.6 cm2/V s of the conventional SPC process to 30.4 cm2/V s, and it reduced the absolute value of the threshold voltage (Vth) from 4.13 to 3.62 V. The subthreshold swing also decreased from 0.72 to 0.60 V/decade. This improvement is attributed mainly to the reduction in defect density at the oxide/poly-Si interface and in the poly-Si film by the high pressure annealing (HPA) process. Since the realization of excellent performance at the oxide/poly-Si interface and in poly-Si depends on the defect density, t...