Several tetratricopeptide repeat (TPR) motifs of FANCG are required for assembly of the BRCA2/D1-D2-G-X3 complex, FANCD2 monoubiquitylation and phleomycin resistance

Energy Technology Data Exchange (ETDEWEB)

Wilson, James B. [Molecular Oncology and Stem Cell Research Group, School of Biological Sciences, University of Liverpool, Biosciences Building, Crown Street, Liverpool L69 7ZB (United Kingdom); Blom, Eric [Department of Clinical Genetics and Human Genetics, VU University Medical Center, Van der Boechorststraat 7, NL-1081 BT Amsterdam (Netherlands); Cunningham, Ryan; Xiao, Yuxuan [Molecular Oncology and Stem Cell Research Group, School of Biological Sciences, University of Liverpool, Biosciences Building, Crown Street, Liverpool L69 7ZB (United Kingdom); Kupfer, Gary M. [Departments of Pediatrics and Pathology, Yale University School of Medicine, Section of Hematology/Oncology, 333 Cedar Street, New Haven, CT 0652 (United States); Jones, Nigel J., E-mail: njjones@liv.ac.uk [Molecular Oncology and Stem Cell Research Group, School of Biological Sciences, University of Liverpool, Biosciences Building, Crown Street, Liverpool L69 7ZB (United Kingdom)

2010-07-07

The Fanconi anaemia (FA) FANCG protein is an integral component of the FA nuclear core complex that is required for monoubiquitylation of FANCD2. FANCG is also part of another protein complex termed D1-D2-G-X3 that contains FANCD2 and the homologous recombination repair proteins BRCA2 (FANCD1) and XRCC3. Formation of the D1-D2-G-X3 complex is mediated by serine-7 phosphorylation of FANCG and occurs independently of the FA core complex and FANCD2 monoubiquitylation. FANCG contains seven tetratricopeptide repeat (TPR) motifs that mediate protein-protein interactions and here we show that mutation of several of the TPR motifs at a conserved consensus residue ablates the in vivo binding activity of FANCG. Expression of mutated TPR1, TPR2, TPR5 and TPR6 in Chinese hamster fancg mutant NM3 fails to functionally complement its hypersensitivities to mitomycin C (MMC) and phleomycin and fails to restore FANCD2 monoubiquitylation. Using co-immunoprecipitation analysis, we demonstrate that these TPR-mutated FANCG proteins fail to interact with BRCA2, XRCC3, FANCA or FANCF. The interactions of other proteins in the D1-D2-G-X3 complex are also absent, including the interaction of BRCA2 with both the monoubiquitylated (FANCD2-L) and non-ubiquitylated (FANCD2-S) isoforms of FANCD2. Interestingly, a mutation of TPR7 (R563E), that complements the MMC and phleomycin hypersensitivity of human FA-G EUFA316 cells, fails to complement NM3, despite the mutated FANCG protein co-precipitating with FANCA, BRCA2 and XRCC3. Whilst interaction of TPR7-mutated FANCG with FANCF does appear to be reduced in NM3, FANCD2 is monoubiquitylated suggesting that sub-optimal interactions of FANCG in the core complex and the D1-D2-G-X3 complex are responsible for the observed MMC- and phleomycin-hypersensitivity, rather than a defect in FANCD2 monoubiquitylation. Our data demonstrate that FANCG functions as a mediator of protein-protein interactions and is vital for the assembly of multi-protein complexes

ANTI-CORRELATED TIME LAGS IN THE Z SOURCE GX 5-1: POSSIBLE EVIDENCE FOR A TRUNCATED ACCRETION DISK

Energy Technology Data Exchange (ETDEWEB)

Sriram, K.; Choi, C. S. [Korea Astronomy and Space Science Institute, Daejeon 305-348 (Korea, Republic of); Rao, A. R., E-mail: astrosriram@yahoo.co.in [Tata Institute of Fundamental Research, Mumbai 400005 (India)

2012-06-01

We investigate the nature of the inner accretion disk in the neutron star source GX 5-1 by making a detailed study of time lags between X-rays of different energies. Using the cross-correlation analysis, we found anti-correlated hard and soft time lags of the order of a few tens to a few hundred seconds and the corresponding intensity states were mostly the horizontal branch (HB) and upper normal branch. The model independent and dependent spectral analysis showed that during these time lags the structure of the accretion disk significantly varied. Both eastern and western approaches were used to unfold the X-ray continuum and systematic changes were observed in soft and hard spectral components. These changes along with a systematic shift in the frequency of quasi-periodic oscillations (QPOs) made it substantially evident that the geometry of the accretion disk is truncated. Simultaneous energy spectral and power density spectral study shows that the production of the horizontal branch oscillations (HBOs) is closely related to the Comptonizing region rather than the disk component in the accretion disk. We found that as the HBO frequency decreases from the hard apex to upper HB, the disk temperature increases along with an increase in the coronal temperature, which is in sharp contrast with the changes found in black hole binaries where the decrease in the QPO frequency is accompanied by a decrease in the disk temperature and a simultaneous increase in the coronal temperature. We discuss the results in the context of re-condensation of coronal material in the inner region of the disk.

SPITZER OBSERVATIONS OF GX17+2: CONFIRMATION OF A PERIODIC SYNCHROTRON SOURCE

International Nuclear Information System (INIS)

Harrison, Thomas E.; McNamara, Bernard J.; Bornak, Jillian; Gelino, Dawn M.; Wachter, Stefanie; Rupen, Michael P.; Gelino, Christopher R.

2011-01-01

GX17+2 is a low-mass X-ray binary (LMXB) that is also a member of a small family of LMXBs known as 'Z-sources' that are believed to have persistent X-ray luminosities that are very close to the Eddington limit. GX17+2 is highly variable at both radio and X-ray frequencies, a feature common to Z-sources. What sets GX17+2 apart is its dramatic variability in the near-infrared, where it changes by ΔK ∼ 3 mag. Previous investigations have shown that these brightenings are periodic, recurring every 3.01 days. Given its high extinction (A V ≥ 9 mag), it has not been possible to ascertain the nature of these events with ground-based observations. We report mid-infrared Spitzer observations of GX17+2 which indicate a synchrotron spectrum for the infrared brightenings. In addition, GX17+2 is highly variable in the mid-infrared during these events. The combination of the large-scale outbursts, the presence of a synchrotron spectrum, and the dramatic variability in the mid-infrared suggest that the infrared brightening events are due to the periodic transit of a synchrotron jet across our line of sight. An analysis of both new, and archival, infrared observations has led us to revise the period for these events to 3.0367 days. We also present new Rossi X-Ray Timing Explorer (RXTE) data for GX17+2 obtained during two predicted infrared brightening events. Analysis of these new data, and data from the RXTE archive, indicates that there is no correlation between the X-ray behavior of this source and the observed infrared brightenings. We examine various scenarios that might produce periodic jet emission.

Testing GxG interactions between coinfecting microbial parasite genotypes within hosts

Directory of Open Access Journals (Sweden)

Rebecca D Schulte

2014-05-01

Full Text Available Host-parasite interactions represent one of the strongest selection pressures in nature. They are often governed by genotype-specific (GxG interactions resulting in host genotypes that differ in resistance and parasite genotypes that differ in virulence depending on the antagonist’s genotype. Another type of GxG interactions, which is often neglected but which certainly influences host-parasite interactions, are those between coinfecting parasite genotypes. Mechanistically, within-host parasite interactions may range from competition for limited host resources to cooperation for more efficient host exploitation. The exact type of interaction, i.e. whether competitive or cooperative, is known to affect life-history traits such as virulence. However, the latter has been shown for chosen genotype combinations only, not considering whether the specific genotype combination per se may influence the interaction (i.e. GxG interactions. Here, we want to test for the presence of GxG interactions between coinfections of the bacterium Bacillus thuringiensis infecting the nematode Caenorhabditis elegans by combining two non-pathogenic and five pathogenic strains in all possible ways. Furthermore, we evaluate whether the type of interaction, reflected by the direction of virulence change of multiple compared to single infections, is genotype-specific. Generally, we found no indication for GxG interactions between non-pathogenic and pathogenic bacterial strains, indicating that virulence of pathogenic strains is equally affected by both non-pathogenic strains. Specific genotype combinations, however, differ in the strength of virulence change, indicating that the interaction type between coinfecting parasite strains and thus the virulence mechanism is specific for different genotype combinations. Such interactions are expected to influence host-parasite interactions and to have strong implications for coevolution.

Two-phase X-ray burst from GX 3+1 observed by INTEGRAL

DEFF Research Database (Denmark)

Chenevez, Jérôme; Falanga, M.F.; Brandt, Søren

2006-01-01

INTEGRAL detected on August 31, 2004, an unusual thermonuclear X-ray burst from the low-mass X-ray binary GX 3 3+1. Its duration was 30 min, which is between the normal burst durations for this source (less than or similar to 10 s) and the superburst observed in 1998 ( several hours). We see...... emission up to 30 keV energy during the first few seconds of the burst where the bolometric peak luminosity approaches the Eddington limit. This peculiar burst is characterized by two distinct phases: an initial short spike of similar to 6 s consistent with being similar to a normal type I X-ray burst...... in the present case); and 3) limited carbon burning at an unusually shallow depth triggered by unstable helium ignition. Though none of these provide a satisfactory description of this uncommon event, the former one seems the most probable....

Effect of acute exposure to hypergravity (GX vs. GZ) on dynamic cerebral autoregulation

Science.gov (United States)

Serrador, J. M.; Wood, S. J.; Picot, P. A.; Stein, F.; Kassam, M. S.; Bondar, R. L.; Rupert, A. H.; Schlegel, T. T.

2001-01-01

We examined the effects of 30 min of exposure to either +3GX (front-to-back) or +GZ (head-to-foot) centrifugation on cerebrovascular responses to 80 degrees head-up tilt (HUT) in 14 healthy individuals. Both before and after +3 GX or +3 GZ centrifugation, eye-level blood pressure (BP(eye)), end tidal PCO2 (PET(CO2)), mean cerebral flow velocity (CFV) in the middle cerebral artery (transcranial Doppler ultrasound), cerebral vascular resistance (CVR), and dynamic cerebral autoregulatory gain (GAIN) were measured with subjects in the supine position and during subsequent 80 degrees HUT for 30 min. Mean BP(eye) decreased with HUT in both the GX (n = 7) and GZ (n = 7) groups (P centrifugation only in the GZ group (P centrifugation. CFV decreased during HUT more significantly after centrifugation than before centrifugation in both groups (P centrifugation compared with before centrifugation, GAIN increased in both groups (P centrifugation resulted in a leftward shift of the cerebral autoregulation curve. We speculate that this leftward shift may have been due to vestibular activation (especially during +GX) or potentially to an adaptation to reduced cerebral perfusion pressure during +GZ.

5 CFR 185.122 - Discovery.

Science.gov (United States)

2010-01-01

... 5 Administrative Personnel 1 2010-01-01 2010-01-01 false Discovery. 185.122 Section 185.122 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT CIVIL SERVICE REGULATIONS PROGRAM FRAUD CIVIL REMEDIES..., answers, records, accounts, papers, and other data and documentary evidence. Nothing contained herein...

Discovery of pyrazolo[1,5-a]pyrimidine-based CHK1 inhibitors: A template-based approach-Part 2

Energy Technology Data Exchange (ETDEWEB)

Labroli, Marc; Paruch, Kamil; Dwyer, Michael P.; Alvarez, Carmen; Keertikar, Kartik; Poker, Cory; Rossman, Randall; Duca, Jose S.; Fischmann, Thierry O.; Madison, Vincent; Parry, David; Davis, Nicole; Seghezzi, Wolfgang; Wiswell, Derek; Guzi, Timothy J. [Merck

2013-11-20

Previous efforts by our group have established pyrazolo[1,5-a]pyrimidine as a viable core for the development of potent and selective CDK inhibitors. As part of an effort to utilize the pyrazolo[1,5-a]pyrimidine core as a template for the design and synthesis of potent and selective kinase inhibitors, we focused on a key regulator in the cell cycle progression, CHK1. Continued SAR development of the pyrazolo[1,5-a]pyrimidine core at the C5 and C6 positions, in conjunction with previously disclosed SAR at the C3 and C7 positions, led to the discovery of potent and selective CHK1 inhibitors.

GxGrare: gene-gene interaction analysis method for rare variants from high-throughput sequencing data.

Science.gov (United States)

Kwon, Minseok; Leem, Sangseob; Yoon, Joon; Park, Taesung

2018-03-19

With the rapid advancement of array-based genotyping techniques, genome-wide association studies (GWAS) have successfully identified common genetic variants associated with common complex diseases. However, it has been shown that only a small proportion of the genetic etiology of complex diseases could be explained by the genetic factors identified from GWAS. This missing heritability could possibly be explained by gene-gene interaction (epistasis) and rare variants. There has been an exponential growth of gene-gene interaction analysis for common variants in terms of methodological developments and practical applications. Also, the recent advancement of high-throughput sequencing technologies makes it possible to conduct rare variant analysis. However, little progress has been made in gene-gene interaction analysis for rare variants. Here, we propose GxGrare which is a new gene-gene interaction method for the rare variants in the framework of the multifactor dimensionality reduction (MDR) analysis. The proposed method consists of three steps; 1) collapsing the rare variants, 2) MDR analysis for the collapsed rare variants, and 3) detect top candidate interaction pairs. GxGrare can be used for the detection of not only gene-gene interactions, but also interactions within a single gene. The proposed method is illustrated with 1080 whole exome sequencing data of the Korean population in order to identify causal gene-gene interaction for rare variants for type 2 diabetes. The proposed GxGrare performs well for gene-gene interaction detection with collapsing of rare variants. GxGrare is available at http://bibs.snu.ac.kr/software/gxgrare which contains simulation data and documentation. Supported operating systems include Linux and OS X.

Changes of structure and properties of cast steels GX10NiCrNb32-20 and GX10NiCrNb3-25 after long-term tempering at 600-1000 C

International Nuclear Information System (INIS)

Gommans, R.; Schrijen, H.; Sundermann, J.; Steinkusch, W.; Hering, W.

2001-01-01

Low-alloy cast steels of type GX 10NiCrNb 32.20 are commonly used for the outlet section of reformer and cracker tubes for the temperature range of 600-1000 C. There was a lack of data on the ductility of the 25%Cr alloyed cast steel GX10NiCrNb 35.25 at room temperature after tempering, which was investigated in a joint project of Pose-Marre and DSM. Mechanical tests were carried out at room temperature and at elevated temperatures. Apart from light microscopy, also SEM/EDX, SAM and TEM analyses were carried out. The 25% alloy has lower ductility than the 20% alloy, owing primarily to the more pronounced development of M 6 C carbide from primary NbC carbide, which takes up Ni and Si during tempering. The microstructure and composition of the M 6 C carbide wre not fully clarified. Information is presented on the potential application of low-carbon materials of the type GX10NiCrNb35.25 [de

A connection between the X-ray spectral branches and the radio brightness in GX17+2

International Nuclear Information System (INIS)

Penninx, Wim; Lewin, W.H.G.; Paradijs, J. van; Klis, M. van der

1988-01-01

GX17 + 2(4U 1813 - 14) is a bright X-ray binary in which matter is accreting on to a neutron star from a nearby companion. X-ray bursts are sometimes observed, as well as quasiperiodic oscillations in the X-ray flux. The frequencies of the quasiperiodic oscillations depend on the spectral state of the source, which manifests itself as three distinct spectral 'branches' in an X-ray colour-colour diagram. GX17 + 2 is also a variable radio source; there is no believable optical counterpart. We report here on simultaneous X-ray and radio observations which showed a connection between the spectral branches and the radio brightness. The 6-cm and 20-cm flux density increased by factors of 30±5 and 40± 10, respectively, as the X-ray state changed from the so-called 'flaring branch' to the 'horizontal branch'. (author)

A curious case of the accretion-powered X-ray pulsar GX 1+4

DEFF Research Database (Denmark)

Jaisawal, Gaurava K.; Naik, Sachindra; Gupta, Shivangi

2018-01-01

We present detailed spectral and timing studies using a NuSTAR observation of GX 1+4 in 2015 October during an intermediate-intensity state. The measured spin period of 176.778 s is found to be one of the highest values since its discovery. In contrast to a broad sinusoidal-like pulse profile......, a peculiar sharp peak is observed in profiles below ∼25 keV. The profiles at higher energies are found to be significantly phase shifted compared to the soft X-ray profiles. Broad-band energy spectra of GX 1+4, obtained from NuSTAR and Swift observations, are described with various continuum models. Among...

7 CFR 1.322 - Discovery.

Science.gov (United States)

2010-01-01

... 7 Agriculture 1 2010-01-01 2010-01-01 false Discovery. 1.322 Section 1.322 Agriculture Office of... Under the Program Fraud Civil Remedies Act of 1986 § 1.322 Discovery. (a) The following types of discovery are authorized: (1) Requests for production, inspection and photocopying of documents; (2...

47 CFR 1.729 - Discovery.

Science.gov (United States)

2010-10-01

... 47 Telecommunication 1 2010-10-01 2010-10-01 false Discovery. 1.729 Section 1.729..., and Reports Involving Common Carriers Formal Complaints § 1.729 Discovery. (a) Subject to paragraph (i... seek discovery of any non-privileged matter that is relevant to the material facts in dispute in the...

Spectro-Timing Study of GX 339-4 in a Hard Intermediate State

DEFF Research Database (Denmark)

Fürst, F.; Grinberg, V.; Tomsick, J. A.

2016-01-01

We present an analysis of Nuclear Spectroscopic Telescope Array observations of a hard intermediate state of the transient black hole GX 339-4 taken in 2015 January. With the source softening significantly over the course of the 1.3 day long observation we split the data into 21 sub-sets and find...... that the spectrum of all of them can be well described by a power-law continuum with an additional relativistically blurred reflection component. The photon index increases from ∼1.69 to ∼1.77 over the course of the observation. The accretion disk is truncated at around nine gravitational radii in all spectra. We...

Broadband Correlations Provide Evidence for Synchrotron Self-Compton X-rays from the Black Hole Binary GX 339-4

International Nuclear Information System (INIS)

Coriat, M.; Corbel, S.; Buxton, M. M.; Baylin, C. D.

2009-01-01

GX 339-4 has been one of the key sources for unravelling the accretion ejection coupling in accreting stellar mass black holes. After a long period of quiescence between 1999 and 2002, GX 339-4 underwent a series of 4 outbursts that have been intensively observed by many ground based observatories (radio/infrared/optical) and satellites (X-rays). Here, we present some specific results of these broad band observational campaigns, focusing on the optical-infrared/X-ray flux correlations over the four outbursts. Thanks to our extensive data-set, we found a strong OIR/X-ray correlation over four decades with the presence of a break in the correlation index. These results seem to favour a synchrotron self-Compton origin for the X-ray emission in GX 339-4 during the hard state and could also provide an indirect detection of the break frequency in the synchrotron spectrum of the compact jets.

Optical photometry and polarimetry of GX 339-4 during its outburst rise

NARCIS (Netherlands)

Russell, D.M.; Lewis, F.; Casella, P.; Pretorius, M.L.; Fender, R.P.; Roche, P.; Clark, S.

2009-01-01

GX 339-4 is currently brightening at X-ray, UV, optical and radio frequencies (ATel #1945, #1954, #1960). Our monitoring campaign with the Faulkes Telescope South (ATel #1586) gives the following recent magnitudes (light curves are below; errors are ~ 0.02 mag): 2009-02-20 (MJD 54882.65): i' ~ 16.66

THE HOST GALAXY OF THE SUPER-LUMINOUS SN 2010gx AND LIMITS ON EXPLOSIVE 56Ni PRODUCTION

International Nuclear Information System (INIS)

Chen, Ting-Wan; Smartt, Stephen J.; Kotak, Rubina; McCrum, Matt; Fraser, Morgan; Bresolin, Fabio; Kudritzki, Rolf-Peter; Pastorello, Andrea; Valenti, Stefano

2013-01-01

Super-luminous supernovae have a tendency to occur in faint host galaxies which are likely to have low mass and low metallicity. While these extremely luminous explosions have been observed from z = 0.1 to 1.55, the closest explosions allow more detailed investigations of their host galaxies. We present a detailed analysis of the host galaxy of SN 2010gx (z = 0.23), one of the best studied super-luminous type Ic supernovae. The host is a dwarf galaxy (M g = –17.42 ± 0.17) with a high specific star formation rate. It has a remarkably low metallicity of 12 + log (O/H) = 7.5 ± 0.1 dex as determined from the detection of the [O III] λ4363 line. This is the first reliable metallicity determination of a super-luminous stripped-envelope supernova host. We collected deep multi-epoch imaging with Gemini + GMOS between 240 and 560 days after explosion to search for any sign of radioactive 56 Ni, which might provide further insights on the explosion mechanism and the progenitor's nature. We reach griz magnitudes of m AB ∼ 26, but do not detect SN 2010gx at these epochs. The limit implies that any 56 Ni production was similar to or below that of SN 1998bw (a luminous type Ic SN that produced around 0.4 M ☉ of 56 Ni). The low volumetric rates of these supernovae (∼10 –4 of the core-collapse population) could be qualitatively matched if the explosion mechanism requires a combination of low-metallicity (below 0.2 Z ☉ ), high progenitor mass (>60 M ☉ ) and high rotation rate (fastest 10% of rotators).

NuSTAR AND Swift Observations of the Very High State in GX 339-4: Weighing the Black Hole With X-Rays

Science.gov (United States)

Parker, M. L.; Tomsick, J. A.; Kennea, J. A.; Miller, J. M.; Harrison, F. A.; Barret, D.; Boggs, S. E.; Christensen, F. E.; Craig, W. W.; Fabian, A. C.;

The Complex Accretion Geometry of Gx 339–4 as Seen by Nustar and Swift

DEFF Research Database (Denmark)

Fuerst, F.; Nowak, M. A.; Tomsick, J. A.

2015-01-01

We present spectral analyses of five Nuclear Spectroscopic Telescope Array and Swift observations of GX 339-4 taken during a failed outburst during the summer of 2013. These observations cover Eddington luminosity fractions in the range approximate to 0.9%-6%. Throughout this outburst GX 339-4 st....... The iron line around 6.4 keV is clearly broadened, and we detect a superimposed narrow core as well. This core originates from a fluorescent region outside the influence of the strong gravity of the black hole. Additionally, we discuss possible geometries....

The variable cyclotron line of GX 301-2

Energy Technology Data Exchange (ETDEWEB)

Kreykenbohm, I.; Wilms, J.; Coburn, W.; Kuster, M.; Rothschild, R.E.; Heindl, W.A.; Kretschmar, P.; Staubert, R

2004-06-01

We present a 200 ksec observation of the High Mass X-ray Binary GX 301-2 taken in 2000 November with the Rossi X-ray Timing Explorer during the pre-periastron flare and the actual periastron passage of the neutron star. To model the spectrum we use a power law with the Fermi Dirac cutoff and a cyclotron line at higher energies plus either a reflection component or a heavily absorbed partial covering component. Although completely different, both models describe the data equally well. Phase resolved spectra show that the energy and the depth of the cyclotron resonant scattering feature vary strongly with pulse phase: It is deepest in the fall of the main pulse, the rise of the secondary pulse, and the pulse minimum in-between with {tau}{sub C}{approx}0.3. In the other phase bins the line is much less deep with {tau}{sub C}{approx}0.1. The energy of the line correlates strongly with its depth and varies by 25 % from 30.1 keV in the fall of the secondary pulse to 37.9 keV in the fall of the main pulse.

Qualitative and quantitative radiation protection analysis of mucosa of ICR strained mice using selected herbal extracts such as GC-2112 from garlic (Allium sativum) and GX-2137 from ginseng (Panax sp.)

International Nuclear Information System (INIS)

Bunagan, J.B.

2005-01-01

Full text: Earlier reports showed that ginseng has significant radioprotective and stimulatory effect on the recovery of the lymphocytes and leukocytes. Using graded absorbed doses of radiation (1.5, 5, 20, 50 Gy) applied in ICR strain male white mice which was injected with GX-2137 from ginseng (Panax sp.) and GC-2112 from garlic (Allium sativum) was tested to prove some radioprotective efficiency. The herbal extracts were injected intraperitoneally and the experimental mice were sacrificed 2 and 48 hrs post-irradiation. Factors such as analyzing kinetics of critical tissue parameters (length of villi, the number of crypt and villi cells and cell density) and determining the Relative Protection Efficiencies (RPE) using quantitative histopathological techniques were used to quantify the radiation protection assay in the duodenum of ICR strain mice. Results showed that GC-2112 and GX-2137 protected the villi structures. After 2 hrs. post irradiation, tissue degeneration was evident. RPE values of significant radioprotection of the crypts is demonstrated at absorbed dose. It was found that some villi cells are even viable at non-physiologic dose of 50 Gy. (author)

Mesoionic Pyrido[1,2-a]pyrimidinone Insecticides: From Discovery to Triflumezopyrim and Dicloromezotiaz.

Science.gov (United States)

Zhang, Wenming

2017-09-19

One of the greatest global challenges is to feed the ever-increasing world population. The agrochemical tools growers currently utilize are also under continuous pressure, due to a number of factors that contribute to the loss of existing products. Mesoionic pyrido[1,2-a]pyrimidinones are an unusual yet very intriguing class of compounds. Known for several decades, this class of compounds had not been systemically studied until we started our insecticide discovery program. This Account provides an overview of the efforts on mesoionic pyrido[1,2-a]pyridinone insecticide discovery, beginning from the initial high throughput screen (HTS) discovery to ultimate identification of triflumezopyrim (4, DuPont Pyraxalt) and dicloromezotiaz (5) for commercialization as novel insecticides. Mesoionic pyrido[1,2-a]pyrimidinones with a n-propyl group at the 1-position, such as compound 1, were initially isolated as undesired byproducts from reactions for a fungicide discovery program at DuPont Crop Protection. Such compounds showed interesting insecticidal activity in a follow-up screen and against an expanded insect species list. The area became an insecticide hit for exploration and then a lead area for optimization. At the lead optimization stage, variations at three regions of compound 1, i.e., side-chain (n-propyl group), substituents on the 3-phenyl group, and substitutions on the pyrido- moiety, were explored with many analogues prepared and evaluated. Breakthrough discoveries included replacing the n-propyl group with a 2,2,2-trifluoroethyl group to generate compound 2, and then with a 2-chlorothiazol-5-ylmethyl group to form compound 3. 3 possesses potent insecticidal activity not only against a group of hopper species, including corn planthopper (Peregrinus maidis (Ashmead), CPH) and potato leafhopper (Empoasca fabae (Harris), PLH), as well as two key rice hopper species, namely, brown planthopper (Nilaparvata lugens (Stål), BPH) and rice green leafhopper (Nephotettix

Multiwavelength Observations of the 2002 Outburst of GX 339-4: Two Patterns of X-Ray-Optical/Near-Infrared Behavior

Science.gov (United States)

Homan, Jeroen; Buxton, Michelle; Markoff, Sera; Bailyn, Charles D.; Nespoli, Elisa; Belloni, Tomaso

2005-05-01

We report on quasi-simultaneous Rossi X-Ray Timing Explorer and optical/near-infrared (NIR) observations of the black hole candidate X-ray transient GX 339-4. Our observations were made over a time span of more than 8 months in 2002 and cover the initial rise and transition from a hard to a soft spectral state in X-rays. Two distinct patterns of correlated X-ray-optical/NIR behavior were found. During the hard state, the optical/NIR and X-ray fluxes correlated well, with a NIR versus X-ray flux power-law slope similar to that of the correlation found between X-ray and radio fluxes in previous studies of GX 339-4 and other black hole binaries. As the source went through an intermediate state, the optical/NIR fluxes decreased rapidly, and once it had entered the spectrally soft state, the optical/NIR spectrum of GX 339-4 was much bluer, and the ratio of X-ray to NIR flux was higher by a factor of more than 10 compared to the hard state. In the spectrally soft state, changes in the NIR preceded those in the soft X-rays by more than 2 weeks, indicating a disk origin of the NIR emission and providing a measure of the viscous timescale. A sudden onset of NIR flaring of ~0.5 mag on a timescale of 1 day was also observed during this period. We present spectral energy distributions, including radio data, and discuss possible sources for the optical/NIR emission. We conclude that, in the hard state, this emission probably originates in the optically thin part of a jet and that in none of the X-ray states is X-ray reprocessing the dominant source of optical/NIR emission. Finally, comparing the light curves from the all-sky monitor (ASM) and Proportional Counter Array (PCA) instruments, we find that the X-ray/NIR delay depends critically on the sensitivity of the X-ray detector, with the delay inferred from the PCA (if present at all) being a factor of 3-6 times shorter than the delay inferred from the ASM; this may be important in interpreting previously reported X

Influence of heat treatment on microstructure and properties of GX12CrMoVNbN9-1 cast steel

Directory of Open Access Journals (Sweden)

G. Golański

2010-07-01

Full Text Available The paper presents results of research on the influence of multistage heat treatment on microstructure and properties of high-chromiummartensitic GX12CrMoVNbN9 – 1 (GP91 steel. The material under investigation were samples taken out from a test coupon. Heattreatment of GP91 cast steel was performed at the parameters of temperature and time typical of treatment for multi-ton steel casts. The research has proved that in the as-received condition (as-cast state GP91 cast steel was characterized by a coarse grain, martensitic microstructure which provided the required standard mechanical properties. The heat treatment of GP91 cast steel contributed to obtainment of a fine grain microstructure of high tempered martensite with numerous precipitations of carbides of diverse size. The GP91 cast steel structure received through heat treatment made it possible to obtain high plastic properties, particularly impact strength, maintaining strength properties on the level of the required minimum.

PROPERTIES OF THE 24 DAY MODULATION IN GX 13+1 FROM NEAR-INFRARED AND X-RAY OBSERVATIONS

International Nuclear Information System (INIS)

Corbet, Robin H. D.; Pearlman, Aaron B.; Buxton, Michelle; Levine, Alan M.

2010-01-01

A 24 day period for the low-mass X-ray binary (LMXB) GX 13+1 was previously proposed on the basis of seven years of RXTE All-Sky Monitor (ASM) observations and it was suggested that this was the orbital period of the system. This would make it one of the longest known orbital periods for a Galactic LMXB powered by Roche lobe overflow. We present here the results of (1) K-band photometry obtained with the SMARTS Consortium CTIO 1.3 m telescope on 68 nights over a 10 month interval; (2) continued monitoring with the RXTE ASM, analyzed using a semi-weighted power spectrum instead of the data filtering technique previously used; and (3) Swift Burst Alert Telescope (BAT) hard X-ray observations. Modulation near 24 days is seen in both the K band and additional statistically independent ASM X-ray observations. However, the modulation in the ASM is not strictly periodic. The periodicity is also not detected in the Swift BAT observations, but modulation at the same relative level as seen with the ASM cannot be ruled out. If the 24 day period is the orbital period of system, this implies that the X-ray modulation is caused by structure that is not fixed in location. A possible mechanism for the X-ray modulation is the dipping behavior recently reported from XMM-Newton observations.

Is there a highly magnetized neutron star in GX 301-2?

Science.gov (United States)

Doroshenko, V.; Santangelo, A.; Suleimanov, V.; Kreykenbohm, I.; Staubert, R.; Ferrigno, C.; Klochkov, D.

2010-06-01

We present the results of an in-depth study of the long-period X-ray pulsar GX 301-2. Using archival data of INTEGRAL, RXTE ASM, and CGRO BATSE, we study the spectral and timing properties of the source. Comparison of our timing results with previously published work reveals a secular decay of the orbital period at a rate of ≃ - 3.25 × 10-5 d yr-1, which is an order of magnitude faster than for other known systems. We argue that this is probably result either of the apsidal motion or of gravitational coupling of the matter lost by the optical companion with the neutron star, although current observations do not allow us to distinguish between those possibilities. We also propose a model to explain the observed long pulse period. We find that a very strong magnetic field B ~ 1014 G can explain the observed pulse period in the framework of existing models for torques affecting the neutron star. We show that the apparent contradiction with the magnetic field strength BCRSF ~ 4 × 1012 G derived from the observed cyclotron line position may be resolved if the line formation region resides in a tall accretion column of height ~2.5-3 RNS. The color temperature measured from the spectrum suggests that such a column may indeed be present, and our estimates show that its height is sufficient to explain the observed cyclotron line position.

16 CFR 5.61 - Prehearing procedures; motions; interlocutory appeals; summary decision; discovery; compulsory...

Science.gov (United States)

2010-01-01

... 16 Commercial Practices 1 2010-01-01 2010-01-01 false Prehearing procedures; motions; interlocutory appeals; summary decision; discovery; compulsory process. 5.61 Section 5.61 Commercial Practices FEDERAL TRADE COMMISSION ORGANIZATION, PROCEDURES AND RULES OF PRACTICE STANDARDS OF CONDUCT Disciplinary...

NuSTARand Swift observations of the very high state in GX 339-4: Weighing the black hole with X-rays

DEFF Research Database (Denmark)

Parker, M. L.; Tomsick, J. A.; Kennea, J. A.

2016-01-01

We present results from spectral fitting of the very high state of GX 339-4 with Nuclear Spectroscopic Telescope Array (NuSTAR) and Swift. We use relativistic reflection modeling to measure the spin of the black hole and inclination of the inner disk and find a spin of a = 0.95(-0.08)(+0.02) and ......We present results from spectral fitting of the very high state of GX 339-4 with Nuclear Spectroscopic Telescope Array (NuSTAR) and Swift. We use relativistic reflection modeling to measure the spin of the black hole and inclination of the inner disk and find a spin of a = 0...

A NICER View of the Accretion Disk in GX 339-4

Science.gov (United States)

Steiner, James Francis; Bulbul, Esra; Cackett, Ed; Fabian, Andy; Gendreau, Keith C.; Neilsen, Joseph; Ranga Reddy Pasham, Dheeraj; Remillard, Ron; Uttley, Phil; Wood, Kent S.

2018-01-01

The poster-child black hole transient GX 339-4 has gone into outburst once again. With no pileup, low-background, and high fidelity in the soft X-ray bandpass, NICER is uniquely positioned to detect emergent thermal disk emission from an optically thick accretion flow approaching the innermost-stable circular orbit. We present NICER's results on the 2017 outburst, and detail its implications for the disk-truncation controversy. We also investigate the X-ray state evolution, as seen in NICER's spectral range of 0.2 to 12 keV.

Crystal structure and magnetic state of pseudo-binary intermetallic compounds Ho(Cosub(1-x)Nisub(x))sub(5)

International Nuclear Information System (INIS)

Chuev, V.V.; Kelarev, V.V.; Pirogov, A.N.; Sidorov, S.K.; Koryakova, V.S.

1983-01-01

In the range of 1.8-1000 K intermetallic compounds Ho(Cosub(1-x)Nisub(x))sub(5) have been investigated neutronographically and roentgenographically. Crystal structure of two series of samples: HoCosub(5.5-5.5x)Nisub(5x) and HoCosub(5-5x)Nisub(5x) is studied. It is shown that Ni atoms mainly occupy positions 2c, Co atoms - positions 3g; coordinates of atoms and position occupation of TbCu 7 type structure are specified. Analysis of magnetic structure is made, angles of magnetic momenta orientation as to crystallographic axes are determined. Magnetic phase diagram is built. Concentrational dependences of sublattice magnetization: Msub(Ho)(x), Mdsub(2c)(x), Mdsub(3g)(x) are determined

Revisiting galactic black hole binary GX 339-4 by using 2007 – 2014 Swift XRT observations

International Nuclear Information System (INIS)

Azizi, Febrie Ahmad; Vierdayanti, Kiki; Putra, Mahasena

2015-01-01

This work aims to study the X-ray properties of the galactic black hole binary GX 339-4. Focus of the study is on exploration of data from Swift-XRT in exclusively photon-counting mode. We use data from 2007 up to August 2014, which contain about 40 pointing observations with level 1 data. The flux of GX 339-4 varies in a factor of 100 during this period of observations. For the purpose of this work, we also try to develop a system to conduct standard SWIFT XRT data reduction automatically, in order to greatly reduce time when working with data bulk, which produces images, lightcurves as well as spectra. We also develop another system to conduct fitting of bulk spectral data with a two-component model, disk blackbody and power-law. The fitting results show that no data have a reduced chi-squared > 2. The fraction of the disk to total flux and the power-law to total flux range from 0.00389 – 0.994 and 0.00605 – 0.996, respectively. From the analysis of the disk component, we obtain the value of the innermost disk radius that does not show any large scale truncation which is in a good agreement with a previous study that used 2007 – 2011 Swift-XRT data, indicating that the systems we developed work properly

STECH VOL5 (1) FEBRUARY, 2016

African Journals Online (AJOL)

Copyright 1AARR 2012-2016: www.afrrevjo.net

STECH VOL 5 (1) FEBRUARY, 2016. Vol. 5 (1), S/No11, February, 2016: 1-13 ..... Knowledge produce is an act of discovery which involves exploring, analyzing .... Architectural Research, Elsevier: Higher Education Press Limited Company.

Discovery of 1-5 Hz flaring at high luminosity in SAX J1808.4-3658

Energy Technology Data Exchange (ETDEWEB)

Bult, Peter; Van der Klis, Michiel, E-mail: p.m.bult@uva.nl [Anton Pannekoek Institute, University of Amsterdam, Postbus 94249, 1090 GE Amsterdam (Netherlands)

2014-07-10

We report the discovery of a 1-5 Hz X-ray flaring phenomenon observed at >30 mCrab near peak luminosity in the 2008 and 2011 outbursts of the accreting millisecond X-ray pulsar SAX J1808.4-3658 in observations with the Rossi X-ray Timing Explorer. In each of the two outbursts this high luminosity flaring is seen for ∼3 continuous days and switches on and off on a timescale of 1-2 hr. The flaring can be seen directly in the light curve, where it shows sharp spikes of emission at quasi-regular separation. In the power spectrum it produces a broad noise component, which peaks at 1-5 Hz. The total 0.05-10 Hz variability has a fractional rms amplitude of 20%-45%, well in excess of the 8%-12% rms broadband noise usually seen in power spectra of SAX J1808.4-3658. We perform a detailed timing analysis of the flaring and study its relation to the 401 Hz pulsations. We find that the pulse amplitude varies proportionally with source flux through all phases of the flaring, indicating that the flaring is likely due to mass density variations created at or outside the magnetospheric boundary. We suggest that this 1-5 Hz flaring is a high mass accretion rate version of the 0.5-2 Hz flaring which is known to occur at low luminosity (<13 mCrab), late in the tail of outbursts of SAX J1808.4-3658. We propose the dead-disk instability, previously suggested as the mechanism for the 0.5-2 Hz flaring, as a likely mechanism for the high luminosity flaring reported here.

The Evolution of the Phase Lags Associated with the Type-C Quasi-periodic Oscillation in GX 339-4 during the 2006/2007 Outburst

NARCIS (Netherlands)

Zhang, Liang; Wang, Yanan; Méndez, Mariano; Chen, Li; Qu, Jinlu; Altamirano, Diego; Belloni, Tomaso

2017-01-01

We present the evolution of the phase lags associated with the type-C QPO in GX 339-4 during the rising phase of the 2006/2007 outburst. We find that the phase lags at the QPO frequency are always positive (hard) and show very different behavior between QPOs with frequencies below and above ˜1.7 Hz:

Developing a distributed HTML5-based search engine for geospatial resource discovery

Science.gov (United States)

ZHOU, N.; XIA, J.; Nebert, D.; Yang, C.; Gui, Z.; Liu, K.

2013-12-01

With explosive growth of data, Geospatial Cyberinfrastructure(GCI) components are developed to manage geospatial resources, such as data discovery and data publishing. However, the efficiency of geospatial resources discovery is still challenging in that: (1) existing GCIs are usually developed for users of specific domains. Users may have to visit a number of GCIs to find appropriate resources; (2) The complexity of decentralized network environment usually results in slow response and pool user experience; (3) Users who use different browsers and devices may have very different user experiences because of the diversity of front-end platforms (e.g. Silverlight, Flash or HTML). To address these issues, we developed a distributed and HTML5-based search engine. Specifically, (1)the search engine adopts a brokering approach to retrieve geospatial metadata from various and distributed GCIs; (2) the asynchronous record retrieval mode enhances the search performance and user interactivity; (3) the search engine based on HTML5 is able to provide unified access capabilities for users with different devices (e.g. tablet and smartphone).

Discovery of potent 1H-imidazo[4,5-b]pyridine-based c-Met kinase inhibitors via mechanism-directed structural optimization.

Science.gov (United States)

An, Xiao-De; Liu, Hongyan; Xu, Zhong-Liang; Jin, Yi; Peng, Xia; Yao, Ying-Ming; Geng, Meiyu; Long, Ya-Qiu

2015-02-01

Starting from our previously identified novel c-Met kinase inhibitors bearing 1H-imidazo[4,5-h][1,6]naphthyridin-2(3H)-one scaffold, a global structural exploration was conducted to furnish an optimal binding motif for further development, directed by the enzyme inhibitory mechanism. First round SAR study picked two imidazonaphthyridinone frameworks with 1,8- and 3,5-disubstitution pattern as class I and class II c-Met kinase inhibitors, respectively. Further structural optimization on type II inhibitors by truncation of the imidazonaphthyridinone core and incorporation of an N-phenyl cyclopropane-1,1-dicarboxamide pharmacophore led to the discovery of novel imidazopyridine-based c-Met kinase inhibitors, displaying nanomolar enzyme inhibitory activity and improved Met kinase selectivity. More significantly, the new chemotype c-Met kinase inhibitors effectively inhibited Met phosphorylation and its downstream signaling as well as the proliferation of Met-dependent EBC-1 human lung cancer cells at submicromolar concentrations. Copyright © 2014 Elsevier Ltd. All rights reserved.

Mechanics and composition of middle cerebral arteries from simulated microgravity rats with and without 1-h/d -Gx gravitation.

Directory of Open Access Journals (Sweden)

Jiu-Hua Cheng

Full Text Available BACKGROUND: To elucidate further from the biomechanical aspect whether microgravity-induced cerebral vascular mal-adaptation might be a contributing factor to postflight orthostatic intolerance and the underlying mechanism accounting for the potential effectiveness of intermittent artificial gravity (IAG in preventing this adverse effect. METHODOLOGY/PRINCIPAL FINDINGS: Middle cerebral arteries (MCAs were isolated from 28-day SUS (tail-suspended, head-down tilt rats to simulate microgravity effect, S+D (SUS plus 1-h/d -Gx gravitation by normal standing to simulate IAG, and CON (control rats. Vascular myogenic reactivity and circumferential stress-strain and axial force-pressure relationships and overall stiffness were examined using pressure arteriography and calculated. Acellular matrix components were quantified by electron microscopy. The results demonstrate that myogenic reactivity is susceptible to previous pressure-induced, serial constrictions. During the first-run of pressure increments, active MCAs from SUS rats can strongly stiffen their wall and maintain the vessels at very low strains, which can be prevented by the simulated IAG countermeasure. The strains are 0.03 and 0.14 respectively for SUS and S+D, while circumferential stress being kept at 0.5 (106 dyn/cm2. During the second-run pressure steps, both the myogenic reactivity and active stiffness of the three groups declined. The distensibility of passive MCAs from S+D is significantly higher than CON and SUS, which may help to attenuate the vasodilatation impairment at low levels of pressure. Collagen and elastin percentages were increased and decreased, respectively, in MCAs from SUS and S+D as compared with CON; however, elastin was higher in S+D than SUS rats. CONCLUSIONS: Susceptibility to previous myogenic constrictions seems to be a self-limiting protective mechanism in cerebral small resistance arteries to prevent undue cerebral vasoconstriction during orthostasis at 1-G

14 CFR 1264.120 - Discovery.

Science.gov (United States)

2010-01-01

... 14 Aeronautics and Space 5 2010-01-01 2010-01-01 false Discovery. 1264.120 Section 1264.120... PENALTIES ACT OF 1986 § 1264.120 Discovery. (a) The following types of discovery are authorized: (1..., discovery is available only as ordered by the presiding officer. The presiding officer shall regulate the...

Fatigue Resistance of GX12CrMoVNbN9-1 Cast Steel after Ageing Process

Directory of Open Access Journals (Sweden)

Stanisław MROZIŃSKI

2014-12-01

Full Text Available In the present paper, low cycle fatigue behaviour of GX12CrMoVNbN9-1 (GP91 cast steel is presented. Fatigue tests were performed under isothermal conditions at room temperature and at 550 and 600oC, on five levels of total strain amplitude value ɛac = 0.25÷0.60%. The cast steel subject to investigation was in the as-received condition (after heat treatment and after 8000 hours of ageing at the temperature of 600oC. Performed research has shown an insignificant influence of the ageing process on mechanical properties of GP91 cast steel, determined with the static test of tension. Analysis of the performed tests has proved that GP91 cast steel in the as-received condition and after ageing process was characterized by strong cyclic softening without a clear period of stabilization of the hysteresis loop parameters. The fatigue lifetime curves at each temperature were obtained based on Basquin and Coffin – Manson equations. The process of ageing of GP91 cast steel contributed to a decrease in its fatigue life Nf from a few to a few dozen percent, and the level of fatigue life was dependent on the value of strain amplitude ɛac. It has also been stated that the fatigue life Nf of GP91 cast steel is determined by its plastic properties, and the degree of changes in fatigue life Nf was dependent not only on the temperature of testing, but also on the value of strain amplitude ɛac. DOI: http://dx.doi.org/10.5755/j01.ms.20.4.6077

Interaction between FKBP5 variability and recent life events in the anxiety spectrum: Evidence for the differential susceptibility model.

Directory of Open Access Journals (Sweden)

Beatriz Pérez-Pérez

Full Text Available Gene-environment interaction (GxE research has highlighted the importance of investigating the FK506 binding protein 51 (FKBP5 gene as a sensitivity gene. However, previous GxE studies with FKBP5 have not measured the full environmental spectrum or applied statistical tests to discern whether the GxE interaction fits better with the differential-susceptibility or diathesis-stress hypotheses. This study examined whether single nucleotide polymorphisms (SNPs on FKBP5 gene moderate the association of positive and negative recent life events (LEs with depressive symptoms, state-anxiety, neuroticism, and social anxiety traits.A total of 86 nonclinical young adults were administered psychological measures and were genotyped for five FKBP5 SNPs (rs3800373, rs9296158, rs1360780, rs9470080 and rs4713916.Regression analyses indicated significant GxE interactions for social anxiety and neuroticism. The interactions predicting neuroticism fit different models for different SNPs, although the overall effect indicated by the haplotype was consistent with the differential-susceptibility hypothesis: the risk-haplotype group presented higher neuroticism in the presence of more negative LEs and lower neuroticism in the presence of more positive LEs. The GxE interactions for social anxiety were consistent with the diathesis-stress model. The lack of significance in the for-better side for social anxiety might be related to the fact that it mapped onto low extraversion, which is associated with a lower permeability to positive experiences.Findings underscore the importance of testing the differential-susceptibility model in relation to FKBP5 to adequately characterize its role in healthy and pathological developmental processes.

Anti-correlated Soft Lags in the Intermediate State of Black Hole Source GX 339-4

OpenAIRE

Sriram, K.; Rao, A. R.; Choi, C. S.

2010-01-01

We report the few hundred second anti-correlated soft lags between soft and hard energy bands in the source GX 339-4 using RXTE observations. In one observation, anti-correlated soft lags were observed using the ISGRI/INTEGRAL hard energy band and the PCA/RXTE soft energy band light curves. The lags were observed when the source was in hard and soft intermediate states, i.e., in a steep power-law state.We found that the temporal and spectral properties were changed during the lag timescale. T...

Protective efficacy of an inactivated Eurasian avian-like H1N1 swine influenza vaccine against homologous H1N1 and heterologous H1N1 and H1N2 viruses in mice.

Science.gov (United States)

Sui, Jinyu; Yang, Dawei; Qiao, Chuanling; Xu, Huiyang; Xu, Bangfeng; Wu, Yunpu; Yang, Huanliang; Chen, Yan; Chen, Hualan

2016-07-19

Eurasian avian-like H1N1 (EA H1N1) swine influenza viruses are prevalent in pigs in Europe and Asia, but occasionally cause human infection, which raises concern about their pandemic potential. Here, we produced a whole-virus inactivated vaccine with an EA H1N1 strain (A/swine/Guangxi/18/2011, SW/GX/18/11) and evaluated its efficacy against homologous H1N1 and heterologous H1N1 and H1N2 influenza viruses in mice. A strong humoral immune response, which we measured by hemagglutination inhibition (HI) and virus neutralization (VN), was induced in the vaccine-inoculated mice upon challenge. The inactivated SW/GX/18/11 vaccine provided complete protection against challenge with homologous SW/GX/18/11 virus in mice and provided effective protection against challenge with heterologous H1N1 and H1N2 viruses with distinctive genomic combinations. Our findings suggest that this EA H1N1 vaccine can provide protection against both homologous H1N1 and heterologous H1N1 or H1N2 virus infection. As such, it is an excellent vaccine candidate to prevent H1N1 swine influenza. Copyright © 2016 Elsevier Ltd. All rights reserved.

Computer-aided drug discovery [v1; ref status: indexed, http://f1000r.es/5ij

Directory of Open Access Journals (Sweden)

Jürgen Bajorath

2015-08-01

Full Text Available Computational approaches are an integral part of interdisciplinary drug discovery research. Understanding the science behind computational tools, their opportunities, and limitations is essential to make a true impact on drug discovery at different levels. If applied in a scientifically meaningful way, computational methods improve the ability to identify and evaluate potential drug molecules, but there remain weaknesses in the methods that preclude naïve applications. Herein, current trends in computer-aided drug discovery are reviewed, and selected computational areas are discussed. Approaches are highlighted that aid in the identification and optimization of new drug candidates. Emphasis is put on the presentation and discussion of computational concepts and methods, rather than case studies or application examples. As such, this contribution aims to provide an overview of the current methodological spectrum of computational drug discovery for a broad audience.

Interaction between FKBP5 variability and recent life events in the anxiety spectrum: Evidence for the differential susceptibility model

Science.gov (United States)

Sheinbaum, Tamara; Kwapil, Thomas R.; Ballespí, Sergi; Peña, Elionora; de Castro-Catala, Marta; Riba, Maria Dolors; Rosa, Araceli

2018-01-01

Background Gene-environment interaction (GxE) research has highlighted the importance of investigating the FK506 binding protein 51 (FKBP5) gene as a sensitivity gene. However, previous GxE studies with FKBP5 have not measured the full environmental spectrum or applied statistical tests to discern whether the GxE interaction fits better with the differential-susceptibility or diathesis-stress hypotheses. This study examined whether single nucleotide polymorphisms (SNPs) on FKBP5 gene moderate the association of positive and negative recent life events (LEs) with depressive symptoms, state-anxiety, neuroticism, and social anxiety traits. Methods A total of 86 nonclinical young adults were administered psychological measures and were genotyped for five FKBP5 SNPs (rs3800373, rs9296158, rs1360780, rs9470080 and rs4713916). Results Regression analyses indicated significant GxE interactions for social anxiety and neuroticism. The interactions predicting neuroticism fit different models for different SNPs, although the overall effect indicated by the haplotype was consistent with the differential-susceptibility hypothesis: the risk-haplotype group presented higher neuroticism in the presence of more negative LEs and lower neuroticism in the presence of more positive LEs. The GxE interactions for social anxiety were consistent with the diathesis-stress model. The lack of significance in the for-better side for social anxiety might be related to the fact that it mapped onto low extraversion, which is associated with a lower permeability to positive experiences. Discussion Findings underscore the importance of testing the differential-susceptibility model in relation to FKBP5 to adequately characterize its role in healthy and pathological developmental processes. PMID:29466454

29 CFR 1905.25 - Discovery.

Science.gov (United States)

2010-07-01

... 29 Labor 5 2010-07-01 2010-07-01 false Discovery. 1905.25 Section 1905.25 Labor Regulations... OCCUPATIONAL SAFETY AND HEALTH ACT OF 1970 Hearings § 1905.25 Discovery. (a) Depositions. (1) For reasons of... discovery. Whenever appropriate to a just disposition of any issue in a hearing, the presiding hearing...

Characteristics of centrifugally cast GX25CrNiSi18-9 steel

Directory of Open Access Journals (Sweden)

R. Zapała

2011-07-01

Full Text Available The paper presents the results of microstructural examinations of the industrial heat-resistant centrifugally cast GX25CrNiSi18-9 steel characterised by increased content of Cu. The study included changes in the microstructure of base cast steel respective of the steel held at a temperature of 900 and 950°C for 48 hours. Based on the results obtained, an increase in microhardness of the examined cast steel matrix with increasing temperature was stated, which was probably caused by fine precipitates enriched in Cr, Mo, and C forming inside the matrix grains.The layer of scale formed on the tested cast steel oxidised in the atmosphere of air at 900 and 950°C was characterised by an increased tendency to degradation with increasing temperature of the conducted tests.

CCR5 receptor antagonists: discovery and SAR study of guanylhydrazone derivatives.

Science.gov (United States)

Wei, Robert G; Arnaiz, Damian O; Chou, Yuo-Ling; Davey, Dave; Dunning, Laura; Lee, Wheeseong; Lu, Shou-Fu; Onuffer, James; Ye, Bin; Phillips, Gary

2007-01-01

High throughput screening (HTS) led to the identification of the guanylhydrazone of 2-(4-chlorobenzyloxy)-5-bromobenzaldehyde as a CCR5 receptor antagonist. Initial modifications of the guanylhydrazone series indicated that substitution of the benzyl group at the para-position was well tolerated. Substitution at the 5-position of the central phenyl ring was critical for potency. Replacement of the guanylhydrazone group led to the discovery of a novel series of CCR5 antagonists.

Explosive Transient Camera (ETC) Program

Science.gov (United States)

1991-10-01

Discovery of the first of the slow X-ray pulsars , GX 1+4 (1970). • Discovery of the size and shape of the hard X-ray emitting region of the Crab Nebula (1974... pulsars (1968), gamma-ray bursters (1970), and X-ray bursters (1973). For each of these classes of objects, the initial discovery was made by non-optical...ray galaxies typified by NGC5506 (1977) • Discovery of the first "X-ray QSO," MR2251-178 (1977). Development of a highly efficient ground-based, solid

BROADBAND SPECTROSCOPY USING TWO SUZAKU OBSERVATIONS OF THE HMXB GX 301-2

Energy Technology Data Exchange (ETDEWEB)

Suchy, Slawomir; Markowitz, Alex; Rothschild, Richard E. [Center for Astrophysics and Space Sciences, University of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093-0424 (United States); Fuerst, Felix; Kreykenbohm, Ingo; Wilms, Joern [Dr. Karl Remeis Sternwarte and Erlangen Center for Astroparticle Physics, Sternwartstr. 7, 96049 Bamberg (Germany); Pottschmidt, Katja [Center for Space Science and Technology, University of Maryland Baltimore County, 1000 Hilltop Circle, Baltimore, MD 21250 (United States); Caballero, Isabel, E-mail: ssuchy@ucsd.edu [CEA Saclay, DSM/IRFU/SAp-UMR AIM (7158), CNRS/CEA, University Paris 7, Diderot, Gif sur Yvette (France)

2012-02-01

We present the analysis of two Suzaku observations of GX 301-2 at two orbital phases after the periastron passage. Variations in the column density of the line-of-sight absorber are observed, consistent with accretion from a clumpy wind. In addition to a cyclotron resonance scattering feature (CRSF), multiple fluorescence emission lines were detected in both observations. The variations in the pulse profiles and the CRSF throughout the pulse phase have a signature of a magnetic dipole field. Using a simple dipole model we calculated the expected magnetic field values for different pulse phases and were able to extract a set of geometrical angles, loosely constraining the dipole geometry in the neutron star. From the variation of the CRSF width and energy, we found a geometrical solution for the dipole, making the inclination consistent with previously published values.

Genome-wide search for gene-gene interactions in colorectal cancer.

Directory of Open Access Journals (Sweden)

Shuo Jiao

Full Text Available Genome-wide association studies (GWAS have successfully identified a number of single-nucleotide polymorphisms (SNPs associated with colorectal cancer (CRC risk. However, these susceptibility loci known today explain only a small fraction of the genetic risk. Gene-gene interaction (GxG is considered to be one source of the missing heritability. To address this, we performed a genome-wide search for pair-wise GxG associated with CRC risk using 8,380 cases and 10,558 controls in the discovery phase and 2,527 cases and 2,658 controls in the replication phase. We developed a simple, but powerful method for testing interaction, which we term the Average Risk Due to Interaction (ARDI. With this method, we conducted a genome-wide search to identify SNPs showing evidence for GxG with previously identified CRC susceptibility loci from 14 independent regions. We also conducted a genome-wide search for GxG using the marginal association screening and examining interaction among SNPs that pass the screening threshold (p<10(-4. For the known locus rs10795668 (10p14, we found an interacting SNP rs367615 (5q21 with replication p = 0.01 and combined p = 4.19×10(-8. Among the top marginal SNPs after LD pruning (n = 163, we identified an interaction between rs1571218 (20p12.3 and rs10879357 (12q21.1 (nominal combined p = 2.51×10(-6; Bonferroni adjusted p = 0.03. Our study represents the first comprehensive search for GxG in CRC, and our results may provide new insight into the genetic etiology of CRC.

Spectro-Timing Study of GX 339-4 in a Hard Intermediate State

Science.gov (United States)

Furst, F.; Grinberg, V.; Tomsick, J. A.; Bachetti, M.; Boggs, S. E.; Brightman, M.; Christensen, F. E.; Craig, W. W.; Ghandi, P.; Zhang, William W.

2016-01-01

We present an analysis of Nuclear Spectroscopic Telescope Array observations of a hard intermediate state of the transient black hole GX 339-4 taken in 2015 January. With the source softening significantly over the course of the 1.3 day long observation we split the data into 21 sub-sets and find that the spectrum of all of them can be well described by a power-law continuum with an additional relativistically blurred reflection component. The photon index increases from approx. 1.69 to approx. 1.77 over the course of the observation. The accretion disk is truncated at around nine gravitational radii in all spectra. We also perform timing analysis on the same 21 individual data sets, and find a strong type-C quasi-periodic oscillation (QPO), which increases in frequency from approx. 0.68 to approx. 1.05 Hz with time. The frequency change is well correlated with the softening of the spectrum. We discuss possible scenarios for the production of the QPO and calculate predicted inner radii in the relativistic precession model as well as the global disk mode oscillations model. We find discrepancies with respect to the observed values in both models unless we allow for a black hole mass of approx. 100 Mass compared to the Sun, which is highly unlikely. We discuss possible systematic uncertainties, in particular with the measurement of the inner accretion disk radius in the relativistic reflection model. We conclude that the combination of observed QPO frequencies and inner accretion disk radii, as obtained from spectral fitting, is difficult to reconcile with current models.

Discovery of the first selective inhibitor of excitatory amino acid transporter subtype 1

DEFF Research Database (Denmark)

Jensen, Anders Asbjørn; Erichsen, Mette Navy; Nielsen, Christina Wøhlk

2009-01-01

The discovery of the first class of subtype-selective inhibitors of the human excitatory amino acid transporter subtype 1 (EAAT1) and its rat orthologue GLAST is reported. An opening structure-activity relationship of 25 analogues is presented that addresses the influence of substitutions at the 4......- and 7-positions of the parental skeleton 2-amino-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile. The most potent analogue 1o displays high nanomolar inhibitory activity at EAAT1 and a >400-fold selectivity over EAAT2 and EAAT3, making it a highly valuable pharmacological tool....

[Phylogenetic analysis of human/swine/avian gene reassortant H1N2 influenza A virus isolated from a pig in China].

Science.gov (United States)

Chen, Yixiang; Meng, Xueqiong; Liu, Qi; Huang, Xia; Huang, Shengbin; Liu, Cuiquan; Shi, Kaichuang; Guo, Jiangang; Chen, Fangfang; Hu, Liping

2008-04-01

Our aim in this study was to determine the genetic characterization and probable origin of the H1N2 swine influenza virus (A/Swine/Guangxi/13/2006) (Sw/GX/13/06) from lung tissue of a pig in Guangxi province, China. Eight genes of Sw/GX/13/06 were cloned and genetically analyzed. The hemagglutinin (HA), nucleoprotein (NP), matrix (M) and non-structural (NS) genes of Sw/GX/13/06 were most closely related to genes from the classical swine H1N1 influenza virus lineage. The neuraminidase (NA) and PB1 genes were most closely related to the corresponding genes from the human influenza H3N2 virus lineage. The remaining two genes PA and PB2 polymerase genes were most closely related to the genes from avian influenza virus lineage. Phylogenetic analyses revealed that Sw/GX/13/06 was a human/swine/avian H1N2 virus, and closely related to H1N2 viruses isolated from pigs in United States (1999-2001) and Korea (2002). To our knowledge, Sw/GX/13/06 was the first triple-reassortant H1N2 influenza A virus isolated from a pig in China. Whether the Sw/GX/13/06 has a potential threat to breeding farm and human health remains to be further investigated.

BROADBAND SPECTROSCOPY USING TWO SUZAKU OBSERVATIONS OF THE HMXB GX 301–2

International Nuclear Information System (INIS)

Suchy, Slawomir; Markowitz, Alex; Rothschild, Richard E.; Fürst, Felix; Kreykenbohm, Ingo; Wilms, Jörn; Pottschmidt, Katja; Caballero, Isabel

2012-01-01

We present the analysis of two Suzaku observations of GX 301–2 at two orbital phases after the periastron passage. Variations in the column density of the line-of-sight absorber are observed, consistent with accretion from a clumpy wind. In addition to a cyclotron resonance scattering feature (CRSF), multiple fluorescence emission lines were detected in both observations. The variations in the pulse profiles and the CRSF throughout the pulse phase have a signature of a magnetic dipole field. Using a simple dipole model we calculated the expected magnetic field values for different pulse phases and were able to extract a set of geometrical angles, loosely constraining the dipole geometry in the neutron star. From the variation of the CRSF width and energy, we found a geometrical solution for the dipole, making the inclination consistent with previously published values.

Discovery of Three New Millisecond Pulsars in Terzan 5

Science.gov (United States)

Cadelano, M.; Ransom, S. M.; Freire, P. C. C.; Ferraro, F. R.; Hessels, J. W. T.; Lanzoni, B.; Pallanca, C.; Stairs, I. H.

2018-03-01

We report on the discovery of three new millisecond pulsars (MSPs; namely J1748‑2446aj, J1748‑2446ak, and J1748‑2446al) in the inner regions of the dense stellar system Terzan 5. These pulsars have been discovered thanks to a method, alternative to the classical search routines, that exploited the large set of archival observations of Terzan 5 acquired with the Green Bank Telescope over five years (from 2010 to 2015). This technique allowed the analysis of stacked power spectra obtained by combining ∼206 hr of observation. J1748‑2446aj has a spin period of ∼2.96 ms, J1748‑2446ak of ∼1.89 ms (thus it is the fourth fastest pulsar in the cluster) and J1748‑2446al of ∼5.95 ms. All three MSPs are isolated, and currently we have timing solutions only for J1748‑2446aj and J1748‑2446ak. For these two systems, we evaluated the contribution to the measured spin-down rate of the acceleration due to the cluster potential field, thus estimating the intrinsic spin-down rates, which are in agreement with those typically measured for MSPs in globular clusters (GCs). Our results increase the number of pulsars known in Terzan 5 to 37, which now hosts 25% of the entire pulsar population identified, so far, in GCs.

Glutathiolactaldehyde as a probe of the overall stereochemical course of glyoxalase-I catalyzed reactions

International Nuclear Information System (INIS)

Brush, E.J.; Kozarich, J.W.

1986-01-01

The overall stereochemical course of the reactions catalyzed by glyoxalase-I (GX-I) has remained elusive as the substrates are equilibrium mixtures of rapidly interconverting diastereomeric thiohemiacetals. However, with the discovery of inverse substrate processing by Kozarich and coworkers, it is possible to design GX-I substrate analogs that are intrinsically more stable than the thiohemiacetals. Hence, Chari and Kozarich reported that glutathiohydroxyacetone (GHA, GSCH 2 COCH 2 OH) undergoes GX-I catalyzed exchange of the pro-S hydroxymethyl proton with solvent deuterium. Their data suggest that GX-I processes a single diastereomeric thiohemiacetal, and are consistent with a cis-enediol intermediate. To test this hypothesis and to follow the overall stereochemistry on a single substrate, they have prepared glutathiolactaldehyde (GLA, GSCH 2 CHOHCHO) as a potential inverse substrate. Human erythrocyte GX-I catalyzes the isomerization of GLA to GHA as evidenced by UV and NMR spectra of the product. Solvent deuterium is incorporated into the hydroxymethyl position, and NMR data suggest that incorporation is stereospecific. Furthermore, 50% of the expected amount of GHA is produced indicating that only one diastereomer of GLA is processed by GX-I. Identification of the absolute stereochemistry of the substrate diastereomer will lead to a clarification of the overall stereochemical and mechanistic course of GX-I catalyzed reactions

3β-Methyl-Neurosteroid Analogs are Preferential Positive Allosteric Modulators and Direct Activators of Extrasynaptic δGABA-A Receptors in the Hippocampus Dentate Gyrus Subfield.

Science.gov (United States)

Chuang, Shu-Hui; Reddy, Doodipala Samba

2018-03-30

Neurosteroids are powerful modulators of GABA-A receptors. Ganaxolone (3α-hydroxy-3β-methyl-5α-pregnan-20-one, GX) and synthetic analogs of the neurosteroid allopregnanolone (AP) are designed to treat epilepsy and related conditions. However, their precise mechanism of action in native neurons remains unclear. Here, we sought to determine the mode of action of GX and its analogs at GABA-A receptors in native hippocampal neurons by analyzing extrasynaptic receptor-mediated tonic currents and synaptic receptor-mediated phasic currents. Concentration-response profiles of GX were determined in two cell types: δ-containing dentate gyrus granule cells (DGGCs) and γ2-containing CA1 pyramidal cells (CA1PCs). GX produced significantly greater potentiation of the GABA-A receptor-activated chloride currents in DGGCs (500%) than CA1PCs (200%). In the absence of GABA, GX evoked 2-fold greater inward currents in DGGCs than CA1PCs, which were 2-fold greater than AP within DGGCs. In hippocampus slices, GX potentiated and directly activated tonic currents in DGGCs. These responses were significantly diminished in DGGCs from δ-subunit knockout (δKO) mice, confirming GX's selectivity for δGABA-A receptors. Like AP, GX potentiation of tonic currents was prevented by protein kinase C inhibition. Furthermore, GX's protection against hippocampus kindled seizures was significantly diminished in δKO mice. GX analogs exhibited greater potency and efficacy than GX on δGABA-A receptor-mediated tonic inhibition. In summary, these results provide strong evidence that GX and its analogs are preferential allosteric modulators and direct activators of extrasynaptic δGABA-A receptors regulating network inhibition and seizures in the dentate gyrus. Therefore, these findings provide a mechanistic rationale for the clinical use of synthetic neurosteroids in epilepsy and seizure disorders. The American Society for Pharmacology and Experimental Therapeutics.

Erbium-based optical coherent transient correlator for the 1.5-micron communication bands

Science.gov (United States)

Harris, Todd Louis

2001-08-01

Correlators are needed in communications, memory, and signal processing applications to perform cross- correlations for tasks such as address-header decoding for data-packet switching, spread spectrum and code division multiple access communication, associative memory, database searching, and pattern recognition. Correlators based on optical coherent transients, Fourier theory, and holography can potentially perform real-time correlations with multi-phase encoded information at gigahertz bandwidths, a capability conventional electronics lack. The first operation of spatial-spectral holographic correlators in the 1.5-gm communication bands was demonstrated at 1536 nm using Er3+:Y 2SiO5 and the correlator processed multi-phase encoded optical pulses. Real-time decoding of 20-bit binary-phase-shift key encoded address-header pulses is demonstrated using stimulated photon echoes in a phase-matched crossed-beam configuration; this function is required for coherent transient optical data routing and packet switching. Optical 30-symbol quadriphase-shift keyed (QPSK) and binary-phase-shift keyed (BPSK) codes were processed, and the results demonstrated the ability of such correlators to process QPSK codes and BPSK codes with the same apparatus. The high-fidelity correlations exhibit the low sidelobe characteristics expected for the codes used. The 4I15/2 and 4I13/2 crystal field levels of 0.005% Er3+:Y2O3 were measured by absorption and laser excited fluorescence on oriented samples. Site selective fluorescence distinguished transitions of Er3+ in crystallographic sites of C2 and C3i symmetry. The paramagnetic g-tensors for ions in sites of C2 symmetry were measured by orientation dependent Zeeman absorption spectroscopy. For the lowest crystal field level of 4I15/2 the g-tensor principal x-axis in the (100) plane is tipped +2.06° from [001] and principal g-values are: gz = 11.93, gx = 1.603, and gy = 4.711. For the lowest crystal field level of 4I13/2 the g

Discovery of (1R,2S)-2-{[(2,4-Dimethylpyrimidin-5-yl)oxy]methyl}-2-(3-fluorophenyl)-N-(5-fluoropyridin-2-yl)cyclopropanecarboxamide (E2006): A Potent and Efficacious Oral Orexin Receptor Antagonist.

Science.gov (United States)

Yoshida, Yu; Naoe, Yoshimitsu; Terauchi, Taro; Ozaki, Fumihiro; Doko, Takashi; Takemura, Ayumi; Tanaka, Toshiaki; Sorimachi, Keiichi; Beuckmann, Carsten T; Suzuki, Michiyuki; Ueno, Takashi; Ozaki, Shunsuke; Yonaga, Masahiro

2015-06-11

The orexin/hypocretin receptors are a family of G protein-coupled receptors and consist of orexin-1 (OX1) and orexin-2 (OX2) receptor subtypes. Orexin receptors are expressed throughout the central nervous system and are involved in the regulation of the sleep/wake cycle. Because modulation of these receptors constitutes a promising target for novel treatments of disorders associated with the control of sleep and wakefulness, such as insomnia, the development of orexin receptor antagonists has emerged as an important focus in drug discovery research. Here, we report the design, synthesis, characterization, and structure-activity relationships (SARs) of novel orexin receptor antagonists. Various modifications made to the core structure of a previously developed compound (-)-5, the lead molecule, resulted in compounds with improved chemical and pharmacological profiles. The investigation afforded a potential therapeutic agent, (1R,2S)-2-{[(2,4-dimethylpyrimidin-5-yl)oxy]methyl}-2-(3-fluorophenyl)-N-(5-fluoropyridin-2-yl)cyclopropanecarboxamide (E2006), an orally active, potent orexin antagonist. The efficacy was demonstrated in mice in an in vivo study by using sleep parameter measurements.

Dietary 2-oxoglutarate mitigates gastrectomy-evoked structural changes in cartilage of female rats.

Science.gov (United States)

Dobrowolski, Piotr; Tomaszewska, Ewa; Kurlak, Paulina; Pierzynowski, Stefan G

2016-01-01

Gastrectomy (Gx) leads to osteopenia/osteoporosis in humans and animals. However, little is known about the influence of Gx on the cartilage in this regard. Recent studies have demonstrated a protective effect of 2-oxoglutaric acid (2-Ox) on bone and cartilage. Hence, the purpose of this study was to investigate whether 2-Ox can mitigate eventual Gx-induced cartilage impairment. Twenty female Sprague-Dawley rats were subjected to Gx and randomly divided into two groups: Gx + 2-Ox and Gx. Another 20 rats were sham-operated (ShO) and randomly divided into two groups: ShO + 2-Ox and ShO. The daily dose of 2-Ox administered to the rats in the drinking water was 0.43 g per 100 g rat. After eight weeks, rats were euthanized and femora and tibiae were collected. Histology and histomorphometry analyses of the articular cartilage and the growth plate were done. Gx resulted in a 32% (±44.5 femur, ±35.8 tibia) decrease in overall thickness of articular cartilage in both bones (femur: ShO 279.1 ± 48.5 vs. Gx 190.2 ± 38.4 µm, tibia: ShO 222.9 ± 50.3 µm vs. Gx 151.3 ± 52.6 µm) (in some zones up to 58 ± 28.0%), and in the growth plate up to 20% (±22.4) (femur: ShO 243.0 ± 34.0 vs. Gx 207.0 ± 33.7 µm, tibia: ShO 220.0 ± 24.6 µm vs. Gx 171.1 ± 16.1 µm). Gx altered the spatial distribution of thick and thin collagen fibers, and chondrocyte shape and size. 2-Ox administration prevented the reduction in both cartilages thickness (Gx + 2-Ox: articular cartilage 265.2 ± 53.8 µm, 235.6 ± 42.7 µm, growth plate 236.7 ± 39.2 µm, 191.3 ± 16.5 µm in femur and tibia, respectively), and abolished the spatial changes in collagen distribution and structure induced by Gx. Gx affects cartilage structure and thickness, however, 2-Ox administration mitigates these effects and showed protective and stimulatory properties. Our observations suggest that dietary 2-Ox can be used to offset

49 CFR 386.37 - Discovery.

Science.gov (United States)

2010-10-01

... 49 Transportation 5 2010-10-01 2010-10-01 false Discovery. 386.37 Section 386.37 Transportation... and Hearings § 386.37 Discovery. (a) Parties may obtain discovery by one or more of the following...; and requests for admission. (b) Discovery may not commence until the matter is pending before the...

Discovery and development of 5-[(5S,9R)-9-(4-cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-7-yl-methyl]-3-thiophenecarboxylic acid (BMS-587101)--a small molecule antagonist of leukocyte function associated antigen-1.

Science.gov (United States)

Potin, Dominique; Launay, Michele; Monatlik, Francoise; Malabre, Patrice; Fabreguettes, Maud; Fouquet, Andre; Maillet, Magali; Nicolai, Eric; Dorgeret, Loïc; Chevallier, François; Besse, Dominique; Dufort, Monique; Caussade, François; Ahmad, Syed Z; Stetsko, Dawn K; Skala, Stacey; Davis, Patricia M; Balimane, Praveen; Patel, Karishma; Yang, Zheng; Marathe, Punit; Postelneck, Jennifer; Townsend, Robert M; Goldfarb, Valentina; Sheriff, Steven; Einspahr, Howard; Kish, Kevin; Malley, Mary F; DiMarco, John D; Gougoutas, Jack Z; Kadiyala, Pathanjali; Cheney, Daniel L; Tejwani, Ravindra W; Murphy, Denette K; Mcintyre, Kim W; Yang, Xiaoxia; Chao, Sam; Leith, Leslie; Xiao, Zili; Mathur, Arvind; Chen, Bang-Chi; Wu, Daugh-Rurng; Traeger, Sarah C; McKinnon, Murray; Barrish, Joel C; Robl, Jeffrey A; Iwanowicz, Edwin J; Suchard, Suzanne J; Dhar, T G Murali

2006-11-30

LFA-1 (leukocyte function-associated antigen-1), is a member of the beta2-integrin family and is expressed on all leukocytes. This letter describes the discovery and preliminary SAR of spirocyclic hydantoin based LFA-1 antagonists that culminated in the identification of analog 8 as a clinical candidate. We also report the first example of the efficacy of a small molecule LFA-1 antagonist in combination with CTLA-4Ig in an animal model of transplant rejection.

Discovery of N-(Naphtho[1,2-b]Furan-5-Yl Benzenesulfonamides as Novel Selective Inhibitors of Triple-Negative Breast Cancer (TNBC

Directory of Open Access Journals (Sweden)

Ya Chen

2018-03-01

Full Text Available Any type of breast cancer not expressing genes of the estrogen receptor (ER, progesterone receptor (PR, or human epidermal growth factor receptor 2 (HER2 is referred to as triple-negative breast cancer (TNBC. Accordingly, TNBCs do not respond to hormonal therapies or medicines targeting the ER, PR, or HER2. Systemic chemotherapy is therefore the only treatment option available today and prognoses remain poor. We report the discovery and characterization of N-(naphtho[1,2-b]furan-5-ylbenzenesulfonamides as selective inhibitors of TNBCs. These inhibitors were identified by virtual screening and inhibited different TNBC cell lines with IC50 values of 2–3 μM. The compounds did not inhibit normal (i.e. MCF-7 and MCF-10A cells in vitro, indicating their selectivity against TNBC cells. Considering the selectivity of these inhibitors for TNBC, these compounds and analogs can serve as a promising starting point for further research on effective TNBC inhibitors.

Constrained Combinatorial Libraries of Gp2 Proteins Enhance Discovery of PD-L1 Binders.

Science.gov (United States)

Kruziki, Max A; Sarma, Vidur; Hackel, Benjamin J

2018-06-05

Engineered protein ligands are used for molecular therapy, diagnostics, and industrial biotechnology. The Gp2 domain is a 45-amino acid scaffold that has been evolved for specific, high-affinity binding to multiple targets by diversification of two solvent-exposed loops. Inspired by sitewise enrichment of select amino acids, including cysteine pairs, in earlier Gp2 discovery campaigns, we hypothesized that the breadth and efficiency of de novo Gp2 discovery will be aided by sitewise amino acid constraint within combinatorial library design. We systematically constructed eight libraries and comparatively evaluated their efficacy for binder discovery via yeast display against a panel of targets. Conservation of a cysteine pair at the termini of the first diversified paratope loop increased binder discovery 16-fold ( p libraries with conserved cysteine pairs, within the second loop or an interloop pair, did not aid discovery thereby indicating site-specific impact. Via a yeast display protease resistance assay, Gp2 variants from the loop one cysteine pair library were 3.3 ± 2.1-fold ( p = 0.005) more stable than nonconstrained variants. Sitewise constraint of noncysteine residues-guided by previously evolved binders, natural Gp2 homology, computed stability, and structural analysis-did not aid discovery. A panel of binders to programmed death ligand 1 (PD-L1), a key target in cancer immunotherapy, were discovered from the loop 1 cysteine constraint library. Affinity maturation via loop walking resulted in strong, specific cellular PD-L1 affinity ( K d = 6-9 nM).

Cardiac safety implications of hNav1.5 blockade and a framework for preclinical evaluation

Directory of Open Access Journals (Sweden)

Gul eErdemli

2012-01-01

Full Text Available The human cardiac sodium channel (hNav1.5, encoded by the SCN5A gene is critical for action potential generation and propagation in the heart. Drug-induced sodium channel inhibition decreases the rate of cardiomyocyte depolarization and consequently conduction velocity and can have serious implications for cardiac safety. Genetic mutations in hNav1.5 have also been linked to a number of cardiac diseases. Therefore, off-target hNav1.5 inhibition may be considered a risk marker for a drug candidate. Given the potential safety implications for patients and the costs of late stage drug development, detection and mitigation of hNav1.5 liabilities early in drug discovery and development becomes important. In this review, we describe a preclinical strategy to identify hNav1.5 liabilities that incorporates in vitro, in vivo, and in silico techniques and the application of this information in the integrated risk assessment at different stages of drug discovery and development.

22 CFR 224.21 - Discovery.

Science.gov (United States)

2010-04-01

... 22 Foreign Relations 1 2010-04-01 2010-04-01 false Discovery. 224.21 Section 224.21 Foreign....21 Discovery. (a) The following types of discovery are authorized: (1) Requests for production of... parties, discovery is available only as ordered by the ALJ. The ALJ shall regulate the timing of discovery...

Open Access Could Transform Drug Discovery: A Case Study of JQ1.

Science.gov (United States)

Arshad, Zeeshaan; Smith, James; Roberts, Mackenna; Lee, Wen Hwa; Davies, Ben; Bure, Kim; Hollander, Georg A; Dopson, Sue; Bountra, Chas; Brindley, David

2016-01-01

The cost to develop a new drug from target discovery to market is a staggering $1.8 billion, largely due to the very high attrition rate of drug candidates and the lengthy transition times during development. Open access is an emerging model of open innovation that places no restriction on the use of information and has the potential to accelerate the development of new drugs. To date, no quantitative assessment has yet taken place to determine the effects and viability of open access on the process of drug translation. This need is addressed within this study. The literature and intellectual property landscapes of the drug candidate JQ1, which was made available on an open access basis when discovered, and conventionally developed equivalents that were not are compared using the Web of Science and Thomson Innovation software, respectively. Results demonstrate that openly sharing the JQ1 molecule led to a greater uptake by a wider and more multi-disciplinary research community. A comparative analysis of the patent landscapes for each candidate also found that the broader scientific diaspora of the publically released JQ1 data enhanced innovation, evidenced by a greater number of downstream patents filed in relation to JQ1. The authors' findings counter the notion that open access drug discovery would leak commercial intellectual property. On the contrary, JQ1 serves as a test case to evidence that open access drug discovery can be an economic model that potentially improves efficiency and cost of drug discovery and its subsequent commercialization.

15 CFR 25.21 - Discovery.

Science.gov (United States)

2010-01-01

... 15 Commerce and Foreign Trade 1 2010-01-01 2010-01-01 false Discovery. 25.21 Section 25.21... Discovery. (a) The following types of discovery are authorized: (1) Requests for production of documents for..., discovery is available only as ordered by the ALJ. The ALJ shall regulate the timing of discovery. (d...

Small Molecule Drug Discovery at the Glucagon-Like Peptide-1 Receptor

Directory of Open Access Journals (Sweden)

Francis S. Willard

2012-01-01

Full Text Available The therapeutic success of peptide glucagon-like peptide-1 (GLP-1 receptor agonists for the treatment of type 2 diabetes mellitus has inspired discovery efforts aimed at developing orally available small molecule GLP-1 receptor agonists. Although the GLP-1 receptor is a member of the structurally complex class B1 family of GPCRs, in recent years, a diverse array of orthosteric and allosteric nonpeptide ligands has been reported. These compounds include antagonists, agonists, and positive allosteric modulators with intrinsic efficacy. In this paper, a comprehensive review of currently disclosed small molecule GLP-1 receptor ligands is presented. In addition, examples of “ligand bias” and “probe dependency” for the GLP-1 receptor are discussed; these emerging concepts may influence further optimization of known molecules or persuade designs of expanded screening strategies to identify novel chemical starting points for GLP-1 receptor drug discovery.

Have there been improvements in Alzheimer's disease drug discovery over the past 5 years?

Science.gov (United States)

Cacabelos, Ramón

2018-06-01

Alzheimer's disease (AD) is the most important neurodegenerative disorder with a global cost worldwide of over $700 billion. Pharmacological treatment accounts for 10-20% of direct costs; no new drugs have been approved during the past 15 years; and the available medications are not cost-effective. Areas covered: A massive scrutiny of AD-related PubMed publications (ps)(2013-2017) identified 42,053ps of which 8,380 (19.60%) were associated with AD treatments. The most prevalent pharmacological categories included neurotransmitter enhancers (11.38%), multi-target drugs (2.45%), anti-Amyloid agents (13.30%), anti-Tau agents (2.03%), natural products and derivatives (25.58%), novel drugs (8.13%), novel targets (5.66%), other (old) drugs (11.77%), anti-inflammatory drugs (1.20%), neuroprotective peptides (1.25%), stem cell therapy (1.85%), nanocarriers/nanotherapeutics (1.52%), and others (discovery programs, (vi) the updating of regulatory requirements, (vii) the introduction of pharmacogenomics in drug development and personalized treatments, and (viii) the implementation of preventive programs.

Overcoming hERG affinity in the discovery of maraviroc; a CCR5 antagonist for the treatment of HIV.

Science.gov (United States)

Price, David A; Armour, Duncan; de Groot, Marcel; Leishman, Derek; Napier, Carolyn; Perros, Manos; Stammen, Blanda L; Wood, Anthony

2008-01-01

Avoiding cardiac liability associated with blockade of hERG (human ether a go-go) is key for successful drug discovery and development. This paper describes the work undertaken in the discovery of a potent CCR5 antagonist, maraviroc 34, for the treatment of HIV. In particular the use of a pharmacophore model of the hERG channel and a high throughput binding assay for the hERG channel are described that were critical to elucidate SAR to overcome hERG liabilities. The key SAR involves the introduction of polar substituents into regions of the molecule where it is postulated to undergo hydrophobic interactions with the ion channel. Within the CCR5 project there appeared to be no strong correlation between hERG affinity and physiochemical parameters such as pKa or lipophilicity. It is believed that chemists could apply these same strategies early in drug discovery to remove hERG interactions associated with lead compounds while retaining potency at the primary target.

14 CFR 16.213 - Discovery.

Science.gov (United States)

2010-01-01

... 14 Aeronautics and Space 1 2010-01-01 2010-01-01 false Discovery. 16.213 Section 16.213... PRACTICE FOR FEDERALLY-ASSISTED AIRPORT ENFORCEMENT PROCEEDINGS Hearings § 16.213 Discovery. (a) Discovery... discovery permitted by this section if a party shows that— (1) The information requested is cumulative or...

40 CFR 27.21 - Discovery.

Science.gov (United States)

2010-07-01

... 40 Protection of Environment 1 2010-07-01 2010-07-01 false Discovery. 27.21 Section 27.21... Discovery. (a) The following types of discovery are authorized: (1) Requests for production of documents for..., discovery is available only as ordered by the presiding officer. The presiding officer shall regulate the...

42 CFR 1005.7 - Discovery.

Science.gov (United States)

2010-10-01

... 42 Public Health 5 2010-10-01 2010-10-01 false Discovery. 1005.7 Section 1005.7 Public Health... OF EXCLUSIONS, CIVIL MONEY PENALTIES AND ASSESSMENTS § 1005.7 Discovery. (a) A party may make a... and any forms of discovery, other than those permitted under paragraph (a) of this section, are not...

The Evolution of the Phase Lags Associated with the Type-C Quasi-periodic Oscillation in GX 339–4 during the 2006/2007 Outburst

Energy Technology Data Exchange (ETDEWEB)

Zhang, Liang; Chen, Li [Department of Astronomy, Beijing Normal University, Beijing 100875 (China); Wang, Yanan; Méndez, Mariano [Kapteyn Astronomical Institute, University of Groningen, P.O. Box 800, NL-9700 AV Groningen (Netherlands); Qu, Jinlu [Key Laboratory for Particle Astrophysics, Institute of High Energy Physics, CAS, Beijing 100049 (China); Altamirano, Diego [Department of Physics and Astronomy, University of Southampton, Southampton, Hampshire SO17 1BJ (United Kingdom); Belloni, Tomaso, E-mail: 201431160006@mail.bnu.edu.cn [INAF-Osservatorio Astronomico di Brera, via E. Bianchi 46, I-23807 Merate (Italy)

2017-08-20

We present the evolution of the phase lags associated with the type-C QPO in GX 339–4 during the rising phase of the 2006/2007 outburst. We find that the phase lags at the QPO frequency are always positive (hard) and show very different behavior between QPOs with frequencies below and above ∼1.7 Hz: when the QPO frequency is below ∼1.7 Hz, the phase lags increase both with QPO frequency and energy, while when the QPO frequency is above ∼1.7 Hz, the phase lags remain more or less constant. When the QPO frequency is higher than ∼1.7 Hz, a broad feature is always present in the lag–energy spectra at around 6.5 keV, suggesting that the reflection component may have a significant contribution to the phase lags. Below ∼1.7 Hz, the QPO rms first decreases with energy and then turns to almost flat, while above ∼1.7 Hz, the QPO rms increases with energy. During the transition from the low-hard state to the hard-intermediate state, the second harmonic and subharmonic of this QPO appear in the power density spectra. The second-harmonic and subharmonic phase lags show very similar evolutions for their centroid frequencies. However, the energy dependence of the second-harmonic and subharmonic phase lags are quite different. Our results suggest that, at different phases of the outburst, different mechanisms may be responsible for the phase lags of the QPO. We briefly discuss the possible scenarios for producing the lags.

43 CFR 35.21 - Discovery.

Science.gov (United States)

2010-10-01

... 43 Public Lands: Interior 1 2010-10-01 2010-10-01 false Discovery. 35.21 Section 35.21 Public... AND STATEMENTS § 35.21 Discovery. (a) The following types of discovery are authorized: (1) Requests...) Unless mutually agreed to by the parties, discovery is available only as ordered by the ALJ. The ALJ...

Computational discovery of picomolar Q(o) site inhibitors of cytochrome bc1 complex.

Science.gov (United States)

Hao, Ge-Fei; Wang, Fu; Li, Hui; Zhu, Xiao-Lei; Yang, Wen-Chao; Huang, Li-Shar; Wu, Jia-Wei; Berry, Edward A; Yang, Guang-Fu

2012-07-11

A critical challenge to the fragment-based drug discovery (FBDD) is its low-throughput nature due to the necessity of biophysical method-based fragment screening. Herein, a method of pharmacophore-linked fragment virtual screening (PFVS) was successfully developed. Its application yielded the first picomolar-range Q(o) site inhibitors of the cytochrome bc(1) complex, an important membrane protein for drug and fungicide discovery. Compared with the original hit compound 4 (K(i) = 881.80 nM, porcine bc(1)), the most potent compound 4f displayed 20 507-fold improved binding affinity (K(i) = 43.00 pM). Compound 4f was proved to be a noncompetitive inhibitor with respect to the substrate cytochrome c, but a competitive inhibitor with respect to the substrate ubiquinol. Additionally, we determined the crystal structure of compound 4e (K(i) = 83.00 pM) bound to the chicken bc(1) at 2.70 Å resolution, providing a molecular basis for understanding its ultrapotency. To our knowledge, this study is the first application of the FBDD method in the discovery of picomolar inhibitors of a membrane protein. This work demonstrates that the novel PFVS approach is a high-throughput drug discovery method, independent of biophysical screening techniques.

Kv2 Channel Regulation of Action Potential Repolarization and Firing Patterns in Superior Cervical Ganglion Neurons and Hippocampal CA1 Pyramidal Neurons

Science.gov (United States)

Liu, Pin W.

2014-01-01

Kv2 family “delayed-rectifier” potassium channels are widely expressed in mammalian neurons. Kv2 channels activate relatively slowly and their contribution to action potential repolarization under physiological conditions has been unclear. We explored the function of Kv2 channels using a Kv2-selective blocker, Guangxitoxin-1E (GxTX-1E). Using acutely isolated neurons, mixed voltage-clamp and current-clamp experiments were done at 37°C to study the physiological kinetics of channel gating and action potentials. In both rat superior cervical ganglion (SCG) neurons and mouse hippocampal CA1 pyramidal neurons, 100 nm GxTX-1E produced near-saturating block of a component of current typically constituting ∼60–80% of the total delayed-rectifier current. GxTX-1E also reduced A-type potassium current (IA), but much more weakly. In SCG neurons, 100 nm GxTX-1E broadened spikes and voltage clamp experiments using action potential waveforms showed that Kv2 channels carry ∼55% of the total outward current during action potential repolarization despite activating relatively late in the spike. In CA1 neurons, 100 nm GxTX-1E broadened spikes evoked from −70 mV, but not −80 mV, likely reflecting a greater role of Kv2 when other potassium channels were partially inactivated at −70 mV. In both CA1 and SCG neurons, inhibition of Kv2 channels produced dramatic depolarization of interspike voltages during repetitive firing. In CA1 neurons and some SCG neurons, this was associated with increased initial firing frequency. In all neurons, inhibition of Kv2 channels depressed maintained firing because neurons entered depolarization block more readily. Therefore, Kv2 channels can either decrease or increase neuronal excitability depending on the time scale of excitation. PMID:24695716

30 CFR 44.24 - Discovery.

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2010-07-01

... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Discovery. 44.24 Section 44.24 Mineral... Discovery. Parties shall be governed in their conduct of discovery by appropriate provisions of the Federal... discovery. Alternative periods of time for discovery may be prescribed by the presiding administrative law...

24 CFR 180.500 - Discovery.

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2010-04-01

... 24 Housing and Urban Development 1 2010-04-01 2010-04-01 false Discovery. 180.500 Section 180.500... OPPORTUNITY CONSOLIDATED HUD HEARING PROCEDURES FOR CIVIL RIGHTS MATTERS Discovery § 180.500 Discovery. (a) In general. This subpart governs discovery in aid of administrative proceedings under this part. Discovery in...

Human parechovirus type 1, 3, 4, 5, and 6 detection in picornavirus cultures

NARCIS (Netherlands)

de Vries, Michel; Pyrc, Krzysztof; Berkhout, Ron; Vermeulen-Oost, Wilma; Dijkman, Ronald; Jebbink, Maarten F.; Bruisten, Sylvia; Berkhout, Ben; van der Hoek, Lia

2008-01-01

Picornavirus cultures that could not be typed in neutralization assays were analyzed by VP1 reverse transcription-PCR (RT-PCR) and a virus discovery tool (VIDISCA). Human parechoviruses (HPeVs) were frequently identified, among which were the uncommon isolates HPeV-4, HPeV-5, and HPeV-6. The HPeV-5

Systematic analysis of low/hard state RXTE spectra of GX 339–4 to constrain the geometry of the system

Science.gov (United States)

Bagri, Kalyani; Misra, Ranjeev; Rao, Anjali; Singh Yadav, Jagdish; Pandey, Shiv Kumar

2018-05-01

One of the popular models for the low/hard state of black hole binaries is that the standard accretion disk is truncated and the hot inner region produces, via Comptonization, hard X-ray flux. This is supported by the value of the high energy photon index, which is often found to be small, ∼ 1.7(2. This would mean that the medium is not photon deficient, reconciling the presence of a broad Fe line in the observed hard state. To test this hypothesis, we have analyzed the RXTE observations of GX 339–4 from the four outbursts during 2002–2011 and identify observations when the system was in the hard state and showed a broad Fe line. We have then attempted to fit these observationswith models,which include smeared reflection, to understandwhether the intrinsic photon index can indeed be large. We find that, while for some observations the inclusion of reflection does increase the photon index, there are hard state observations with a broad Fe line that have photon indices less than 2.

The serotonin transporter gene polymorphism 5-HTTLPR moderates the effects of stress on attention-deficit/hyperactivity disorder

NARCIS (Netherlands)

van der Meer, Dennis; Hartman, Catharina A.; Richards, Jennifer; Bralten, Janita B.; Franke, Barbara; Oosterlaan, Jaap; Heslenfeld, Dirk J.; Faraone, Stephen V.; Buitelaar, Jan K.; Hoekstra, Pieter J.

2014-01-01

IntroductionThe role of the serotonin transporter gene polymorphism 5-HTTLPR in attention-deficit/hyperactivity disorder (ADHD) is unclear. Heterogeneity of findings may be explained by gene-environment interactions (GxE), as it has been suggested that S-allele carriers are more reactive to

The serotonin transporter gene polymorphism 5-HTTLPR moderates the effects of stress on attention-deficit/hyperactivity disorder

NARCIS (Netherlands)

Meer, D. van der; Hartman, C.A.; Richards, J.; Bralten, J.B.; Franke, B.; Oosterlaan, J.; Heslenfeld, D.J.; Faraone, S.V.; Buitelaar, J.K.; Hoekstra, P.J.

2014-01-01

INTRODUCTION: The role of the serotonin transporter gene polymorphism 5-HTTLPR in attention-deficit/hyperactivity disorder (ADHD) is unclear. Heterogeneity of findings may be explained by gene-environment interactions (GxE), as it has been suggested that S-allele carriers are more reactive to

The serotonin transporter gene polymorphism 5-HTTLPR moderates the effects of stress on attention-deficit/hyperactivity disorder

NARCIS (Netherlands)

van der Meer, D.; Hartman, C.A.; Richards, J.; Bralten, J.; Franke, B.; Oosterlaan, J.; Heslenfeld, D.J.

2015-01-01

Introduction The role of the serotonin transporter gene polymorphism 5-HTTLPR in attention-deficit/hyperactivity disorder (ADHD) is unclear. Heterogeneity of findings may be explained by gene-environment interactions (GxE), as it has been suggested that S-allele carriers are more reactive to

The serotonin transporter gene polymorphism 5-HTTLPR moderates the effects of stress on attention-deficit/hyperactivity disorder

NARCIS (Netherlands)

van der Meer, D.; Hartman, C.A.; Richards, J.; Bralten, J.; Franke, B.; Oosterlaan, J.; Heslenfeld, D.J.; Faraone, S.V.; Buitelaar, J.K.; Hoekstra, P.J.

2014-01-01

Introduction The role of the serotonin transporter gene polymorphism 5-HTTLPR in attention-deficit/hyperactivity disorder (ADHD) is unclear. Heterogeneity of findings may be explained by gene-environment interactions (GxE), as it has been suggested that S-allele carriers are more reactive to

39 CFR 963.14 - Discovery.

Science.gov (United States)

2010-07-01

... 39 Postal Service 1 2010-07-01 2010-07-01 false Discovery. 963.14 Section 963.14 Postal Service... PANDERING ADVERTISEMENTS STATUTE, 39 U.S.C. 3008 § 963.14 Discovery. Discovery is to be conducted on a... such discovery as he or she deems reasonable and necessary. Discovery may include one or more of the...

Assessment of protocols in cone beam CT with symmetric and asymmetric beam using effective dose and Pka

International Nuclear Information System (INIS)

Batista, W. O.; Linhares de O, M. V.; Soares, M. R.; Maia, A. F.; Caldas, L. V. E.

2014-08-01

The cone beam CT is an emerging technology in dental radiology with significant differences the point of view of design technology between the various manufacturers on the world market. This study aims to evaluate and compare protocols with similar purposes in a cone beam CT scanner using TLDs and air kerma - area product (P ka ) as kerma index. Measurements were performed on two protocols used to obtain the image the maxilla-mandible in equipment Gendex GXCB 500: Protocol [GX1] extended diameter and asymmetric beam (14 cm x 8.5 cm - maxilla / mandible) and protocol [GX2] symmetrical beam (8.5 cm x 8.5 cm - maxillary / mandible). Was used LiF dosimeters (TLD 100) inserted into a female anthropomorphic phantom manufactured by Radiology Support Devices. For all protocols evaluated the value of P ka using a meter Diamentor E2 and PTW system Radcal Rapidose. The results obtained for Effective Dose / P ka these measurements were separated by protocol image. Protocol [GX1]: 44.5 μSv/478 mGy cm 2 ; protocol [GX2]: 54.8 μSv/507 mGy cm 2 . These values indicate that the relationship between the diameter of the image acquired in the protocol [GX1] and the diameter of the image in the protocol [GX2] is equal to 1.65, the Effective Dose for the first protocol has lower value at 18%. P ka values reveal very similar results between the two protocols, although, common sense leads to the interpretation that imaging protocols with field of view (Fov) of large diameters imply high values of effective dose when compared to small diameters. However, in this particular case, this is not true due to the asymmetrical beam technology. Conclude that for the cases where the scanner uses asymmetric beam to obtain images with large diameters that cover the entire face there are advantages from the point of view of reducing the exposure of patients with respect to the use of symmetrical beam and / or to Fov images with a smaller diameter. (Author)

22 CFR 35.21 - Discovery.

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2010-04-01

... 22 Foreign Relations 1 2010-04-01 2010-04-01 false Discovery. 35.21 Section 35.21 Foreign Relations DEPARTMENT OF STATE CLAIMS AND STOLEN PROPERTY PROGRAM FRAUD CIVIL REMEDIES § 35.21 Discovery. (a) The following types of discovery are authorized: (1) Requests for production of documents for...

49 CFR 31.21 - Discovery.

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2010-10-01

... 49 Transportation 1 2010-10-01 2010-10-01 false Discovery. 31.21 Section 31.21 Transportation Office of the Secretary of Transportation PROGRAM FRAUD CIVIL REMEDIES § 31.21 Discovery. (a) The following types of discovery are authorized: (1) Requests for production of documents for inspection and...

37 CFR 11.52 - Discovery.

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2010-07-01

... 37 Patents, Trademarks, and Copyrights 1 2010-07-01 2010-07-01 false Discovery. 11.52 Section 11... Disciplinary Proceedings; Jurisdiction, Sanctions, Investigations, and Proceedings § 11.52 Discovery. Discovery... establishes that discovery is reasonable and relevant, the hearing officer, under such conditions as he or she...

Discovery of a New Nearby Star

Science.gov (United States)

Teegarden, B. J.; Pravdo, S. H.; Covey, K.; Frazier, O.; Hawley, S. L.; Hicks, M.; Lawrence, K.; McGlynn, T.; Reid, I. N.; Shaklan, S. B.

2003-01-01

We report the discovery of a nearby star with a very large proper motion of 5.06 +/- 0.03 arcsec/yr. The star is called SO025300.5+165258 and referred to herein as HPMS (high proper motion star). The discovery came as a result of a search of the SkyMorph database, a sensitive and persistent survey that is well suited for finding stars with high proper motions. There are currently only 7 known stars with proper motions greater than 5 arcsec/yr. We have determined a preliminary value for the parallax of pi = 0.43 +/- 0.13 arcsec. If this value holds our new star ranks behind only the Alpha Centauri system (including Proxima Centauri) and Barnard's star in the list of our nearest stellar neighbours. The spectrum and measured tangential velocity indicate that HPMS is a main-sequence star with spectral type M6.5. However, if our distance measurement is correct, the HPMS is underluminous by 1.2 +/- 0.7 mag.

Electronic structure of UCl5: A reexamination

International Nuclear Information System (INIS)

Soule, E.; Edelstein, N.

1980-01-01

On the basis of the absorption spectrum of UCl 5 recorded at 4.2 K, Leung and Poon attempted a determination of both the spin-orbit coupling constant and the crystal field parameters. Their parameters, however, led to a calculated g-tensor at variance with the position of the electron paramagnetic resonance line observed by Miyake et al. It was therefore attempted to simultaneously interpret both spectra (absorption and EPR), assuming the validity of the Newman superposition model, and taking the point symmetry group on each uranium of the (UCl 5 ) 2 dimer as C 2 sub(v). We obtain one and only one satisfactory solution, namely a set of parameters that reasonably reproduce the observed absorption peaks, and lead to the following principal values of the g-tensor: gx = 0.226 (unobservable); gy = 1.187; gz = 1.186. Therefore the paradox stemming from the apparent isotropy of the EPR signal for a species of low point symmetry is resolved. (orig.)

6 CFR 13.21 - Discovery.

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2010-01-01

... 6 Domestic Security 1 2010-01-01 2010-01-01 false Discovery. 13.21 Section 13.21 Domestic Security DEPARTMENT OF HOMELAND SECURITY, OFFICE OF THE SECRETARY PROGRAM FRAUD CIVIL REMEDIES § 13.21 Discovery. (a) In general. (1) The following types of discovery are authorized: (i) Requests for production of...

20 CFR 355.21 - Discovery.

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2010-04-01

... 20 Employees' Benefits 1 2010-04-01 2010-04-01 false Discovery. 355.21 Section 355.21 Employees... UNDER THE PROGRAM FRAUD CIVIL REMEDIES ACT OF 1986 § 355.21 Discovery. (a) The following types of discovery are authorized: (1) Requests for production of documents for inspection and copying; (2) Requests...

10 CFR 2.1018 - Discovery.

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2010-01-01

... 10 Energy 1 2010-01-01 2010-01-01 false Discovery. 2.1018 Section 2.1018 Energy NUCLEAR REGULATORY... Geologic Repository § 2.1018 Discovery. (a)(1) Parties, potential parties, and interested governmental participants in the high-level waste licensing proceeding may obtain discovery by one or more of the following...

34 CFR 33.21 - Discovery.

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2010-07-01

... 34 Education 1 2010-07-01 2010-07-01 false Discovery. 33.21 Section 33.21 Education Office of the Secretary, Department of Education PROGRAM FRAUD CIVIL REMEDIES ACT § 33.21 Discovery. (a) The following types of discovery are authorized: (1) Requests for production of documents for inspection and copying...

45 CFR 79.21 - Discovery.

Science.gov (United States)

2010-10-01

... 45 Public Welfare 1 2010-10-01 2010-10-01 false Discovery. 79.21 Section 79.21 Public Welfare DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL ADMINISTRATION PROGRAM FRAUD CIVIL REMEDIES § 79.21 Discovery. (a) The following types of discovery are authorized: (1) Requests for production of documents for...

Discovery of a Bacterial 5-Methylcytosine Deaminase

Science.gov (United States)

2015-01-01

5-Methylcytosine is found in all domains of life, but the bacterial cytosine deaminase from Escherichia coli (CodA) will not accept 5-methylcytosine as a substrate. Since significant amounts of 5-methylcytosine are produced in both prokaryotes and eukaryotes, this compound must eventually be catabolized and the fragments recycled by enzymes that have yet to be identified. We therefore initiated a comprehensive phylogenetic screen for enzymes that may be capable of deaminating 5-methylcytosine to thymine. From a systematic analysis of sequence homologues of CodA from thousands of bacterial species, we identified putative cytosine deaminases where a “discriminating” residue in the active site, corresponding to Asp-314 in CodA from E. coli, was no longer conserved. Representative examples from Klebsiella pneumoniae (locus tag: Kpn00632), Rhodobacter sphaeroides (locus tag: Rsp0341), and Corynebacterium glutamicum (locus tag: NCgl0075) were demonstrated to efficiently deaminate 5-methylcytosine to thymine with values of kcat/Km of 1.4 × 105, 2.9 × 104, and 1.1 × 103 M–1 s–1, respectively. These three enzymes also catalyze the deamination of 5-fluorocytosine to 5-fluorouracil with values of kcat/Km of 1.2 × 105, 6.8 × 104, and 2.0 × 102 M–1 s–1, respectively. The three-dimensional structure of Kpn00632 was determined by X-ray diffraction methods with 5-methylcytosine (PDB id: 4R85), 5-fluorocytosine (PDB id: 4R88), and phosphonocytosine (PDB id: 4R7W) bound in the active site. When thymine auxotrophs of E. coli express these enzymes, they are capable of growth in media lacking thymine when supplemented with 5-methylcytosine. Expression of these enzymes in E. coli is toxic in the presence of 5-fluorocytosine, due to the efficient transformation to 5-fluorouracil. PMID:25384249

37 CFR 41.150 - Discovery.

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2010-07-01

... 37 Patents, Trademarks, and Copyrights 1 2010-07-01 2010-07-01 false Discovery. 41.150 Section 41... COMMERCE PRACTICE BEFORE THE BOARD OF PATENT APPEALS AND INTERFERENCES Contested Cases § 41.150 Discovery. (a) Limited discovery. A party is not entitled to discovery except as authorized in this subpart. The...

14 CFR 13.220 - Discovery.

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2010-01-01

... 14 Aeronautics and Space 1 2010-01-01 2010-01-01 false Discovery. 13.220 Section 13.220... INVESTIGATIVE AND ENFORCEMENT PROCEDURES Rules of Practice in FAA Civil Penalty Actions § 13.220 Discovery. (a) Initiation of discovery. Any party may initiate discovery described in this section, without the consent or...

24 CFR 26.18 - Discovery.

Science.gov (United States)

2010-04-01

... 24 Housing and Urban Development 1 2010-04-01 2010-04-01 false Discovery. 26.18 Section 26.18... PROCEDURES Hearings Before Hearing Officers Discovery § 26.18 Discovery. (a) General. The parties are encouraged to engage in voluntary discovery procedures, which may commence at any time after an answer has...

42 CFR 426.532 - Discovery.

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2010-10-01

... 42 Public Health 3 2010-10-01 2010-10-01 false Discovery. 426.532 Section 426.532 Public Health... § 426.532 Discovery. (a) General rule. If the Board orders discovery, the Board must establish a reasonable timeframe for discovery. (b) Protective order—(1) Request for a protective order. Any party...

22 CFR 128.6 - Discovery.

Science.gov (United States)

2010-04-01

... 22 Foreign Relations 1 2010-04-01 2010-04-01 false Discovery. 128.6 Section 128.6 Foreign... Discovery. (a) Discovery by the respondent. The respondent, through the Administrative Law Judge, may... discovery if the interests of national security or foreign policy so require, or if necessary to comply with...

24 CFR 26.42 - Discovery.

Science.gov (United States)

2010-04-01

... 24 Housing and Urban Development 1 2010-04-01 2010-04-01 false Discovery. 26.42 Section 26.42... PROCEDURES Hearings Pursuant to the Administrative Procedure Act Discovery § 26.42 Discovery. (a) General. The parties are encouraged to engage in voluntary discovery procedures, which may commence at any time...

Discovery of three z > 6.5 quasars in the VISTA kilo-degree infrared galaxy (VIKING) survey

Energy Technology Data Exchange (ETDEWEB)

Venemans, B. P. [Max-Planck Institute for Astronomy, Königstuhl 17, D-69117 Heidelberg (Germany); Findlay, J. R. [Department of Physics, Durham University, South Road, Durham, DH1 3LE (United Kingdom); Sutherland, W. J. [Astronomy Unit, School of Mathematical Sciences, Queen Mary, University of London, London, E1 4NS (United Kingdom); De Rosa, G. [Department of Astronomy, The Ohio State University, 140 West 18th Avenue, Columbus, OH 43210 (United States); McMahon, R. G.; González-Solares, E. A.; Lewis, J. R. [Institute of Astronomy, University of Cambridge, Madingley Road, Cambridge, CB3 0HA (United Kingdom); Simcoe, R. [MIT-Kavli Center for Astrophysics and Space Research, 77 Massachusetts Avenue, Cambridge, MA 02139 (United States); Kuijken, K., E-mail: venemans@mpia.de [Leiden Observatory, Leiden University, Niels Bohrweg 2, NL-2333 CA Leiden (Netherlands)

2013-12-10

Studying quasars at the highest redshifts can constrain models of galaxy and black hole formation, and it also probes the intergalactic medium in the early universe. Optical surveys have to date discovered more than 60 quasars up to z ≅ 6.4, a limit set by the use of the z-band and CCD detectors. Only one z ≳ 6.4 quasar has been discovered, namely the z = 7.08 quasar ULAS J1120+0641, using near-infrared imaging. Here we report the discovery of three new z ≳ 6.4 quasars in 332 deg{sup 2} of the Visible and Infrared Survey Telescope for Astronomy Kilo-degree Infrared Galaxy (VIKING) survey, thus extending the number from 1 to 4. The newly discovered quasars have redshifts of z = 6.60, 6.75, and 6.89. The absolute magnitudes are between –26.0 and –25.5, 0.6-1.1 mag fainter than ULAS J1120+0641. Near-infrared spectroscopy revealed the Mg II emission line in all three objects. The quasars are powered by black holes with masses of ∼(1-2) × 10{sup 9} M {sub ☉}. In our probed redshift range of 6.44 < z < 7.44 we can set a lower limit on the space density of supermassive black holes of ρ(M {sub BH} > 10{sup 9} M {sub ☉}) > 1.1 × 10{sup –9} Mpc{sup –3}. The discovery of three quasars in our survey area is consistent with the z = 6 quasar luminosity function when extrapolated to z ∼ 7. We do not find evidence for a steeper decline in the space density of quasars with increasing redshift from z = 6 to z = 7.

29 CFR 22.21 - Discovery.

Science.gov (United States)

2010-07-01

... 29 Labor 1 2010-07-01 2010-07-01 true Discovery. 22.21 Section 22.21 Labor Office of the Secretary of Labor PROGRAM FRAUD CIVIL REMEDIES ACT OF 1986 § 22.21 Discovery. (a) The following types of discovery are authorized: (1) Requests for production of documents for inspection and copying; (2) Requests...

42 CFR 426.432 - Discovery.

Science.gov (United States)

2010-10-01

... 42 Public Health 3 2010-10-01 2010-10-01 false Discovery. 426.432 Section 426.432 Public Health... § 426.432 Discovery. (a) General rule. If the ALJ orders discovery, the ALJ must establish a reasonable timeframe for discovery. (b) Protective order—(1) Request for a protective order. Any party receiving a...

10 CFR 13.21 - Discovery.

Science.gov (United States)

2010-01-01

... 10 Energy 1 2010-01-01 2010-01-01 false Discovery. 13.21 Section 13.21 Energy NUCLEAR REGULATORY COMMISSION PROGRAM FRAUD CIVIL REMEDIES § 13.21 Discovery. (a) The following types of discovery are...) Unless mutually agreed to by the parties, discovery is available only as ordered by the ALJ. The ALJ...

22 CFR 521.21 - Discovery.

Science.gov (United States)

2010-04-01

... 22 Foreign Relations 2 2010-04-01 2010-04-01 true Discovery. 521.21 Section 521.21 Foreign... Discovery. (a) The following types of discovery are authorized: (1) Requests for production of documents for... interpreted to require the creation of a document. (c) Unless mutually agreed to by the parties, discovery is...

31 CFR 10.71 - Discovery.

Science.gov (United States)

2010-07-01

... 31 Money and Finance: Treasury 1 2010-07-01 2010-07-01 false Discovery. 10.71 Section 10.71 Money... SERVICE Rules Applicable to Disciplinary Proceedings § 10.71 Discovery. (a) In general. Discovery may be... relevance, materiality and reasonableness of the requested discovery and subject to the requirements of § 10...

39 CFR 955.15 - Discovery.

Science.gov (United States)

2010-07-01

... 39 Postal Service 1 2010-07-01 2010-07-01 false Discovery. 955.15 Section 955.15 Postal Service... APPEALS § 955.15 Discovery. (a) The parties are encouraged to engage in voluntary discovery procedures. In connection with any deposition or other discovery procedure, the Board may issue any order which justice...

Vitamin K2 improves femoral bone strength without altering bone mineral density in gastrectomized rats.

Science.gov (United States)

Iwamoto, Jun; Sato, Yoshihiro; Matsumoto, Hideo

2014-01-01

Gastrectomy (GX) induces osteopenia in rats. The present study examined the skeletal effects of vitamin K2 in GX rats. Thirty male Sprague-Dawley rats (12 wk old) were randomized by the stratified weight method into the following three groups of 10 animals each: sham operation (control) group; GX group; and GX+oral vitamin K2 (menatetrenone, 30 mg/kg, 5 d/wk) group. Treatment was initiated at 1 wk after surgery. After 6 wk of treatment, the bone mineral content (BMC), bone mineral density (BMD), and mechanical strength of the femoral diaphysis and distal metaphysis were determined by peripheral quantitative computed tomography and mechanical strength tests, respectively. GX induced decreases in the BMC, BMD, and ultimate force of the femoral diaphysis and distal metaphysis. Vitamin K2 did not significantly influence the BMC or BMD of the femoral diaphysis or distal metaphysis in GX rats, but attenuated the decrease in the ultimate force and increased the stiffness of the femoral diaphysis. The present study showed that administration of vitamin K2 to GX rats improved the bone strength of the femoral diaphysis without altering the BMC or BMD, suggesting effects of vitamin K2 on the cortical bone quality.

13 CFR 134.213 - Discovery.

Science.gov (United States)

2010-01-01

... 13 Business Credit and Assistance 1 2010-01-01 2010-01-01 false Discovery. 134.213 Section 134.213... OFFICE OF HEARINGS AND APPEALS Rules of Practice for Most Cases § 134.213 Discovery. (a) Motion. A party may obtain discovery only upon motion, and for good cause shown. (b) Forms. The forms of discovery...

31 CFR 16.21 - Discovery.

Science.gov (United States)

2010-07-01

... 31 Money and Finance: Treasury 1 2010-07-01 2010-07-01 false Discovery. 16.21 Section 16.21 Money... FRAUD CIVIL REMEDIES ACT OF 1986 § 16.21 Discovery. (a) The following types of discovery are authorized... to require the creation of a document. (c) Unless mutually agreed to by the parties, discovery is...

Biomarker Discovery in Gulf War Veterans: Development of a War Illness Diagnostic Panel

Science.gov (United States)

2016-12-01

Award Number: W81XWH-12-1-0382 TITLE: Biomarker Discovery in Gulf War Veterans: Development of a War Illness Diagnostic Panel PRINCIPAL...SUBTITLE Biomarker Discovery in Gulf War Veterans: Development of a War Illness Diagnostic Panel 5a. CONTRACT NUMBER W81XWH-12-1-0382 5b. GRANT...of the 1990-1991 Gulf War are affected by Gulf War illness (GWI), the chronic condition currently defined only by veterans’ self-reported symptoms

The Structure of the Silumin Coat on Alloy Cast Steels

Directory of Open Access Journals (Sweden)

T. Szymczak

2012-04-01

Full Text Available The work presents the analysis results of the structure of the coat obtained by dipping in silumin AlSi5 of two grades of alloy cast steel: GX6CrNiTi18-10 (LH18N9T and GX39Cr13 (LH14. The temperature of the silumin bath was 750±5°C, and the hold-up time of the cast steel element τ = 180 s. The absolute thickness of the coat obtained in the given conditions was g = 104 μm on cast steel GX6CrNiTi18-10 and g = 132 μm on GX39Cr13. The obtained coat consisted of three layers of different phase structure. The first layer from the base “g1`” was constructed of the phase AlFe including Si and alloy additives of the tested cast steel grades: Cr and Ni (GX6CrNiTi18-10 and Cr (GX39Cr13. The second layer “g1``” of intermetallic phases AlFe which also contains Si and Cr crystallizes on it. The last, external layer “g2” of the coat consists of the silumin containing the intermetallic phases AlFeSi which additionally can contain alloy additives of the cast steel. It was shown that there were no carbides on the coat of the tested cast steels which are the component of their microstructure, as it took place in the case of the coat on the high speed steels.

Discovery of an Energetic Pulsar Associated with SNR G76.9+1.0

Science.gov (United States)

Arzoumanian, Zaven; Gotthelf, E. V.; Ransom, S. M.; Safi-Harb, S.; Kothes, R.; Landecker, T. L.

2012-01-01

We report the discovery of PSR J2022-pulsar in the supernova remnant G76.9+i.0, in observations with the Chandra X-ray telescope, the Robert C. Byrd Green Bank Radio Telescope, and the Rossi X-ray Timing Explorer (RXTE). The pulsar's spin-down rate implies a rotation-powered luminosity E = 1.2 X 10(exp 38) erg/s, a surface dipole magnetic field strength B(sub S), = 1.0 X 10(exp 12) G, and a characteristic age of 8.9 kyr. PSR J2022+3842 is thus the second-most energetic Galactic pulsar known, after the Crab, as well as the most rapidly-rotating young, radio-bright pulsar known. The radio pulsations are highly dispersed and broadened by interstellar scattering, and we find that a large (delta f/f approximates 1.9 x 10(exp -6)) spin glitch must have occurred between our discovery and confirmation observations. The X-ray pulses are narrow (0.06 cycles FWHM) and visible up to 20 keV, consistent with magnetospheric emission from a rotation-powered pulsar. The Chandra X-ray image identifies the pulsar with a hard, unresolved source at the midpoint of the double-lobed radio morphology of G76.9+ 1.0 and embedded within faint, compact X-ray nebulosity. The spatial relationship of the X-ray and radio emissions is remarkably similar to extended structure seen around the Vela pulsar. The combined Chandra and RXTE pulsar spectrum is well-fitted by an absorbed power-law model with column density N(sub H) = (1.7 +/- 0.3) x 10(exp 22) / sq cm and photon index Gamma = 1.0 +/- 0.2; it implies that the Chandra point-source flux is virtually 100% pulsed. For a distance of 10 kpc, the X-ray luminosity of PSR J2022+3842 is L(sub x){2-1O keV) = 7.0 x 10(exp 33) erg/s. Despite being extraordinarily energetic, PSR J2022+3842 lacks a bright X-ray wind nebula and has an unusually low conversion efficiency of spin-down power to X-ray luminosity, Lx/E = 5.9 X 10(exp-5).

DISCOVERY OF TeV GAMMA-RAY EMISSION FROM CTA 1 BY VERITAS

Energy Technology Data Exchange (ETDEWEB)

Aliu, E.; Errando, M. [Department of Physics and Astronomy, Barnard College, Columbia University, NY 10027 (United States); Archambault, S. [Physics Department, McGill University, Montreal, QC H3A 2T8 (Canada); Arlen, T. [Department of Physics and Astronomy, University of California, Los Angeles, CA 90095 (United States); Aune, T.; Bouvier, A. [Santa Cruz Institute for Particle Physics and Department of Physics, University of California, Santa Cruz, CA 95064 (United States); Beilicke, M.; Buckley, J. H.; Bugaev, V.; Dickherber, R. [Department of Physics, Washington University, St. Louis, MO 63130 (United States); Benbow, W. [Fred Lawrence Whipple Observatory, Harvard-Smithsonian Center for Astrophysics, Amado, AZ 85645 (United States); Cesarini, A.; Connolly, M. P. [School of Physics, National University of Ireland Galway, University Road, Galway (Ireland); Ciupik, L. [Astronomy Department, Adler Planetarium and Astronomy Museum, Chicago, IL 60605 (United States); Collins-Hughes, E. [School of Physics, University College Dublin, Belfield, Dublin 4 (Ireland); Cui, W. [Department of Physics, Purdue University, West Lafayette, IN 47907 (United States); Duke, C. [Department of Physics, Grinnell College, Grinnell, IA 50112-1690 (United States); Dumm, J. [School of Physics and Astronomy, University of Minnesota, Minneapolis, MN 55455 (United States); Dwarkadas, V. V. [Department of Astronomy and Astrophysics, University of Chicago, Chicago, IL 60637 (United States); Falcone, A., E-mail: muk@astro.columbia.edu, E-mail: smcarthur@ulysses.uchicago.edu [Department of Astronomy and Astrophysics, 525 Davey Lab, Pennsylvania State University, University Park, PA 16802 (United States); and others

2013-02-10

We report the discovery of TeV gamma-ray emission coincident with the shell-type radio supernova remnant (SNR) CTA 1 using the VERITAS gamma-ray observatory. The source, VER J0006+729, was detected as a 6.5 standard deviation excess over background and shows an extended morphology, approximated by a two-dimensional Gaussian of semimajor (semiminor) axis 0. Degree-Sign 30 (0. Degree-Sign 24) and a centroid 5' from the Fermi gamma-ray pulsar PSR J0007+7303 and its X-ray pulsar wind nebula (PWN). The photon spectrum is well described by a power-law dN/dE = N {sub 0}(E/3 TeV){sup -{Gamma}}, with a differential spectral index of {Gamma} = 2.2 {+-} 0.2{sub stat} {+-} 0.3{sub sys}, and normalization N {sub 0} = (9.1 {+-} 1.3{sub stat} {+-} 1.7{sub sys}) Multiplication-Sign 10{sup -14} cm{sup -2} s{sup -1} TeV{sup -1}. The integral flux, F {sub {gamma}} = 4.0 Multiplication-Sign 10{sup -12} erg cm{sup -2} s{sup -1} above 1 TeV, corresponds to 0.2% of the pulsar spin-down power at 1.4 kpc. The energetics, colocation with the SNR, and the relatively small extent of the TeV emission strongly argue for the PWN origin of the TeV photons. We consider the origin of the TeV emission in CTA 1.

Biased small-molecule ligands for selective inhibition of HIV-1 cell entry via CCR5

DEFF Research Database (Denmark)

Berg, Christian; Spiess, Katja; von Lüttichau, Hans Rudolf

2016-01-01

Since the discovery of HIV's use of CCR5 as the primary coreceptor in fusion, the focus on developing small-molecule receptor antagonists for inhibition hereof has only resulted in one single drug, Maraviroc. We therefore investigated the possibility of using small-molecule CCR5 agonists as HIV-1...

STS-105/Discovery/ISS 7A.1: Pre-Launch Activities, Launch, Orbit Activities and Landing

Science.gov (United States)

2001-01-01

The crew of Space Shuttle Discovery on STS-105 is introduced at their pre-launch meal and at suit-up. The crew members include Commander Scott Horowitz, Pilot Rick Sturckow, and Mission Specialists Patrick Forrester and Daniel Barry, together with the Expedition 3 crew of the International Space Station (ISS). The Expedition 3 crew includes Commander Frank Culbertson, Soyuz Commander Vladimir Dezhurov, and Flight Engineer Mikhail Tyurin. When the astronauts depart for the launch pad in the Astrovan, their convoy is shown from above. Upon reaching the launch pad, they conduct a walk around of the shuttle, display signs for family members while being inspected in the White Room, and are strapped into their seats onboard Disciovery. The video includes footage of Discovery in the Orbiter Processing Facility, and some of the pre-launch procedures at the Launch Control Center are shown. The angles of launch replays include: TV-1, Beach Tracker, VAB, Pad A, Tower 1, UCS-15, Grandstand, OTV-70, Onboard, IGOR, and UCS-23. The moment of docking between Discovery and the ISS is shown from inside Discovery's cabin. While in orbit, the crew conducted extravehicular activities (EVAs) to attach an experiments container, and install handrails on the Destiny module of the ISS. The video shows the docking and unloading of the Leonardo Multipurpose Logistics Module (MPLM) onto the ISS. The deployment of a satellite from Discovery with the coast of the Gulf of Mexico in the background is shown. Cape Canaveral is also shown from space. Landing replays include VAB, Tower 1, mid-field, South End SLF, North End SLF, Tower 2, Playalinda DOAMS, UCS-23, and Pilot Point of View (PPOV). NASA Administrator Dan Goldin meets the crew upon landing and participates in their walk around of Discovery. The video concludes with a short speech by commander Horowitz.

Discovery of a Hepatitis C Virus NS5B Replicase Palm Site Allosteric Inhibitor (BMS-929075) Advanced to Phase 1 Clinical Studies

Energy Technology Data Exchange (ETDEWEB)

Yeung, Kap-Sun; Beno, Brett R.; Parcella, Kyle; Bender, John A.; Grant-Young, Katherine A.; Nickel, Andrew; Gunaga, Prashantha; Anjanappa, Prakash; Bora, Rajesh Onkardas; Selvakumar, Kumaravel; Rigat, Karen; Wang, Ying-Kai; Liu, Mengping; Lemm, Julie; Mosure, Kathy; Sheriff, Steven; Wan, Changhong; Witmer, Mark; Kish, Kevin; Hanumegowda, Umesh; Zhuo, Xiaoliang; Shu, Yue-Zhong; Parker, Dawn; Haskell, Roy; Ng, Alicia; Gao, Qi; Colston, Elizabeth; Raybon, Joseph; Grasela, Dennis M.; Santone, Kenneth; Gao, Min; Meanwell, Nicholas A.; Sinz, Michael; Soars, Matthew G.; Knipe, Jay O.; Roberts, Susan B.; Kadow, John F.

2017-05-04

The hepatitis C virus (HCV) NS5B replicase is a prime target for the development of direct-acting antiviral drugs for the treatment of chronic HCV infection. Inspired by the overlay of bound structures of three structurally distinct NS5B palm site allosteric inhibitors, the high-throughput screening hit anthranilic acid 4, the known benzofuran analogue 5, and the benzothiadiazine derivative 6, an optimization process utilizing the simple benzofuran template 7 as a starting point for a fragment growing approach was pursued. A delicate balance of molecular properties achieved via disciplined lipophilicity changes was essential to achieve both high affinity binding and a stringent targeted absorption, distribution, metabolism, and excretion profile. These efforts led to the discovery of BMS-929075 (37), which maintained ligand efficiency relative to early leads, demonstrated efficacy in a triple combination regimen in HCV replicon cells, and exhibited consistently high oral bioavailability and pharmacokinetic parameters across preclinical animal species. The human PK properties from the Phase I clinical studies of 37 were better than anticipated and suggest promising potential for QD administration.

Neuregulin 1: a prime candidate for research into gene-environment interactions in schizophrenia? Insights from genetic rodent models

Directory of Open Access Journals (Sweden)

Tim eKarl

2013-08-01

Full Text Available Schizophrenia is a multi-factorial disease characterized by a high heritability and environmental risk factors. In recent years, an increasing number of researchers worldwide have started investigating the ‘two-hit hypothesis’ of schizophrenia predicting that genetic and environmental risk factors (GxE interactively cause the development of the disorder. This work is starting to produce valuable new animal models and reveal novel insights into the pathophysiology of schizophrenia. This mini review will focus on recent advancements in the field made by challenging mutant and transgenic rodent models for the schizophrenia candidate gene neuregulin 1 (NRG1 with particular environmental factors. It will outline results obtained from mouse and rat models for various Nrg1 isoforms/isoform types (e.g. transmembrane domain Nrg1, Type II Nrg1, which have been exposed to different forms of stress (acute versus chronic, restraint versus social and housing conditions (standard laboratory versus minimally enriched housing. These studies suggest Nrg1 as a prime candidate for GxE interactions in schizophrenia rodent models and that the use of rodent models will enable a better understanding of GxE interactions and the underlying mechanisms.

Discovery of a novel allosteric modulator of 5-HT3 receptor

DEFF Research Database (Denmark)

Trattnig, Sarah M; Harpsøe, Kasper; Thygesen, Sarah B

2012-01-01

The ligand-gated ion channels in the Cysloop receptor superfamily mediate the effects of neurotransmitters acetylcholine, serotonin, GABA and glycine. Cysloop receptor signaling is susceptible to modulation by ligands acting through numerous allosteric sites. Here we report the discovery of a novel...... receptor guided by a homology model, PU02 is demonstrated to act through a transmembrane intersubunit site situated in the upper three helical turns of TM2 and TM3 in the (+)subunit and TM1 and TM2 in the (minus)subunit. The Ser248, Leu288, Ile290, Thr294 and Gly306 residues are identified as important...

Recognition of 5-Hydroxymethylcytosine by the Uhrf1 SRA Domain

Science.gov (United States)

Bultmann, Sebastian; Casa, Valentina; Cardoso, M. Cristina; Antes, Iris; Leonhardt, Heinrich

2011-01-01

Recent discovery of 5-hydroxymethylcytosine (5hmC) in genomic DNA raises the question how this sixth base is recognized by cellular proteins. In contrast to the methyl-CpG binding domain (MBD) of MeCP2, we found that the SRA domain of Uhrf1, an essential factor in DNA maintenance methylation, binds 5hmC and 5-methylcytosine containing substrates with similar affinity. Based on the co-crystal structure, we performed molecular dynamics simulations of the SRA:DNA complex with the flipped cytosine base carrying either of these epigenetic modifications. Our data indicate that the SRA binding pocket can accommodate 5hmC and stabilizes the flipped base by hydrogen bond formation with the hydroxyl group. PMID:21731699

15 CFR 280.210 - Discovery.

Science.gov (United States)

2010-01-01

... 15 Commerce and Foreign Trade 1 2010-01-01 2010-01-01 false Discovery. 280.210 Section 280.210... STANDARDS AND TECHNOLOGY, DEPARTMENT OF COMMERCE ACCREDITATION AND ASSESSMENT PROGRAMS FASTENER QUALITY Enforcement § 280.210 Discovery. (a) General. The parties are encouraged to engage in voluntary discovery...

12 CFR 509.102 - Discovery.

Science.gov (United States)

2010-01-01

... 12 Banks and Banking 5 2010-01-01 2010-01-01 false Discovery. 509.102 Section 509.102 Banks and Banking OFFICE OF THRIFT SUPERVISION, DEPARTMENT OF THE TREASURY RULES OF PRACTICE AND PROCEDURE IN ADJUDICATORY PROCEEDINGS Local Rules § 509.102 Discovery. (a) In general. A party may take the deposition of an...

10 CFR 1013.21 - Discovery.

Science.gov (United States)

2010-01-01

... 10 Energy 4 2010-01-01 2010-01-01 false Discovery. 1013.21 Section 1013.21 Energy DEPARTMENT OF ENERGY (GENERAL PROVISIONS) PROGRAM FRAUD CIVIL REMEDIES AND PROCEDURES § 1013.21 Discovery. (a) The following types of discovery are authorized: (1) Requests for production of documents for inspection and...

37 CFR 2.120 - Discovery.

Science.gov (United States)

2010-07-01

... 37 Patents, Trademarks, and Copyrights 1 2010-07-01 2010-07-01 false Discovery. 2.120 Section 2... COMMERCE RULES OF PRACTICE IN TRADEMARK CASES Procedure in Inter Partes Proceedings § 2.120 Discovery. (a... to disclosure and discovery shall apply in opposition, cancellation, interference and concurrent use...

45 CFR 96.65 - Discovery.

Science.gov (United States)

2010-10-01

... 45 Public Welfare 1 2010-10-01 2010-10-01 false Discovery. 96.65 Section 96.65 Public Welfare DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL ADMINISTRATION BLOCK GRANTS Hearing Procedure § 96.65 Discovery. The use of interrogatories, depositions, and other forms of discovery shall not be allowed. ...

Virtual screening, SAR, and discovery of 5-(indole-3-yl)-2-[(2-nitrophenyl)amino] [1,3,4]-oxadiazole as a novel Bcl-2 inhibitor.

Science.gov (United States)

Ziedan, Noha I; Hamdy, Rania; Cavaliere, Alessandra; Kourti, Malamati; Prencipe, Filippo; Brancale, Andrea; Jones, Arwyn T; Westwell, Andrew D

2017-07-01

A new series of oxadiazoles were designed to act as inhibitors of the anti-apoptotic Bcl-2 protein. Virtual screening led to the discovery of new hits that interact with Bcl-2 at the BH3 binding pocket. Further study of the structure-activity relationship of the most active compound of the first series, compound 1, led to the discovery of a novel oxadiazole analogue, compound 16j, that was a more potent small-molecule inhibitor of Bcl-2. 16j had good in vitro inhibitory activity with submicromolar IC 50 values in a metastatic human breast cancer cell line (MDA-MB-231) and a human cervical cancer cell line (HeLa). The antitumour effect of 16j is concomitant with its ability to bind to Bcl-2 protein as shown by an enzyme-linked immunosorbent assay (IC 50  = 4.27 μm). Compound 16j has a great potential to develop into highly active anticancer agent. © 2017 John Wiley & Sons A/S.

43 CFR 4.1130 - Discovery methods.

Science.gov (United States)

2010-10-01

... 43 Public Lands: Interior 1 2010-10-01 2010-10-01 false Discovery methods. 4.1130 Section 4.1130... Special Rules Applicable to Surface Coal Mining Hearings and Appeals Discovery § 4.1130 Discovery methods. Parties may obtain discovery by one or more of the following methods— (a) Depositions upon oral...

Assessment of protocols in cone beam CT with symmetric and asymmetric beam using effective dose and P{sub ka}

Energy Technology Data Exchange (ETDEWEB)

Batista, W. O.; Linhares de O, M. V. [Instituto Federal da Bahia, Rua Emidio dos Santos s/n, Barbalho, Salvador, 40301015 Bahia (Brazil); Soares, M. R.; Maia, A. F. [Universidade Federal de Sergipe, Departamento de Fisica, Cidade Universitaria Prof. Jose Aloisio de Campos, Marechal Rondon s/n, Jardim Rosa Elze, 49-100000 Sao Cristovao, Sergipe (Brazil); Caldas, L. V. E., E-mail: wilsonottobatista@gmail.com [Instituto de Pesquisas Energeticas e Nucleares / CNEN, Av. Lineu Prestes 2242, Cidade Universitaria, 05508-000 Sao Paulo (Brazil)

2014-08-15

The cone beam CT is an emerging technology in dental radiology with significant differences the point of view of design technology between the various manufacturers on the world market. This study aims to evaluate and compare protocols with similar purposes in a cone beam CT scanner using TLDs and air kerma - area product (P{sub ka}) as kerma index. Measurements were performed on two protocols used to obtain the image the maxilla-mandible in equipment Gendex GXCB 500: Protocol [GX1] extended diameter and asymmetric beam (14 cm x 8.5 cm - maxilla / mandible) and protocol [GX2] symmetrical beam (8.5 cm x 8.5 cm - maxillary / mandible). Was used LiF dosimeters (TLD 100) inserted into a female anthropomorphic phantom manufactured by Radiology Support Devices. For all protocols evaluated the value of P{sub ka} using a meter Diamentor E2 and PTW system Radcal Rapidose. The results obtained for Effective Dose / P{sub ka} these measurements were separated by protocol image. Protocol [GX1]: 44.5 μSv/478 mGy cm{sup 2}; protocol [GX2]: 54.8 μSv/507 mGy cm{sup 2}. These values indicate that the relationship between the diameter of the image acquired in the protocol [GX1] and the diameter of the image in the protocol [GX2] is equal to 1.65, the Effective Dose for the first protocol has lower value at 18%. P{sub ka} values reveal very similar results between the two protocols, although, common sense leads to the interpretation that imaging protocols with field of view (Fov) of large diameters imply high values of effective dose when compared to small diameters. However, in this particular case, this is not true due to the asymmetrical beam technology. Conclude that for the cases where the scanner uses asymmetric beam to obtain images with large diameters that cover the entire face there are advantages from the point of view of reducing the exposure of patients with respect to the use of symmetrical beam and / or to Fov images with a smaller diameter. (Author)

Discoveries by the Fermi Gamma Ray Space Telescope

Science.gov (United States)

Gehrels, Neil

2011-01-01

Fermi is a large space gamma-ray mission developed by NASA and the DOE with major contributions from France, Germany, Italy, Japan and Sweden. It was launched in June 2008 and has been performing flawlessly since then. The main instrument is the Large Area Telescope (LAT) operating in the 20 MeV to 300 GeV range and a smaller monitor instrument is the Gamma-ray Burst Monitor (GBM) operating in the 8 keV to 40 MeV range. New findings are occurring every week. Some of the key discoveries are: 1) Discovery of many new gamma-ray pulsars, including gamma-ray only and millisecond pulsars. 2) Detection of high energy gamma-ray emission from globular clusters, most likely due to summed emission from msec pulsars. 3) Discovery of delayed and extended high energy gamma-ray emission from short and long gamma-ray busts. 4) Detection of approximately 250 gamma-ray bursts per year with the GBM instrument. 5) Most accurate measurement of the cosmic ray electron spectrum between 30 GeV and 1 TeV, showing some excess above the conventional diffusion model. The talk will present the new discoveries and their implications.

45 CFR 99.23 - Discovery.

Science.gov (United States)

2010-10-01

... 45 Public Welfare 1 2010-10-01 2010-10-01 false Discovery. 99.23 Section 99.23 Public Welfare... DEVELOPMENT FUND Hearing Procedures § 99.23 Discovery. The Department, the Lead Agency, and any individuals or groups recognized as parties shall have the right to conduct discovery (including depositions) against...

28 CFR 71.21 - Discovery.

Science.gov (United States)

2010-07-01

... 28 Judicial Administration 2 2010-07-01 2010-07-01 false Discovery. 71.21 Section 71.21 Judicial... REMEDIES ACT OF 1986 Implementation for Actions Initiated by the Department of Justice § 71.21 Discovery. (a) The following types of discovery are authorized: (1) Requests for production of documents for...

13 CFR 134.310 - Discovery.

Science.gov (United States)

2010-01-01

... 13 Business Credit and Assistance 1 2010-01-01 2010-01-01 false Discovery. 134.310 Section 134.310 Business Credit and Assistance SMALL BUSINESS ADMINISTRATION RULES OF PROCEDURE GOVERNING CASES BEFORE THE... Designations § 134.310 Discovery. Discovery will not be permitted in appeals from size determinations or NAICS...

28 CFR 18.7 - Discovery.

Science.gov (United States)

2010-07-01

... 28 Judicial Administration 1 2010-07-01 2010-07-01 false Discovery. 18.7 Section 18.7 Judicial Administration DEPARTMENT OF JUSTICE OFFICE OF JUSTICE PROGRAMS HEARING AND APPEAL PROCEDURES § 18.7 Discovery.... Such order may be entered upon a showing that the deposition is necessary for discovery purposes, and...

12 CFR 308.520 - Discovery.

Science.gov (United States)

2010-01-01

... 12 Banks and Banking 4 2010-01-01 2010-01-01 false Discovery. 308.520 Section 308.520 Banks and... PROCEDURE Program Fraud Civil Remedies and Procedures § 308.520 Discovery. (a) The following types of discovery are authorized: (1) Requests for production of documents for inspection and copying; (2) Requests...

7 CFR 283.12 - Discovery.

Science.gov (United States)

2010-01-01

... 7 Agriculture 4 2010-01-01 2010-01-01 false Discovery. 283.12 Section 283.12 Agriculture... of $50,000 or More § 283.12 Discovery. (a) Dispositions—(1) Motion for taking deposition. Only upon a... exist if the information sought appears reasonably calculated to lead to the discovery of admissible...

Identification and characterization of NDT 9513727 [N,N-bis(1,3-benzodioxol-5-ylmethyl)-1-butyl-2,4-diphenyl-1H-imidazole-5-methanamine], a novel, orally bioavailable C5a receptor inverse agonist.

Science.gov (United States)

Brodbeck, Robbin M; Cortright, Daniel N; Kieltyka, Andrzej P; Yu, Jianying; Baltazar, Carolyn O; Buck, Marianne E; Meade, Robin; Maynard, George D; Thurkauf, Andrew; Chien, Du-Shieng; Hutchison, Alan J; Krause, James E

2008-12-01

The complement system represents an innate immune mechanism of host defense that has three effector arms, the C3a receptor, the C5a receptor (C5aR), and the membrane attack complex. Because of its inflammatory and immune-enhancing properties, the biological activity of C5a and its classical receptor have been widely studied. Because specific antagonism of the C5aR could have therapeutic benefit without affecting the protective immune response, the C5aR continues to be a promising target for pharmaceutical research. The lack of specific, potent and orally bioavailable small-molecule antagonists has limited the clinical investigation of the C5aR. We report the discovery of NDT 9513727 [N,N-bis(1,3-benzodioxol-5-ylmethyl)-1-butyl-2,4-diphenyl-1H-imidazole-5-methanamine], a small-molecule, orally bioavailable, selective, and potent inverse agonist of the human C5aR. NDT 9513727 was discovered based on the integrated use of in vitro affinity and functional assays in conjunction with medicinal chemistry. NDT 9513727 inhibited C5a-stimulated responses, including guanosine 5'-3-O-(thio)triphosphate binding, Ca(2+) mobilization, oxidative burst, degranulation, cell surface CD11b expression and chemotaxis in various cell types with IC(50)s from 1.1 to 9.2 nM, respectively. In C5a competition radioligand binding experiments, NDT 9513727 exhibited an IC(50) of 11.6 nM. NDT 9513727 effectively inhibited C5a-induced neutropenia in gerbil and cynomolgus macaque in vivo. The findings suggest that NDT 9513727 may be a promising new entity for the treatment of human inflammatory diseases.

45 CFR 150.435 - Discovery.

Science.gov (United States)

2010-10-01

... 45 Public Welfare 1 2010-10-01 2010-10-01 false Discovery. 150.435 Section 150.435 Public Welfare... AND INDIVIDUAL INSURANCE MARKETS Administrative Hearings § 150.435 Discovery. (a) The parties must identify any need for discovery from the opposing party as soon as possible, but no later than the time for...

34 CFR 81.16 - Discovery.

Science.gov (United States)

2010-07-01

... 34 Education 1 2010-07-01 2010-07-01 false Discovery. 81.16 Section 81.16 Education Office of the... Discovery. (a) The parties to a case are encouraged to exchange relevant documents and information voluntarily. (b) The ALJ, at a party's request, may order compulsory discovery described in paragraph (c) of...

45 CFR 160.516 - Discovery.

Science.gov (United States)

2010-10-01

... 45 Public Welfare 1 2010-10-01 2010-10-01 false Discovery. 160.516 Section 160.516 Public Welfare... ADMINISTRATIVE REQUIREMENTS Procedures for Hearings § 160.516 Discovery. (a) A party may make a request to... forms of discovery, other than those permitted under paragraph (a) of this section, are not authorized...

42 CFR 405.1037 - Discovery.

Science.gov (United States)

2010-10-01

... 42 Public Health 2 2010-10-01 2010-10-01 false Discovery. 405.1037 Section 405.1037 Public Health... Appeals Under Original Medicare (Part A and Part B) Alj Hearings § 405.1037 Discovery. (a) General rules. (1) Discovery is permissible only when CMS or its contractor elects to participate in an ALJ hearing...

42 CFR 93.512 - Discovery.

Science.gov (United States)

2010-10-01

... 42 Public Health 1 2010-10-01 2010-10-01 false Discovery. 93.512 Section 93.512 Public Health... Process § 93.512 Discovery. (a) Request to provide documents. A party may only request another party to...) Responses to a discovery request. Within 30 days of receiving a request for the production of documents, a...

42 CFR 3.516 - Discovery.

Science.gov (United States)

2010-10-01

... 42 Public Health 1 2010-10-01 2010-10-01 false Discovery. 3.516 Section 3.516 Public Health PUBLIC... AND PATIENT SAFETY WORK PRODUCT Enforcement Program § 3.516 Discovery. (a) A party may make a request... and any forms of discovery, other than those permitted under paragraph (a) of this section, are not...

Design and syntheses of novel N-(benzothiazol-5-yl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione and N-(benzothiazol-5-yl)isoindoline-1,3-dione as potent protoporphyrinogen oxidase inhibitors.

Science.gov (United States)

Jiang, Li-Li; Zuo, Yang; Wang, Zhi-Fang; Tan, Yin; Wu, Qiong-You; Xi, Zhen; Yang, Guang-Fu

2011-06-08

Discovery of protoporphyrinogen oxidase (PPO, EC 1.3.3.4) inhibitors has been one of the hottest research areas in the field of herbicide development for many years. As a continuation of our research work on the development of new PPO-inhibiting herbicides, a series of novel N-(benzothiazol-5-yl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-diones (1a-p) and N-(benzothiazol-5-yl)isoindoline-1,3-diones (2a-h) were designed and synthesized according to the ring-closing strategy of two ortho-substituents. The bioassay results indicated that some newly synthesized compounds exhibited higher PPO inhibition activity than the control of sulfentrazone. Compound 1a, S-(5-(1,3-dioxo-4,5,6,7-tetrahydro-1H-isoindol-2(3H)-yl)-6-fluorobenzothiazol-2-yl) O-methyl carbonothioate, was identified as the most potent inhibitor with k(i) value of 0.08 μM, about 9 times higher than that of sulfentrazone (k(i) = 0.72 μM). Further green house assay showed that compound 1b, methyl 2-((5-(1,3-dioxo-4,5,6,7-tetrahydro-1H-isoindol-2(3H)-yl)-6-fluorobenzothiazol-2-yl)thio)acetate, exhibited herbicidal activity comparable to that of sulfentrazone even at a concentration of 37.5 g ai/ha. In addition, among six tested crops, wheat exhibited high tolerance to compound 1b even at a dosage of 300 g ai/ha. These results indicated that compound 1b might have the potential to be developed as a new herbicide for weed control of wheat field.

Mass spectrum of spin-1/2 pentaquarks with a c anti c component and their anticipated discovery modes in b-baryon decays

Energy Technology Data Exchange (ETDEWEB)

Ali, Ahmed [Deutsches Elektronen-Synchrotron (DESY), Hamburg (Germany); Ahmed, Ishtiaq; Rehman, Abdur [Quaid-i-Azam University Campus, Islamabad (Pakistan). National Centre for Physics; Aslam, M. Jamil [Quaid-i-Azam University, Islamabad (Pakistan). Physics Dept.

2017-04-15

The LHCb discovery of the two baryonic states P{sub c}{sup +}(4380) and P{sub c}{sup +}(4450), having J{sup P}=3/2{sup -} and J{sup P}=5/2{sup +}, respectively, in the process pp → b anti b → Λ{sub b}X, followed by the decay Λ{sub b}→J/ψpK{sup -}, has motivated a number of theoretical models. Interpreting them as compact { anti c[cu][ud]; L_P=0,1} objects, the mass spectroscopy of the J{sup P}=3/2{sup -} and J{sup P}=5/2{sup +} pentaquarks was worked out by us for the pentaquarks in the SU(3){sub F} multiplets, using an effective Hamiltonian based on constituent diquarks and quarks. Their possible discovery modes in b-baryon decays were also given using the heavy quark spin symmetry. In this paper, we calculate the mass spectrum of the hidden c anti c pentaquarks having J{sup P}=(1)/(2){sup ±} for the SU(3){sub F} multiplets and their anticipated discovery modes in b-baryon decays. Some of the P{sub c}{sup +}(J{sup P}=1/2{sup ±}) pentaquarks, produced in the Λ{sub b} decays may have their masses just below the J/ψ p threshold, in which case they should be searched for in the modes P{sub c}{sup +}(J{sup P}=1/2{sup ±})→η{sub c}p,μ{sup +}μ{sup -}p,e{sup +}e{sup -}p.

21 CFR 17.23 - Discovery.

Science.gov (United States)

2010-04-01

... 21 Food and Drugs 1 2010-04-01 2010-04-01 false Discovery. 17.23 Section 17.23 Food and Drugs FOOD... HEARINGS § 17.23 Discovery. (a) No later than 60 days prior to the hearing, unless otherwise ordered by the..., depositions, and any forms of discovery, other than those permitted under paragraphs (a) and (e) of this...

We have much in common: the similar inter-generational work preferences and career satisfaction among practicing radiologists.

Science.gov (United States)

Moriarity, Andrew K; Brown, Manuel L; Schultz, Lonni R

2014-04-01

There are many reported generational differences regarding workplace motivators, but these have not been previously studied in radiologists. The aim of this study was to assess for generational differences in workplace satisfaction and desired workplace characteristics among practicing radiologists. An electronic survey distributed to ACR, Society of Chairs of Academic Radiology Departments, and Association of Program Directors in Radiology members generated 1,577 responses from baby boom (BG) and generation X (GX) radiologists in active practice. Nineteen workplace characteristics and their associations with workplace satisfaction were tested in a univariate analysis using χ(2) tests and in a multiple logistic regression model to test for associations with satisfaction. Workplace satisfaction among BG and GX radiologists was 78% and 80%, respectively. Both generations reported higher satisfaction if they were optimistic about the future of radiology (87% of BG vs 85% of GX radiologists), believed the difference in the desired versus expected age of retirement was narrow (1.5 ± 3.3 years for BG radiologists vs 3.0 ± 4.1 years for GX radiologists), felt that social interactions in the workplace were important (81% of BG vs 83% of GX radiologists), and believed that professionalism in their peers was important (79% of BG vs 82% of GX radiologists). BG radiologists were more satisfied if they valued staff diversity, while GX radiologists were more satisfied if they felt that job security and the amount of compensation were important. There was no significant association of satisfaction with generation, gender, practice setting, or additional administrative work. Workplace satisfaction among practicing radiologists remains high but has decreased compared with prior surveys. The two dominant generations of practicing radiologists have similar workplace satisfaction rates and desired workplace characteristics. Copyright © 2014 American College of Radiology. Published

Trellis Tone Modulation Multiple-Access for Peer Discovery in D2D Networks

Directory of Open Access Journals (Sweden)

Chiwoo Lim

2018-04-01

Full Text Available In this paper, a new non-orthogonal multiple-access scheme, trellis tone modulation multiple-access (TTMMA, is proposed for peer discovery of distributed device-to-device (D2D communication. The range and capacity of discovery are important performance metrics in peer discovery. The proposed trellis tone modulation uses single-tone transmission and achieves a long discovery range due to its low Peak-to-Average Power Ratio (PAPR. The TTMMA also exploits non-orthogonal resource assignment to increase the discovery capacity. For the multi-user detection of superposed multiple-access signals, a message-passing algorithm with supplementary schemes are proposed. With TTMMA and its message-passing demodulation, approximately 1.5 times the number of devices are discovered compared to the conventional frequency division multiple-access (FDMA-based discovery.

The evolution of the disc variability along the hard state of the black hole transient GX 339-4

Science.gov (United States)

De Marco, B.; Ponti, G.; Muñoz-Darias, T.; Nandra, K.

2015-12-01

We report on the analysis of hard-state power spectral density function (PSD) of GX 339-4 down to the soft X-ray band, where the disc significantly contributes to the total emission. At any luminosity probed, the disc in the hard state is intrinsically more variable than in the soft state. However, the fast decrease of disc variability as a function of luminosity, combined with the increase of disc intensity, causes a net drop of fractional variability at high luminosities and low energies, which reminds the well-known behaviour of disc-dominated energy bands in the soft state. The peak frequency of the high-frequency Lorentzian (likely corresponding to the high-frequency break seen in active galactic nuclei, AGN) scales with luminosity, but we do not find evidence for a linear scaling. In addition, we observe that this characteristic frequency is energy dependent. We find that the normalization of the PSD at the peak of the high-frequency Lorentzian decreases with luminosity at all energies, though in the soft band this trend is steeper. Together with the frequency shift, this yields quasi-constant high-frequency (5-20 Hz) fractional rms at high energies, with less than 10 per cent scatter. This reinforces previous claims suggesting that the high-frequency PSD solely scales with black hole mass. On the other hand, this constancy breaks down in the soft band (where the scatter increases to ˜30 per cent). This is a consequence of the additional contribution from the disc component, and resembles the behaviour of optical variability in AGN.

Combining NMR and X-ray crystallography in fragment-based drug discovery: discovery of highly potent and selective BACE-1 inhibitors.

Science.gov (United States)

Wyss, Daniel F; Wang, Yu-Sen; Eaton, Hugh L; Strickland, Corey; Voigt, Johannes H; Zhu, Zhaoning; Stamford, Andrew W

2012-01-01

Fragment-based drug discovery (FBDD) has become increasingly popular over the last decade. We review here how we have used highly structure-driven fragment-based approaches to complement more traditional lead discovery to tackle high priority targets and those struggling for leads. Combining biomolecular nuclear magnetic resonance (NMR), X-ray crystallography, and molecular modeling with structure-assisted chemistry and innovative biology as an integrated approach for FBDD can solve very difficult problems, as illustrated in this chapter. Here, a successful FBDD campaign is described that has allowed the development of a clinical candidate for BACE-1, a challenging CNS drug target. Crucial to this achievement were the initial identification of a ligand-efficient isothiourea fragment through target-based NMR screening and the determination of its X-ray crystal structure in complex with BACE-1, which revealed an extensive H-bond network with the two active site aspartate residues. This detailed 3D structural information then enabled the design and validation of novel, chemically stable and accessible heterocyclic acylguanidines as aspartic acid protease inhibitor cores. Structure-assisted fragment hit-to-lead optimization yielded iminoheterocyclic BACE-1 inhibitors that possess desirable molecular properties as potential therapeutic agents to test the amyloid hypothesis of Alzheimer's disease in a clinical setting.

Microscale High-Throughput Experimentation as an Enabling Technology in Drug Discovery: Application in the Discovery of (Piperidinyl)pyridinyl-1H-benzimidazole Diacylglycerol Acyltransferase 1 Inhibitors.

Science.gov (United States)

Cernak, Tim; Gesmundo, Nathan J; Dykstra, Kevin; Yu, Yang; Wu, Zhicai; Shi, Zhi-Cai; Vachal, Petr; Sperbeck, Donald; He, Shuwen; Murphy, Beth Ann; Sonatore, Lisa; Williams, Steven; Madeira, Maria; Verras, Andreas; Reiter, Maud; Lee, Claire Heechoon; Cuff, James; Sherer, Edward C; Kuethe, Jeffrey; Goble, Stephen; Perrotto, Nicholas; Pinto, Shirly; Shen, Dong-Ming; Nargund, Ravi; Balkovec, James; DeVita, Robert J; Dreher, Spencer D

2017-05-11

Miniaturization and parallel processing play an important role in the evolution of many technologies. We demonstrate the application of miniaturized high-throughput experimentation methods to resolve synthetic chemistry challenges on the frontlines of a lead optimization effort to develop diacylglycerol acyltransferase (DGAT1) inhibitors. Reactions were performed on ∼1 mg scale using glass microvials providing a miniaturized high-throughput experimentation capability that was used to study a challenging S N Ar reaction. The availability of robust synthetic chemistry conditions discovered in these miniaturized investigations enabled the development of structure-activity relationships that ultimately led to the discovery of soluble, selective, and potent inhibitors of DGAT1.

Fragment-based discovery of potent inhibitors of the anti-apoptotic MCL-1 protein.

Science.gov (United States)

Petros, Andrew M; Swann, Steven L; Song, Danying; Swinger, Kerren; Park, Chang; Zhang, Haichao; Wendt, Michael D; Kunzer, Aaron R; Souers, Andrew J; Sun, Chaohong

2014-03-15

Apoptosis is regulated by the BCL-2 family of proteins, which is comprised of both pro-death and pro-survival members. Evasion of apoptosis is a hallmark of malignant cells. One way in which cancer cells achieve this evasion is thru overexpression of the pro-survival members of the BCL-2 family. Overexpression of MCL-1, a pro-survival protein, has been shown to be a resistance factor for Navitoclax, a potent inhibitor of BCL-2 and BCL-XL. Here we describe the use of fragment screening methods and structural biology to drive the discovery of novel MCL-1 inhibitors from two distinct structural classes. Specifically, cores derived from a biphenyl sulfonamide and salicylic acid were uncovered in an NMR-based fragment screen and elaborated using high throughput analog synthesis. This culminated in the discovery of selective and potent inhibitors of MCL-1 that may serve as promising leads for medicinal chemistry optimization efforts. Copyright © 2014 Elsevier Ltd. All rights reserved.

Fragment Based Strategies for Discovery of Novel HIV-1 Reverse Transcriptase and Integrase Inhibitors.

Science.gov (United States)

Latham, Catherine F; La, Jennifer; Tinetti, Ricky N; Chalmers, David K; Tachedjian, Gilda

2016-01-01

Human immunodeficiency virus (HIV) remains a global health problem. While combined antiretroviral therapy has been successful in controlling the virus in patients, HIV can develop resistance to drugs used for treatment, rendering available drugs less effective and limiting treatment options. Initiatives to find novel drugs for HIV treatment are ongoing, although traditional drug design approaches often focus on known binding sites for inhibition of established drug targets like reverse transcriptase and integrase. These approaches tend towards generating more inhibitors in the same drug classes already used in the clinic. Lack of diversity in antiretroviral drug classes can result in limited treatment options, as cross-resistance can emerge to a whole drug class in patients treated with only one drug from that class. A fresh approach in the search for new HIV-1 drugs is fragment-based drug discovery (FBDD), a validated strategy for drug discovery based on using smaller libraries of low molecular weight molecules (FBDD is aimed at not only finding novel drug scaffolds, but also probing the target protein to find new, often allosteric, inhibitory binding sites. Several fragment-based strategies have been successful in identifying novel inhibitory sites or scaffolds for two proven drug targets for HIV-1, reverse transcriptase and integrase. While any FBDD-generated HIV-1 drugs have yet to enter the clinic, recent FBDD initiatives against these two well-characterised HIV-1 targets have reinvigorated antiretroviral drug discovery and the search for novel classes of HIV-1 drugs.

Discovery of a novel dual fungal CYP51/human 5-lipoxygenase inhibitor: implications for anti-fungal therapy.

Directory of Open Access Journals (Sweden)

Eric K Hoobler

Full Text Available We report the discovery of a novel dual inhibitor targeting fungal sterol 14α-demethylase (CYP51 or Erg11 and human 5-lipoxygenase (5-LOX with improved potency against 5-LOX due to its reduction of the iron center by its phenylenediamine core. A series of potent 5-LOX inhibitors containing a phenylenediamine core, were synthesized that exhibit nanomolar potency and >30-fold selectivity against the LOX paralogs, platelet-type 12-human lipoxygenase, reticulocyte 15-human lipoxygenase type-1, and epithelial 15-human lipoxygenase type-2, and >100-fold selectivity against ovine cyclooxygenase-1 and human cyclooxygnease-2. The phenylenediamine core was then translated into the structure of ketoconazole, a highly effective anti-fungal medication for seborrheic dermatitis, to generate a novel compound, ketaminazole. Ketaminazole was found to be a potent dual inhibitor against human 5-LOX (IC50 = 700 nM and CYP51 (IC50 = 43 nM in vitro. It was tested in whole blood and found to down-regulate LTB4 synthesis, displaying 45% inhibition at 10 µM. In addition, ketaminazole selectively inhibited yeast CYP51 relative to human CYP51 by 17-fold, which is greater selectivity than that of ketoconazole and could confer a therapeutic advantage. This novel dual anti-fungal/anti-inflammatory inhibitor could potentially have therapeutic uses against fungal infections that have an anti-inflammatory component.

Relativistic jets in narrow-line Seyfert 1 galaxies. New discoveries and open questions

Directory of Open Access Journals (Sweden)

D’Ammando F.

2013-12-01

Full Text Available Before the launch of the Fermi satellite only two classes of AGNs were known to produce relativistic jets and thus emit up to the γ-ray energy range: blazars and radio galaxies, both hosted in giant elliptical galaxies. The first four years of observations by the Large Area Telescope on board Fermi confirmed that these two are the most numerous classes of identified sources in the extragalactic γ-ray sky, but the discovery of γ-ray emission from 5 radio-loud narrow-line Seyfert 1 galaxies revealed the presence of a possible emerging third class of AGNs with relativistic jets. Considering that narrow-line Seyfert 1 galaxies seem to be typically hosted in spiral galaxy, this finding poses intriguing questions about the nature of these objects, the onset of production of relativistic jets, and the cosmological evolution of radio-loud AGN. Here, we discuss the radio-to-γ-rays properties of the γ-ray emitting narrow-line Seyfert 1 galaxies, also in comparison with the blazar scenario.

29 CFR 18.13 - Discovery methods.

Science.gov (United States)

2010-07-01

... 29 Labor 1 2010-07-01 2010-07-01 true Discovery methods. 18.13 Section 18.13 Labor Office of the... ADMINISTRATIVE LAW JUDGES General § 18.13 Discovery methods. Parties may obtain discovery by one or more of the following methods: Depositions upon oral examination or written questions; written interrogatories...

Discovery of a phosphor for light emitting diode applications and its structural determination, Ba(Si,Al)5(O,N)8:Eu2+.

Science.gov (United States)

Park, Woon Bae; Singh, Satendra Pal; Sohn, Kee-Sun

2014-02-12

Most of the novel phosphors that appear in the literature are either a variant of well-known materials or a hybrid material consisting of well-known materials. This situation has actually led to intellectual property (IP) complications in industry and several lawsuits have been the result. Therefore, the definition of a novel phosphor for use in light-emitting diodes should be clarified. A recent trend in phosphor-related IP applications has been to focus on the novel crystallographic structure, so that a slight composition variance and/or the hybrid of a well-known material would not qualify from either a scientific or an industrial point of view. In our previous studies, we employed a systematic materials discovery strategy combining heuristics optimization and a high-throughput process to secure the discovery of genuinely novel and brilliant phosphors that would be immediately ready for use in light emitting diodes. Despite such an achievement, this strategy requires further refinement to prove its versatility under any circumstance. To accomplish such demands, we improved our discovery strategy by incorporating an elitism-involved nondominated sorting genetic algorithm (NSGA-II) that would guarantee the discovery of truly novel phosphors in the present investigation. Using the improved discovery strategy, we discovered an Eu(2+)-doped AB5X8 (A = Sr or Ba, B = Si and Al, X = O and N) phosphor in an orthorhombic structure (A21am) with lattice parameters a = 9.48461(3) Å, b = 13.47194(6) Å, c = 5.77323(2) Å, α = β = γ = 90°, which cannot be found in any of the existing inorganic compound databases.

41 CFR 60-30.33 - Discovery.

Science.gov (United States)

2010-07-01

... 41 Public Contracts and Property Management 1 2010-07-01 2010-07-01 true Discovery. 60-30.33... 11246 Expedited Hearing Procedures § 60-30.33 Discovery. (a) Any party may serve requests for admissions... with § 60-30.8, the Administrative Law Judge may allow the taking of depositions. Other discovery will...

Earliest porotic hyperostosis on a 1.5-million-year-old hominin, olduvai gorge, Tanzania.

Directory of Open Access Journals (Sweden)

Manuel Domínguez-Rodrigo

Full Text Available Meat-eating was an important factor affecting early hominin brain expansion, social organization and geographic movement. Stone tool butchery marks on ungulate fossils in several African archaeological assemblages demonstrate a significant level of carnivory by Pleistocene hominins, but the discovery at Olduvai Gorge of a child's pathological cranial fragments indicates that some hominins probably experienced scarcity of animal foods during various stages of their life histories. The child's parietal fragments, excavated from 1.5-million-year-old sediments, show porotic hyperostosis, a pathology associated with anemia. Nutritional deficiencies, including anemia, are most common at weaning, when children lose passive immunity received through their mothers' milk. Our results suggest, alternatively, that (1 the developmentally disruptive potential of weaning reached far beyond sedentary Holocene food-producing societies and into the early Pleistocene, or that (2 a hominin mother's meat-deficient diet negatively altered the nutritional content of her breast milk to the extent that her nursing child ultimately died from malnourishment. Either way, this discovery highlights that by at least 1.5 million years ago early human physiology was already adapted to a diet that included the regular consumption of meat.

The Greatest Mathematical Discovery?

Energy Technology Data Exchange (ETDEWEB)

Bailey, David H.; Borwein, Jonathan M.

2010-05-12

What mathematical discovery more than 1500 years ago: (1) Is one of the greatest, if not the greatest, single discovery in the field of mathematics? (2) Involved three subtle ideas that eluded the greatest minds of antiquity, even geniuses such as Archimedes? (3) Was fiercely resisted in Europe for hundreds of years after its discovery? (4) Even today, in historical treatments of mathematics, is often dismissed with scant mention, or else is ascribed to the wrong source? Answer: Our modern system of positional decimal notation with zero, together with the basic arithmetic computational schemes, which were discovered in India about 500 CE.

ANTI-CORRELATED SOFT LAGS IN THE INTERMEDIATE STATE OF BLACK HOLE SOURCE GX 339-4

International Nuclear Information System (INIS)

Sriram, K.; Choi, C. S.; Rao, A. R.

2010-01-01

We report the few hundred second anti-correlated soft lags between soft and hard energy bands in the source GX 339-4 using RXTE observations. In one observation, anti-correlated soft lags were observed using the ISGRI/INTEGRAL hard energy band and the PCA/RXTE soft energy band light curves. The lags were observed when the source was in hard and soft intermediate states, i.e., in a steep power-law state. We found that the temporal and spectral properties were changed during the lag timescale. The anti-correlated soft lags are associated with spectral variability during which the geometry of the accretion disk is changed. The observed temporal and spectral variations are explained using the framework of truncated disk geometry. We found that during the lag timescale, the centroid frequency of quasi-periodic oscillation is decreased, the soft flux is decreased along with an increase in the hard flux, and the power-law index steepens together with a decrease in the disk normalization parameter. We argue that these changes could be explained if we assume that the hot corona condenses and forms a disk in the inner region of the accretion disk. The overall spectral and temporal changes support the truncated geometry of the accretion disk in the steep power-law state or in the intermediate state.

PENGARUH PENGGUNAAN METODE DISCOVERY BERBASIS MEDIA REALITA TERHADAP HASIL BELAJAR MATAKULIAH KONSEP DASAR IPA 1

Directory of Open Access Journals (Sweden)

Idam Ragil Widianto Atmojo

2015-10-01

Full Text Available This study aims to determine how much influence the use of media-based discovery method's realities of the learning outcomes during the course Basic Concepts IPA 1 when compared to those taught using direct instruction-based Power Point (PPT. This research is a quantitative type of experiment using a quasi-experimental method (Quasi-Experimental Design. Experimental Design. Design research is the Control Group Pre-test Post-test. Populations of this study were all students of PGSD FKIP UNS second semester of academic year 2013/2014. Cluster Random Sampling is used in sampling. The technique of collecting data through observation, documentation, and testing. The data analysis technique used is the prerequisite test data analysis and hypothesis testing. For prerequisite test, including normality test with chip-square method and homogeneity test methods Bartlett. Based on the analysis of t test showed the t count> t table (3.599> 2.001, so that H0 is rejected. Thus there is a positive impact on learning outcomes of the course the basic concepts of science one-second semester students are taught using methods of discovery-based media reality. Conclusions This study is the result of learning the basic concepts of science subject 1 student taught by media-based discovery method's realities better than students taught by direct instruction-based power point. Keywords: discovery, media reality, learning outcomes, basic concepts IPA.

What about Th1/Th2 in cutaneous leishmaniasis vaccine discovery?

Directory of Open Access Journals (Sweden)

Campos-Neto A.

2005-01-01

Full Text Available The T helper cell type 1 (Th1 response is essential to resist leishmaniasis, whereas the Th2 response favors the disease. However, many leishmanial antigens, which stimulate a Th1 immune response during the disease or even after the disease is cured, have been shown to have no protective action. Paradoxically, antigens associated with an early Th2 response have been found to be highly protective if the Th1 response to them is generated before infection. Therefore, finding disease-associated Th2 antigens and inducing a Th1 immune response to them using defined vaccination protocols is an interesting unorthodox alternative approach to the discovery of a leishmania vaccine.

Volatility Discovery

DEFF Research Database (Denmark)

Dias, Gustavo Fruet; Scherrer, Cristina; Papailias, Fotis

The price discovery literature investigates how homogenous securities traded on different markets incorporate information into prices. We take this literature one step further and investigate how these markets contribute to stochastic volatility (volatility discovery). We formally show...... that the realized measures from homogenous securities share a fractional stochastic trend, which is a combination of the price and volatility discovery measures. Furthermore, we show that volatility discovery is associated with the way that market participants process information arrival (market sensitivity......). Finally, we compute volatility discovery for 30 actively traded stocks in the U.S. and report that Nyse and Arca dominate Nasdaq....

SU(5) x U(1) phenomenology: Theorems on neutral-current analysis

International Nuclear Information System (INIS)

Zee, A.; Kim, J.E.

1980-01-01

We embed the SU(5) unified theory of Georgi and Glashow in a U(5) theory. This may result from the breaking of an SU(N), N>5, theory or of a GL(5,c) theory. At low energy this leads to an SU(2) x U(1) x U(1) electroweak theory. We show that, with a suitable choice of Higgs representations, the predictions of this theory for neutral-current experiments are characterized by three parameters. For appropriate values of these parameters, the predictions are practically indistinguishable from the standard SU(2) x U(1) theory. Certain theorems on the analysis of neutral-current interactions are proved. (Section V is independent for readers who are interested only in the theorems.) More accurate neutral-current measurement might answer the question of whether SU(5) x U(1) is relevant. Possible verification of the present electroweak theory can result from (roughly) an order suppression relative to the standard prediction on the asymmetries in e + e - → μ + μ - and discovery of two Z bosons around 90 --100 GeV. GL(n,c) gauge theories are formulated in the Appendix

Discovery of a novel, CNS penetrant M4 PAM chemotype based on a 6-fluoro-4-(piperidin-1-yl)quinoline-3-carbonitrile core.

Science.gov (United States)

Bewley, Blake R; Spearing, Paul K; Weiner, Rebecca L; Luscombe, Vincent B; Zhan, Xiaoyan; Chang, Sichen; Cho, Hyekyung P; Rodriguez, Alice L; Niswender, Colleen M; Conn, P Jeffrey; Bridges, Thomas M; Engers, Darren W; Lindsley, Craig W

2017-09-15

This Letter details the discovery and subsequent optimization of a novel M 4 PAM scaffold based on an 6-fluoro-4-(piperidin-1-yl)quinoline-3-carbonitrile core, which represents a distinct departure from the classical M 4 PAM chemotypes. Optimized compounds in this series demonstrated improved M 4 PAM potency on both human and rat M 4 (4 to 5-fold relative to HTS hit), and displayed attractive physicochemical and DMPK profiles, including good CNS penetration (rat brain:plasma K p =5.3, K p,uu =2.4; MDCK-MDR1 (P-gp) ER=1.1). Copyright © 2017 Elsevier Ltd. All rights reserved.

12 CFR 747.24 - Scope of document discovery.

Science.gov (United States)

2010-01-01

... act of Congress, or the principles of common law provide. (d) Time limits. All discovery, including... 12 Banks and Banking 6 2010-01-01 2010-01-01 false Scope of document discovery. 747.24 Section 747... of Practice and Procedure § 747.24 Scope of document discovery. (a) Limits on discovery. (1) Subject...

Discovery and optimization of adamantyl carbamate inhibitors of 11β-HSD1.

Science.gov (United States)

Tice, Colin M; Zhao, Wei; Krosky, Paula M; Kruk, Barbara A; Berbaum, Jennifer; Johnson, Judith A; Bukhtiyarov, Yuri; Panemangalore, Reshma; Scott, Boyd B; Zhao, Yi; Bruno, Joseph G; Howard, Lamont; Togias, Jennifer; Ye, Yuan-Jie; Singh, Suresh B; McKeever, Brian M; Lindblom, Peter R; Guo, Joan; Guo, Rong; Nar, Herbert; Schuler-Metz, Annette; Gregg, Richard E; Leftheris, Katerina; Harrison, Richard K; McGeehan, Gerard M; Zhuang, Linghang; Claremon, David A

2010-11-15

Synthesis of 2-adamantyl carbamate derivatives of piperidines and pyrrolidines led to the discovery of 9a with an IC(50) of 15.2 nM against human 11β-HSD1 in adipocytes. Optimization for increased adipocyte potency, metabolic stability and selectivity afforded 11k and 11l, both of which were >25% orally bioavailable in rat. Copyright © 2010 Elsevier Ltd. All rights reserved.

7 CFR 1.641 - How may parties obtain discovery of information needed for the case?

Science.gov (United States)

2010-01-01

... 7 Agriculture 1 2010-01-01 2010-01-01 false How may parties obtain discovery of information needed for the case? 1.641 Section 1.641 Agriculture Office of the Secretary of Agriculture ADMINISTRATIVE... legal theories of an attorney. (g) Experts. Unless restricted by the ALJ, a party may discover any facts...

The first long-lived mutants: discovery of the insulin/IGF-1 pathway for ageing

OpenAIRE

Kenyon, Cynthia

2011-01-01

Inhibiting insulin/IGF-1 signalling extends lifespan and delays age-related disease in species throughout the animal kingdom. This life-extension pathway, the first to be defined, was discovered through genetic studies in the small roundworm Caenorhabditis elegans. This discovery is described here.

78 FR 62676 - Anthony E. Wicks, M.D. Decision and Order

Science.gov (United States)

2013-10-22

... registration BW7987184, while listing his address as Pain Management of Winter Springs, 165 W. SR 434, Winter... practice address. Id. at 2, ] 5. \\2\\ Documentary evidence, which the Government acquired through... prescriptions for oxycodone,\\4\\ diazepam, and lorazepam.\\5\\ GX 15, at 2, ] 7; GX 13. \\3\\ The documentary...

DISCOVERY OF Fe Kα X-RAY REVERBERATION AROUND THE BLACK HOLES IN MCG-5-23-16 AND NGC 7314

International Nuclear Information System (INIS)

Zoghbi, A.; Reynolds, C.; Cackett, E. M.; Miniutti, G.; Kara, E.; Fabian, A. C.

2013-01-01

Several X-ray observations have recently revealed the presence of reverberation time delays between spectral components in active galactic nuclei. Most of the observed lags are between the power-law Comptonization component, seen directly, and the soft excess produced by reflection in the vicinity of the black hole. NGC 4151 was the first object to show these lags in the iron K band. Here, we report the discovery of reverberation lags in the Fe K band in two other sources: MCG-5-23-16 and NGC 7314. In both objects, the 6-7 keV band, where the Fe Kα line peaks, lags the bands at lower and higher energies with a time delay of ∼1 ks. These lags are unlikely to be due to the narrow Fe Kα line. They are fully consistent with reverberation of the relativistically broadened iron Kα line. The measured lags, their time scale, and spectral modeling indicate that most of the radiation is emitted at ∼5 and 24 gravitational radii for MCG-5-23-16 and NGC 7314, respectively.

NuSTAR and XMM-Newton Observations of the 2015 Outburst Decay of GX 339-4

Energy Technology Data Exchange (ETDEWEB)

Stiele, H.; Kong, A. K. H., E-mail: hstiele@mx.nthu.edu.tw [National Tsing Hua University, Department of Physics and Institute of Astronomy, No. 101 Sect. 2 Kuang-Fu Road, 30013, Hsinchu, Taiwan (China)

2017-07-20

The extent of the accretion disk in the low/hard state of stellar mass black hole X-ray binaries remains an open question. There is some evidence suggesting that the inner accretion disk is truncated and replaced by a hot flow, while the detection of relativistic broadened iron emission lines seems to require an accretion disk extending fully to the innermost stable circular orbit. We present comprehensive spectral and timing analyses of six Nuclear Spectroscopic Telescope Array and XMM-Newton observations of GX 339–4 taken during outburst decay in the autumn of 2015. Using a spectral model consisting of a thermal accretion disk, Comptonized emission, and a relativistic reflection component, we obtain a decreasing photon index, consistent with an X-ray binary during outburst decay. Although we observe a discrepancy in the inner radius of the accretion disk and that of the reflector, which can be attributed to the different underlying assumptions in each model, both model components indicate a truncated accretion disk that resiles with decreasing luminosity. The evolution of the characteristic frequency in Fourier power spectra and their missing energy dependence support the interpretation of a truncated and evolving disk in the hard state. The XMM-Newton data set allowed us to study, for the first time, the evolution of the covariance spectra and ratio during outburst decay. The covariance ratio increases and steeps during outburst decay, consistent with increased disk instabilities.

Discovery of novel dengue virus NS5 methyltransferase non-nucleoside inhibitors by fragment-based drug design.

Science.gov (United States)

Benmansour, Fatiha; Trist, Iuni; Coutard, Bruno; Decroly, Etienne; Querat, Gilles; Brancale, Andrea; Barral, Karine

2017-01-05

With the aim to help drug discovery against dengue virus (DENV), a fragment-based drug design approach was applied to identify ligands targeting a main component of DENV replication complex: the NS5 AdoMet-dependent mRNA methyltransferase (MTase) domain, playing an essential role in the RNA capping process. Herein, we describe the identification of new inhibitors developed using fragment-based, structure-guided linking and optimization techniques. Thermal-shift assay followed by a fragment-based X-ray crystallographic screening lead to the identification of three fragment hits binding DENV MTase. We considered linking two of them, which bind to proximal sites of the AdoMet binding pocket, in order to improve their potency. X-ray crystallographic structures and computational docking were used to guide the fragment linking, ultimately leading to novel series of non-nucleoside inhibitors of flavivirus MTase, respectively N-phenyl-[(phenylcarbamoyl)amino]benzene-1-sulfonamide and phenyl [(phenylcarbamoyl)amino]benzene-1-sulfonate derivatives, that show a 10-100-fold stronger inhibition of 2'-O-MTase activity compared to the initial fragments. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Discovery of the young L dwarf wise J174102.78-464225.5

International Nuclear Information System (INIS)

Schneider, Adam C.; Cushing, Michael C.; Kirkpatrick, J. Davy; Mace, Gregory N.; Gelino, Christopher R.; Fajardo-Acosta, Sergio; Faherty, Jacqueline K.; Sheppard, Scott S.

2014-01-01

We report the discovery of the L dwarf WISE J174102.78–464225.5, which was discovered as part of a search for nearby L dwarfs using the Wide-field Infrared Survey Explorer (WISE). The distinct triangular peak of the H-band portion of its near-infrared spectrum and its red near-infrared colors (J – K S = 2.35 ± 0.08 mag) are indicative of a young age. Via comparison to spectral standards and other red L dwarfs, we estimate a near-infrared spectral type of L7 ± 2 (pec). From a comparison to spectral and low-mass evolutionary models, we determine self-consistent effective temperature, log g, age, and mass values of 1450 ± 100 K, 4.0 ± 0.25 (cm s –2 ), 10-100 Myr, and 4-21 M Jup , respectively. With an estimated distance of 10-30 pc, we explore the possibility that WISE J174102.78–464225.5 belongs to one of the young nearby moving groups via a kinematic analysis and we find potential membership in the β Pictoris or AB Doradus associations. A trigonometric parallax measurement and a precise radial velocity can help to secure its membership in either of these groups.

Full-length genome sequence analysis of four subgroup J avian leukosis virus strains isolated from chickens with clinical hemangioma.

Science.gov (United States)

Lin, Lulu; Wang, Peikun; Yang, Yongli; Li, Haijuan; Huang, Teng; Wei, Ping

2017-12-01

Since 2014, cases of hemangioma associated with avian leukosis virus subgroup J (ALV-J) have been emerging in commercial chickens in Guangxi. In this study, four strains of the subgroup J avian leukosis virus (ALV-J), named GX14HG01, GX14HG04, GX14LT07, and GX14ZS14, were isolated from chickens with clinical hemangioma in 2014 by DF-1 cell culture and then identified with ELISA detection of ALV group specific antigen p27, the detection of subtype specific PCR and indirect immunofluorescence assay (IFA) with ALV-J specific monoclonal antibody. The complete genomes of the isolates were sequenced and it was found that the gag and pol were relatively conservative, while env was variable especially the gp85 gene. Homology analysis of the env gene sequences showed that the env gene of all the four isolates had higher similarities with the hemangioma (HE)-type reference strains than that of the myeloid leukosis (ML)-type strains, and moreover, the HE-type strains' specific deletion of 205-bp sequence covering the rTM and DR1 in 3'UTR fragment was also found in the four isolates. Further analysis on the sequences of subunits of env gene revealed an interesting finding: the gp85 of isolates GX14ZS14 and GX14HG04 had a higher similarity with HPRS-103 and much lower similarity with the HE-type reference strains resulting in GX14ZS14, GX14HG04, and HPRS-103 being clustered in the same branch, while gp37 had higher similarities with the HE-type reference strains when compared to that of HPRS-103, resulted in GX14ZS14, GX14HG04, and HE-type reference strains being clustered in the same branch. The results suggested that isolates GX14ZS14 and GX14HG04 may be the recombinant strains of the foreign strain HPRS-103 with the local epidemic HE-type strains of ALV-J.

A SEARCH FOR L/T TRANSITION DWARFS WITH PAN-STARRS1 AND WISE. II. L/T TRANSITION ATMOSPHERES AND YOUNG DISCOVERIES

International Nuclear Information System (INIS)

Best, William M. J.; Liu, Michael C.; Magnier, Eugene A.; Aller, Kimberly M.; Chambers, K. C.; Flewelling, H.; Hodapp, K. W.; Kaiser, N.; Tonry, J. L.; Wainscoat, R. J.; Waters, C.; Deacon, Niall R.; Redstone, Joshua; Burgett, W. S.; Draper, P.; Metcalfe, N.

2015-01-01

The evolution of brown dwarfs from L to T spectral types is one of the least understood aspects of the ultracool population, partly for lack of a large, well-defined, and well-characterized sample in the L/T transition. To improve the existing census, we have searched ≈28,000 deg 2 using the Pan-STARRS1 and Wide-field Infrared Survey Explorer surveys for L/T transition dwarfs within 25 pc. We present 130 ultracool dwarf discoveries with estimated distances ≈9–130 pc, including 21 that were independently discovered by other authors and 3 that were previously identified as photometric candidates. Seventy-nine of our objects have near-IR spectral types of L6–T4.5, the most L/T transition dwarfs from any search to date, and we have increased the census of L9–T1.5 objects within 25 pc by over 50%. The color distribution of our discoveries provides further evidence for the “L/T gap,” a deficit of objects with (J − K) MKO  ≈ 0.0–0.5 mag in the L/T transition, and thus reinforces the idea that the transition from cloudy to clear photospheres occurs rapidly. Among our discoveries are 31 candidate binaries based on their low-resolution spectral features. Two of these candidates are common proper motion companions to nearby main sequence stars; if confirmed as binaries, these would be rare benchmark systems with the potential to stringently test ultracool evolutionary models. Our search also serendipitously identified 23 late-M and L dwarfs with spectroscopic signs of low gravity implying youth, including 10 with vl-g or int-g gravity classifications and another 13 with indications of low gravity whose spectral types or modest spectral signal-to-noise ratio do not allow us to assign formal classifications. Finally, we identify 10 candidate members of nearby young moving groups (YMG) with spectral types L7–T4.5, including three showing spectroscopic signs of low gravity. If confirmed, any of these would be among the coolest known YMG members and would

Can Full Duplex reduce the discovery time in D2D Communication?

DEFF Research Database (Denmark)

Gatnau, Marta; Berardinelli, Gilberto; Mahmood, Nurul Huda

2016-01-01

Device-to-device (D2D) communication is considered as one of the key technologies to support new types of services, such as public safety and proximity-based applications. D2D communication requires a discovery phase, i.e., the node awareness procedure prior to the communication phase. Conventional...... half duplex transmission may not be sufficient to provide fast discovery and cope with the strict latency targets of future 5G services. On the other hand, in-band full duplex, by allowing simultaneous transmission and reception, may complete the discovery phase faster. In this paper, the potential...... of full duplex in providing fast discovery for the next 5th generation (5G) system supporting D2D communication is investigated. A design for such system is presented and evaluated via simulations, showing that full duplex can accelerate the discovery phase by supporting a higher transmission probability...

Discovery of burst oscillations in the intermittent accretion-powered millisecond pulsar HETE J1900.1-2455

NARCIS (Netherlands)

Watts, A.L.; Altamirano, D.; Linares, M.; Patruno, A.; Casella, P.; Cavecchi, Y.; Degenaar, N.; Rea, N.; Soleri, P.; van der Klis, M.; Wijnands, R.

2009-01-01

We report the discovery of burst oscillations from the intermittent accretion-powered millisecond pulsar (AMP) HETE J1900.1-2455, with a frequency ~1 Hz below the known spin frequency. The burst oscillation properties are far more similar to those of the non-AMPs and Aql X-1 (an intermittent AMP

DISCOVERY OF Fe K{alpha} X-RAY REVERBERATION AROUND THE BLACK HOLES IN MCG-5-23-16 AND NGC 7314

Energy Technology Data Exchange (ETDEWEB)

Zoghbi, A.; Reynolds, C. [Department of Astronomy, University of Maryland, College Park, MD 20742-2421 (United States); Cackett, E. M. [Department of Physics and Astronomy, Wayne State University, 666 W. Hancock St, Detroit, MI 48201 (United States); Miniutti, G. [Centro de Astrobiologia (CSIC-INTA), Dep. de Astrosica, P.O. Box 78, E-28691 Villanueva de la Canada, Madrid (Spain); Kara, E.; Fabian, A. C., E-mail: azoghbi@astro.umd.edu [Institute of Astronomy, Madingley Road, Cambridge CB3 0HA (United Kingdom)

2013-04-20

Several X-ray observations have recently revealed the presence of reverberation time delays between spectral components in active galactic nuclei. Most of the observed lags are between the power-law Comptonization component, seen directly, and the soft excess produced by reflection in the vicinity of the black hole. NGC 4151 was the first object to show these lags in the iron K band. Here, we report the discovery of reverberation lags in the Fe K band in two other sources: MCG-5-23-16 and NGC 7314. In both objects, the 6-7 keV band, where the Fe K{alpha} line peaks, lags the bands at lower and higher energies with a time delay of {approx}1 ks. These lags are unlikely to be due to the narrow Fe K{alpha} line. They are fully consistent with reverberation of the relativistically broadened iron K{alpha} line. The measured lags, their time scale, and spectral modeling indicate that most of the radiation is emitted at {approx}5 and 24 gravitational radii for MCG-5-23-16 and NGC 7314, respectively.

Establishing MALDI-TOF as Versatile Drug Discovery Readout to Dissect the PTP1B Enzymatic Reaction.

Science.gov (United States)

Winter, Martin; Bretschneider, Tom; Kleiner, Carola; Ries, Robert; Hehn, Jörg P; Redemann, Norbert; Luippold, Andreas H; Bischoff, Daniel; Büttner, Frank H

2018-07-01

Label-free, mass spectrometric (MS) detection is an emerging technology in the field of drug discovery. Unbiased deciphering of enzymatic reactions is a proficient advantage over conventional label-based readouts suffering from compound interference and intricate generation of tailored signal mediators. Significant evolvements of matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) MS, as well as associated liquid handling instrumentation, triggered extensive efforts in the drug discovery community to integrate the comprehensive MS readout into the high-throughput screening (HTS) portfolio. Providing speed, sensitivity, and accuracy comparable to those of conventional, label-based readouts, combined with merits of MS-based technologies, such as label-free parallelized measurement of multiple physiological components, emphasizes the advantages of MALDI-TOF for HTS approaches. Here we describe the assay development for the identification of protein tyrosine phosphatase 1B (PTP1B) inhibitors. In the context of this precious drug target, MALDI-TOF was integrated into the HTS environment and cross-compared with the well-established AlphaScreen technology. We demonstrate robust and accurate IC 50 determination with high accordance to data generated by AlphaScreen. Additionally, a tailored MALDI-TOF assay was developed to monitor compound-dependent, irreversible modification of the active cysteine of PTP1B. Overall, the presented data proves the promising perspective for the integration of MALDI-TOF into drug discovery campaigns.

Sensitivity and Discovery Potential of CUORE to Neutrinoless Double-Beta Decay

Energy Technology Data Exchange (ETDEWEB)

Alessandria, F; Ardito, R; Artusa, DR; III, FTA; Azzolini, O; Balata, M; Banks, TI; Bari, G; Beeman, J; Bellini, F; Bersani, A; Biassoni, M; Bloxham, T; Brofferio, C; Bucci, C; Cai, XZ; Canonica, L; Cao, X; Capelli, S; Carbone, L; Cardani, L; Carrettoni, M; Casali, N; Chiesa, D; Chott, N; Clemenza, M; Cosmelli, C; Cremonesi, O; Creswick, RJ; Dafinei, I; Dally, A; Datskov, V; Biasi, AD; Deninno, MM; Domizio, SD; Vacri, MLD; Ejzak, L; Faccini, R; Fang, DQ; Farach, HA; Faverzani, M; Fernandes, G; Ferri, E; Ferroni, F; Fiorini, E; Franceschi, MA; Freedman, SJ; Fujikawa, BK; Giachero, A; Gironi, L; Giuliani, A; Goett, J; Gorla, P; Gotti, C; Guardincerri, E; Gutierrez, TD; Haller, EE; Han, K; Heeger, KM; Huang, HZ; Kadel, R; Kazkaz, K; Keppel, G; Kogler, L; Kolomensky, YG; Lenz, D; Li, YL; Ligi, C; Liu, X; Ma, YG; Maiano, C; Maino, M; Martinez, M; Maruyama, RH; Mei, Y; Moggi, N; Morganti, S; Napolitano, T; Newman, S; Nisi, S; Nones, C; Norman, EB; Nucciotti, A; O' Donnell, T; Orio, F; Orlandi, D; Ouellet, JL; Pallavicini, M; Palmieri, V; Pattavina, L; Pavan, M; Pedretti, M; Pessina, G; Piperno, G; Pirro, S; Previtali, E; Rampazzo, V; Rimondi, F; Rosenfeld, C; Rusconi, C; Sala, E; Sangiorgio, S; Scielzo, ND; Sisti, M; Smith, AR; Stivanello, F; Taffarello, L; Tenconi, M; Tian, WD; Tomei, C; Trentalange, S; Ventura, G; Vignati, M; Wang, BS; Wang, HW; Wise, T; Woodcraft, A; Zanotti, L; Zarra, C; Zhu, BX; Zucchelli, S

2017-07-06

We present a study of the sensitivity and discovery potential of CUORE, a bolometric double-beta decay experiment under construction at the Laboratori Nazionali del Gran Sasso in Italy. Two approaches to the computation of experimental sensitivity for various background scenarios are presented, and an extension of the sensitivity formulation to the discovery potential case is also discussed. Assuming a background rate of 10^-2 cts/(keV kg y), we find that, after 5 years of live time, CUORE has a 1 sigma sensitivity to the neutrinoless double-beta decay half-life of T$0v\\atop{1/2}$(1θ) = 1.6 \\times 10²⁶ y and thus a potential to probe the effective Majorana neutrino mass down to 40-100 meV; the sensitivity at 1.64 sigma, which corresponds to 90% C.L., will be T$0v\\atop{1/2}$(1.64θ) = 9.5 \\times 10²⁵ y. This range is compared with the claim of observation of neutrinoless double-beta decay in ⁷⁶Ge and the preferred range of the neutrino mass parameter space from oscillation results.

Topology Discovery Using Cisco Discovery Protocol

OpenAIRE

Rodriguez, Sergio R.

2009-01-01

In this paper we address the problem of discovering network topology in proprietary networks. Namely, we investigate topology discovery in Cisco-based networks. Cisco devices run Cisco Discovery Protocol (CDP) which holds information about these devices. We first compare properties of topologies that can be obtained from networks deploying CDP versus Spanning Tree Protocol (STP) and Management Information Base (MIB) Forwarding Database (FDB). Then we describe a method of discovering topology ...

Characterization of the Infrared/X-ray sub-second variability for the black-hole transient GX 339-4

Science.gov (United States)

Vincentelli, F. M.; Casella, P.; Maccarone, T. J.; Uttley, P.; Gandhi, P.; Belloni, T.; De Marco, B.; Russell, D. M.; Stella, L.; O'Brien, K.

2018-03-01

We present a detailed analysis of the X-ray/IR fast variability of the Black-Hole Transient GX 339-4 during its low/hard state in August 2008. Thanks to simultaneous high time-resolution observations made with the VLT and RXTE, we performed the first characterisation of the sub-second variability in the near-infrared band - and of its correlation with the X-rays - for a low-mass X-ray binary, using both time- and frequency-domain techniques. We found a power-law correlation between the X-ray and infrared fluxes when measured on timescales of 16 seconds, with a marginally variable slope, steeper than the one found on timescales of days at similar flux levels. We suggest the variable slope - if confirmed - could be due to the infrared flux being a non-constant combination of both optically thin and optically thick synchrotron emission from the jet, as a result of a variable self-absorption break. From cross spectral analysis we found an approximately constant infrared time lag of ≈0.1s, and a very high coherence of ˜90 per cent on timescales of tens of seconds, slowly decreasing toward higher frequencies. Finally, we report on the first detection of a linear rms-flux relation in the emission from a low-mass X-ray binary jet, on timescales where little correlation is found between the X-rays and the jet emission itself. This suggests that either the inflow variations and jet IR emission are coupled by a non-linear or time-variable transform, or that the IR rms-flux relation is not transferred from the inflow to the jet, but is an intrinsic property of emission processes in the jet.

Big Bang Day: 5 Particles - 1. The Electron

CERN Multimedia

Simon Singh

2008-01-01

Simon Singh looks at the stories behind the discovery of 5 of the universe's most significant subatomic particles: the Electron, the Quark, the Anti-particle, the Neutrino and the "next particle". 1. The Electron Just over a century ago, British physicist J.J. Thompson experimenting with electric currents and charged particles inside empty glass tubes, showed that atoms are divisible into indivisible elementary particles. But how could atoms be built up of these so called "corpuscles"? An exciting 30 year race ensued, to grasp the planetary model of the atom with its orbiting electrons, and the view inside the atom was born. Whilst the number of electrons around the nucleus of an atom determines their the chemistry of all elements, the power of electrons themselves have been harnessed for everyday use: electron beams for welding,cathode ray tubes and radiation therapy.

A Sensitive Assay for Virus Discovery in Respiratory Clinical Samples

Science.gov (United States)

de Vries, Michel; Deijs, Martin; Canuti, Marta; van Schaik, Barbera D. C.; Faria, Nuno R.; van de Garde, Martijn D. B.; Jachimowski, Loes C. M.; Jebbink, Maarten F.; Jakobs, Marja; Luyf, Angela C. M.; Coenjaerts, Frank E. J.; Claas, Eric C. J.; Molenkamp, Richard; Koekkoek, Sylvie M.; Lammens, Christine; Leus, Frank; Goossens, Herman; Ieven, Margareta; Baas, Frank; van der Hoek, Lia

2011-01-01

In 5–40% of respiratory infections in children, the diagnostics remain negative, suggesting that the patients might be infected with a yet unknown pathogen. Virus discovery cDNA-AFLP (VIDISCA) is a virus discovery method based on recognition of restriction enzyme cleavage sites, ligation of adaptors and subsequent amplification by PCR. However, direct discovery of unknown pathogens in nasopharyngeal swabs is difficult due to the high concentration of ribosomal RNA (rRNA) that acts as competitor. In the current study we optimized VIDISCA by adjusting the reverse transcription enzymes and decreasing rRNA amplification in the reverse transcription, using hexamer oligonucleotides that do not anneal to rRNA. Residual cDNA synthesis on rRNA templates was further reduced with oligonucleotides that anneal to rRNA but can not be extended due to 3′-dideoxy-C6-modification. With these modifications >90% reduction of rRNA amplification was established. Further improvement of the VIDISCA sensitivity was obtained by high throughput sequencing (VIDISCA-454). Eighteen nasopharyngeal swabs were analysed, all containing known respiratory viruses. We could identify the proper virus in the majority of samples tested (11/18). The median load in the VIDISCA-454 positive samples was 7.2 E5 viral genome copies/ml (ranging from 1.4 E3–7.7 E6). Our results show that optimization of VIDISCA and subsequent high-throughput-sequencing enhances sensitivity drastically and provides the opportunity to perform virus discovery directly in patient material. PMID:21283679

A sensitive assay for virus discovery in respiratory clinical samples.

Directory of Open Access Journals (Sweden)

Michel de Vries

Full Text Available In 5-40% of respiratory infections in children, the diagnostics remain negative, suggesting that the patients might be infected with a yet unknown pathogen. Virus discovery cDNA-AFLP (VIDISCA is a virus discovery method based on recognition of restriction enzyme cleavage sites, ligation of adaptors and subsequent amplification by PCR. However, direct discovery of unknown pathogens in nasopharyngeal swabs is difficult due to the high concentration of ribosomal RNA (rRNA that acts as competitor. In the current study we optimized VIDISCA by adjusting the reverse transcription enzymes and decreasing rRNA amplification in the reverse transcription, using hexamer oligonucleotides that do not anneal to rRNA. Residual cDNA synthesis on rRNA templates was further reduced with oligonucleotides that anneal to rRNA but can not be extended due to 3'-dideoxy-C6-modification. With these modifications >90% reduction of rRNA amplification was established. Further improvement of the VIDISCA sensitivity was obtained by high throughput sequencing (VIDISCA-454. Eighteen nasopharyngeal swabs were analysed, all containing known respiratory viruses. We could identify the proper virus in the majority of samples tested (11/18. The median load in the VIDISCA-454 positive samples was 7.2 E5 viral genome copies/ml (ranging from 1.4 E3-7.7 E6. Our results show that optimization of VIDISCA and subsequent high-throughput-sequencing enhances sensitivity drastically and provides the opportunity to perform virus discovery directly in patient material.

Overcoming HERG affinity in the discovery of the CCR5 antagonist maraviroc.

Science.gov (United States)

Price, David A; Armour, Duncan; de Groot, Marcel; Leishman, Derek; Napier, Carolyn; Perros, Manos; Stammen, Blanda L; Wood, Anthony

2006-09-01

The discovery of maraviroc 17 is described with particular reference to the generation of high selectivity over affinity for the HERG potassium channel. This was achieved through the use of a high throughput binding assay for the HERG channel that is known to show an excellent correlation with functional effects.

Discovery of Five Probable Novae in M81

Science.gov (United States)

Hornoch, K.; Errmann, R.; Sowicka, P.; Humphries, N.; Vaduvescu, O.

2015-10-01

We report the discovery of five probable novae in M81 on a co-added 2000-s narrow-band H-alpha CCD image taken with the 2.5-m Isaac Newton Telescope (INT) + WFC at La Palma under ~1.5" seeing on 2015 Oct. 14.198 UT. The new objects are well visible on the co-added image (see the finding charts linked below), but are not present on numerous narrow-band H-alpha archival images from the INT down to limiting magnitude as faint as H-alpha = 22.3.

The discovery of the most distant known type Ia supernova at redshift 1.914

DEFF Research Database (Denmark)

Jones, Dennis; Rodney, S.A.; Riess, A.G.

2013-01-01

We present the discovery of a Type Ia supernova (SN) at redshift z = 1.914 from the CANDELS multi-cycle treasury program on the Hubble Space Telescope (HST). This SN was discovered in the infrared using the Wide-Field Camera 3, and it is the highest-redshift Type Ia SN yet observed. We classify t...

Performance measurements for the PET/CT Discovery-600 using NEMA NU 2-2007 standards

International Nuclear Information System (INIS)

De Ponti, E.; Morzenti, S.; Guerra, L.; Pasquali, C.; Arosio, M.; Bettinardi, V.; Crespi, A.; Gilardi, M. C.; Messa, C.

2011-01-01

Purpose: The aim of this study was to assess the performance measurements of the new PET/CT system Discovery-600 (D-600, GEMS, Milwaukee, WI). Methods: Performance measures were obtained with the National Electrical Manufacturers Association (NEMA) NU 2-2007 procedures. Results: The transverse (axial) spatial resolution FWHMs were 4.9 (5.6) mm and 5.6 (6.4) mm at 1 and 10 cm off axis, respectively. The sensitivity (average at 0 and 10 cm) was 9.6 cps/kBq. The scatter fraction was 36.6% (low energy threshold: 425 keV). The NEC peak rate (k=1) was 75.2 kcps at 12.9 kBq/cc. The hot contrasts for 10, 13, 17, and 22 mm spheres were 41%, 51%, 62%, and 73% and the cold contrasts for 28 and 37 mm spheres were 68% and 72%. Conclusions: The Discovery-600 has good performance for the NEMA NU 2-2007 parameters, particularly in improved sensitivity compared to the scanners of the same Discovery family, D-ST and D-STE.

RRS "Discovery" Cruise D279, 04 Apr - 10 May 2004. A Transatlantic hydrography section at 24.5N

OpenAIRE

Cunningham, S.A.

2005-01-01

The cruise report describes the acquisition and processing of transatlantic hydrographic, velocity, chemistry and other measurements made during three cruises in Spring 2004 at 24.5°N. Measurements were made from shallow water near Africa to shallow water just off Palm Springs beach on the eastern seaboard of the USA. During the principal cruise, RRS Discovery Cruise D279 (4 April to 10 May 2004), 125 full depth CTD and lowered acoustic Doppler current profiler (LADP) stations were complete...

Design, synthesis, and biological activity of 5'-phenyl-1,2,5,6-tetrahydro-3,3'-bipyridine analogues as potential antagonists of nicotinic acetylcholine receptors.

Science.gov (United States)

Jin, Yafei; Huang, Xiaoqin; Papke, Roger L; Jutkiewicz, Emily M; Showalter, Hollis D; Zhan, Chang-Guo

2017-09-15

Starting from a known non-specific agonist (1) of nicotinic acetylcholine receptors (nAChRs), rationally guided structural-based design resulted in the discovery of a small series of 5'-phenyl-1,2,5,6-tetrahydro-3,3'-bipyridines (3a-3e) incorporating a phenyl ring off the pyridine core of 1. The compounds were synthesized via successive Suzuki couplings on a suitably functionalized pyridine starting monomer 4 to append phenyl and pyridyl substituents off the 3- and 5-positions, respectively, and then subsequent modifications were made on the flanking pyridyl ring to provide target compounds. Compound 3a is a novel antagonist, which is highly selective for α3β4 nAChR (K i =123nM) over the α4β2 and α7 receptors. Copyright © 2017 Elsevier Ltd. All rights reserved.

14 CFR 406.143 - Discovery.

Science.gov (United States)

2010-01-01

... 14 Aeronautics and Space 4 2010-01-01 2010-01-01 false Discovery. 406.143 Section 406.143... Transportation Adjudications § 406.143 Discovery. (a) Initiation of discovery. Any party may initiate discovery... after a complaint has been filed. (b) Methods of discovery. The following methods of discovery are...

2011 HM102: DISCOVERY OF A HIGH-INCLINATION L5 NEPTUNE TROJAN IN THE SEARCH FOR A POST-PLUTO NEW HORIZONS TARGET

International Nuclear Information System (INIS)

Parker, Alex H.; Holman, Matthew J.; McLeod, Brian A.; Buie, Marc W.; Borncamp, David M.; Spencer, John R.; Stern, S. Alan; Osip, David J.; Gwyn, Stephen D. J.; Fabbro, Sébastian; Kavelaars, J. J.; Benecchi, Susan D.; Sheppard, Scott S.; Binzel, Richard P.; DeMeo, Francesca E.; Fuentes, Cesar I.; Trilling, David E.; Gay, Pamela L.; Petit, Jean-Marc; Tholen, David J.

2013-01-01

We present the discovery of a long-term stable L5 (trailing) Neptune Trojan in data acquired to search for candidate trans-Neptunian objects for the New Horizons spacecraft to fly by during an extended post-Pluto mission. This Neptune Trojan, 2011 HM 102 , has the highest inclination (29.°4) of any known member of this population. It is intrinsically brighter than any single L5 Jupiter Trojan at H V ∼ 8.18. We have determined its gri colors (a first for any L5 Neptune Trojan), which we find to be similar to the moderately red colors of the L4 Neptune Trojans, suggesting similar surface properties for members of both Trojan clouds. We also present colors derived from archival data for two L4 Neptune Trojans (2006 RJ 103 and 2007 VL 305 ), better refining the overall color distribution of the population. In this document we describe the discovery circumstances, our physical characterization of 2011 HM 102 , and this object's implications for the Neptune Trojan population overall. Finally, we discuss the prospects for detecting 2011 HM 102 from the New Horizons spacecraft during its close approach in mid- to late-2013.

Higgs Discovery

DEFF Research Database (Denmark)

Sannino, Francesco

2013-01-01

has been challenged by the discovery of a not-so-heavy Higgs-like state. I will therefore review the recent discovery \\cite{Foadi:2012bb} that the standard model top-induced radiative corrections naturally reduce the intrinsic non-perturbative mass of the composite Higgs state towards the desired...... via first principle lattice simulations with encouraging results. The new findings show that the recent naive claims made about new strong dynamics at the electroweak scale being disfavoured by the discovery of a not-so-heavy composite Higgs are unwarranted. I will then introduce the more speculative......I discuss the impact of the discovery of a Higgs-like state on composite dynamics starting by critically examining the reasons in favour of either an elementary or composite nature of this state. Accepting the standard model interpretation I re-address the standard model vacuum stability within...

[Determination of lidocaine and its metabolites in human plasma by liquid chromatography in combination with tandem mass spectrometry].

Science.gov (United States)

Xiang, Jin; Zhang, Cheng; Yu, Qin; Liang, Mao-Zhi; Qin, Yong-Ping; Nan, Feng

2010-07-01

To establish a liquid chromatography tandem mass spectrometry (HPLC-MS/MS) method for the determination of lidocaine (LDC) and its metabolites, monoethylglycinexylidide (MEGX) and glycinexylidide (GX), in human plasma. METHODS; The assay was conducted with an API 3000 HPLC-MS/MS system consisted of a Ultimate C18 column (50 x 4.6 mm, 5 microm). The mobile phase consisted of methanol: 5 mmol/ L ammonium acetate (50:50, pH was adjusted to 5.0 by formic acid) and the flow rate was set at 0.2 mL/min. The alkalinized sample was extracted with ethyl acetate. After evaporation of the organic layer, the residue was dissolved in mobile phase and the drug was determined by HPLC-MS/MS using electrospray ionization. The calibration curve was linear in a range from 15.625 to 2000 ng/mL for LDC. Linear calibration curves were obtained in the range of 1.5625 to 200 ng/mL for both for MEGX and GX. The limit of quantification for LDC, MEGX and GX was set at 15.625, 1.5625 and 1.5625 ng/mL. This method for the quantitative determination of lidocaine and its metabolites in human plasma is simple, rapid, sensitive and accurate. Therefore it can be used for the determination of lidocaine and its metabolites in clinical practice.

A "genome-to-lead" approach for insecticide discovery: pharmacological characterization and screening of Aedes aegypti D(1-like dopamine receptors.

Directory of Open Access Journals (Sweden)

Jason M Meyer

2012-01-01

Full Text Available BACKGROUND: Many neglected tropical infectious diseases affecting humans are transmitted by arthropods such as mosquitoes and ticks. New mode-of-action chemistries are urgently sought to enhance vector management practices in countries where arthropod-borne diseases are endemic, especially where vector populations have acquired widespread resistance to insecticides. METHODOLOGY/PRINCIPAL FINDINGS: We describe a "genome-to-lead" approach for insecticide discovery that incorporates the first reported chemical screen of a G protein-coupled receptor (GPCR mined from a mosquito genome. A combination of molecular and pharmacological studies was used to functionally characterize two dopamine receptors (AaDOP1 and AaDOP2 from the yellow fever mosquito, Aedes aegypti. Sequence analyses indicated that these receptors are orthologous to arthropod D(1-like (Gα(s-coupled receptors, but share less than 55% amino acid identity in conserved domains with mammalian dopamine receptors. Heterologous expression of AaDOP1 and AaDOP2 in HEK293 cells revealed dose-dependent responses to dopamine (EC(50: AaDOP1 = 3.1±1.1 nM; AaDOP2 = 240±16 nM. Interestingly, only AaDOP1 exhibited sensitivity to epinephrine (EC(50 = 5.8±1.5 nM and norepinephrine (EC(50 = 760±180 nM, while neither receptor was activated by other biogenic amines tested. Differential responses were observed between these receptors regarding their sensitivity to dopamine agonists and antagonists, level of maximal stimulation, and constitutive activity. Subsequently, a chemical library screen was implemented to discover lead chemistries active at AaDOP2. Fifty-one compounds were identified as "hits," and follow-up validation assays confirmed the antagonistic effect of selected compounds at AaDOP2. In vitro comparison studies between AaDOP2 and the human D(1 dopamine receptor (hD(1 revealed markedly different pharmacological profiles and identified amitriptyline and doxepin as AaDOP2

Discovery of TUG-770

DEFF Research Database (Denmark)

Christiansen, Elisabeth; Hansen, Steffen V F; Urban, Christian

2013-01-01

Free fatty acid receptor 1 (FFA1 or GPR40) enhances glucose-stimulated insulin secretion from pancreatic β-cells and currently attracts high interest as a new target for the treatment of type 2 diabetes. We here report the discovery of a highly potent FFA1 agonist with favorable physicochemical...

Animal models of gene-environment interaction in schizophrenia: a dimensional perspective

Science.gov (United States)

Ayhan, Yavuz; McFarland, Ross; Pletnikov, Mikhail V.

2015-01-01

Schizophrenia has long been considered as a disorder with multifactorial origins. Recent discoveries have advanced our understanding of the genetic architecture of the disease. However, even with the increase of identified risk variants, heritability estimates suggest an important contribution of non-genetic factors. Various environmental risk factors have been proposed to play a role in the etiopathogenesis of schizophrenia. These include season of birth, maternal infections, obstetric complications, adverse events at early childhood, and drug abuse. Despite the progress in identification of genetic and environmental risk factors, we still have a limited understanding of the mechanisms whereby gene-environment interactions (GxE) operate in schizophrenia and psychoses at large. In this review we provide a critical analysis of current animal models of GxE relevant to psychotic disorders and propose that dimensional perspective will advance our understanding of the complex mechanisms of these disorders. PMID:26510407

A Sensitive Assay for Virus Discovery in Respiratory Clinical Samples

NARCIS (Netherlands)

de Vries, Michel; Deijs, Martin; Canuti, Marta; van Schaik, Barbera D. C.; Faria, Nuno R.; van de Garde, Martijn D. B.; Jachimowski, Loes C. M.; Jebbink, Maarten F.; Jakobs, Marja; Luyf, Angela C. M.; Coenjaerts, Frank E. J.; Claas, Eric C. J.; Molenkamp, Richard; Koekkoek, Sylvie M.; Lammens, Christine; Leus, Frank; Goossens, Herman; Ieven, Margareta; Baas, Frank; van der Hoek, Lia

2011-01-01

In 5-40% of respiratory infections in children, the diagnostics remain negative, suggesting that the patients might be infected with a yet unknown pathogen. Virus discovery cDNA-AFLP (VIDISCA) is a virus discovery method based on recognition of restriction enzyme cleavage sites, ligation of adaptors

Genotype by sex and genotype by age interactions with sedentary behavior: the Portuguese Healthy Family Study.

Directory of Open Access Journals (Sweden)

Daniel M V Santos

Full Text Available Sedentary behavior (SB expression and its underlying causal factors have been progressively studied, as it is a major determinant of decreased health quality. In the present study we applied Genotype x Age (GxAge and Genotype x Sex (GxSex interaction methods to determine if the phenotypic expression of different SB traits is influenced by an interaction between genetic architecture and both age and sex. A total of 1345 subjects, comprising 249 fathers, 327 mothers, 334 sons and 325 daughters, from 339 families of The Portuguese Healthy Family Study were included in the analysis. SB traits were assessed by means of a 3-d physical activity recall, the Baecke and IPAQ questionnaires. GxAge and GxSex interactions were analyzed using SOLAR 4.0 software. Sedentary behaviour heritability estimates were not always statistically significant (p>0.05 and ranged from 3% to 27%. The GxSex and GxAge interaction models were significantly better than the single polygenic models for TV (min/day, EEsed (kcal/day, personal computer (PC usage and physical activty (PA tertiles. The GxAge model is also significantly better than the polygenic model for Sed (min/day. For EEsed, PA tertiles, PC and Sed, the GxAge interaction was significant because the genetic correlation between SB environments was significantly different from 1. Further, PC and Sed variance heterogeneity among distinct ages were observed. The GxSex interaction was significant for EEsed due to genetic variance heterogeneity between genders and for PC due to a genetic correlation less than 1 across both sexes. Our results suggest that SB expression may be influenced by the interactions between genotype with both sex and age. Further, different sedentary behaviors seem to have distinct genetic architectures and are differentially affected by age and sex.

Discovery Mondays

CERN Multimedia

2003-01-01

Many people don't realise quite how much is going on at CERN. Would you like to gain first-hand knowledge of CERN's scientific and technological activities and their many applications? Try out some experiments for yourself, or pick the brains of the people in charge? If so, then the «Lundis Découverte» or Discovery Mondays, will be right up your street. Starting on May 5th, on every first Monday of the month you will be introduced to a different facet of the Laboratory. CERN staff, non-scientists, and members of the general public, everyone is welcome. So tell your friends and neighbours and make sure you don't miss this opportunity to satisfy your curiosity and enjoy yourself at the same time. You won't have to listen to a lecture, as the idea is to have open exchange with the expert in question and for each subject to be illustrated with experiments and demonstrations. There's no need to book, as Microcosm, CERN's interactive museum, will be open non-stop from 7.30 p.m. to 9 p.m. On the first Discovery M...

The discovery of the periodic table as a case of simultaneous discovery.

Science.gov (United States)

Scerri, Eric

2015-03-13

The article examines the question of priority and simultaneous discovery in the context of the discovery of the periodic system. It is argued that rather than being anomalous, simultaneous discovery is the rule. Moreover, I argue that the discovery of the periodic system by at least six authors in over a period of 7 years represents one of the best examples of a multiple discovery. This notion is supported by a new view of the evolutionary development of science through a mechanism that is dubbed Sci-Gaia by analogy with Lovelock's Gaia hypothesis. © 2015 The Author(s) Published by the Royal Society. All rights reserved.

Beyond Discovery

DEFF Research Database (Denmark)

Korsgaard, Steffen; Sassmannshausen, Sean Patrick

2017-01-01

In this chapter we explore four alternatives to the dominant discovery view of entrepreneurship; the development view, the construction view, the evolutionary view, and the Neo-Austrian view. We outline the main critique points of the discovery presented in these four alternatives, as well...

Predictors of timing of pregnancy discovery.

Science.gov (United States)

McCarthy, Molly; Upadhyay, Ushma; Biggs, M Antonia; Anthony, Renaisa; Holl, Jennifer; Roberts, Sarah Cm

2018-04-01

Earlier pregnancy discovery is important in the context of prenatal and abortion care. We evaluated characteristics associated with later pregnancy discovery among women seeking abortion care. Data come from a survey of women seeking abortion care at four family planning facilities in Utah. The participants completed a survey during the state-mandated abortion information visit they are required to complete prior to having an abortion. The outcome in this study was pregnancy discovery before versus after 6 weeks since respondents' last menstrual period (LMP). We used logistic regression to estimate the relationship between sociodemographic and health-related independent variables of interest and pregnancy discovery before versus after 6 weeks. Among the 458 women in the sample, 28% discovered their pregnancy later than 6 weeks since LMP. Most (n=366, 80%) knew the exact date of their LMP and a significant minority estimated it (n=92, 20%). Those who estimated the date of their LMP had higher odds of later pregnancy discovery than those who knew the exact date (adjusted odds ratio (aOR)=1.81[1.07-3.07]). Those who used illicit drugs weekly, daily, or almost daily had higher odds of later pregnancy discovery (aOR=6.33[2.44, 16.40]). Women who did not track their menstrual periods and those who frequently used drugs had higher odds of discovering their pregnancies later. Women who estimated the date of their LMP and who frequently used drugs may benefit from strategies to help them recognize their pregnancies earlier and link them to care when they discover their pregnancies later. Copyright © 2017 Elsevier Inc. All rights reserved.

"Eureka, Eureka!" Discoveries in Science

Science.gov (United States)

Agarwal, Pankaj

2011-01-01

Accidental discoveries have been of significant value in the progress of science. Although accidental discoveries are more common in pharmacology and chemistry, other branches of science have also benefited from such discoveries. While most discoveries are the result of persistent research, famous accidental discoveries provide a fascinating…

Cell and small animal models for phenotypic drug discovery

Directory of Open Access Journals (Sweden)

Szabo M

2017-06-01

Full Text Available Mihaly Szabo,1 Sara Svensson Akusjärvi,1 Ankur Saxena,1 Jianping Liu,2 Gayathri Chandrasekar,1 Satish S Kitambi1 1Department of Microbiology Tumor, and Cell Biology, 2Department of Biochemistry and Biophysics, Karolinska Institutet, Solna, Sweden Abstract: The phenotype-based drug discovery (PDD approach is re-emerging as an alternative platform for drug discovery. This review provides an overview of the various model systems and technical advances in imaging and image analyses that strengthen the PDD platform. In PDD screens, compounds of therapeutic value are identified based on the phenotypic perturbations produced irrespective of target(s or mechanism of action. In this article, examples of phenotypic changes that can be detected and quantified with relative ease in a cell-based setup are discussed. In addition, a higher order of PDD screening setup using small animal models is also explored. As PDD screens integrate physiology and multiple signaling mechanisms during the screening process, the identified hits have higher biomedical applicability. Taken together, this review highlights the advantages gained by adopting a PDD approach in drug discovery. Such a PDD platform can complement target-based systems that are currently in practice to accelerate drug discovery. Keywords: phenotype, screening, PDD, discovery, zebrafish, drug

19 CFR 356.20 - Discovery.

Science.gov (United States)

2010-04-01

... 19 Customs Duties 3 2010-04-01 2010-04-01 false Discovery. 356.20 Section 356.20 Customs Duties... § 356.20 Discovery. (a) Voluntary discovery. All parties are encouraged to engage in voluntary discovery... sanctions proceeding. (b) Limitations on discovery. The administrative law judge shall place such limits...

Chemical Discovery

Science.gov (United States)

Brown, Herbert C.

1974-01-01

The role of discovery in the advance of the science of chemistry and the factors that are currently operating to handicap that function are considered. Examples are drawn from the author's work with boranes. The thesis that exploratory research and discovery should be encouraged is stressed. (DT)

Discovery of novel selenium derivatives as Pin1 inhibitors by high-throughput screening

International Nuclear Information System (INIS)

Subedi, Amit; Shimizu, Takeshi; Ryo, Akihide; Sanada, Emiko; Watanabe, Nobumoto; Osada, Hiroyuki

2016-01-01

Peptidyl prolyl cis/trans isomerization by Pin1 regulates various oncogenic signals during cancer progression, and its inhibition through multiple approaches has established Pin1 as a therapeutic target. However, lack of simplified screening systems has limited the discovery of potent Pin1 inhibitors. We utilized phosphorylation-dependent binding of Pin1 to its specific substrate to develop a screening system for Pin1 inhibitors. Using this system, we screened a chemical library, and identified a novel selenium derivative as Pin1 inhibitor. Based on structure-activity guided chemical synthesis, we developed more potent Pin1 inhibitors that inhibited cancer cell proliferation. -- Highlights: •Novel screening for Pin1 inhibitors based on Pin1 binding is developed. •A novel selenium compound is discovered as Pin1 inhibitor. •Activity guided chemical synthesis of selenium derivatives resulted potent Pin1 inhibitors.

19 CFR 207.109 - Discovery.

Science.gov (United States)

2010-04-01

... 19 Customs Duties 3 2010-04-01 2010-04-01 false Discovery. 207.109 Section 207.109 Customs Duties... and Committee Proceedings § 207.109 Discovery. (a) Discovery methods. All parties may obtain discovery under such terms and limitations as the administrative law judge may order. Discovery may be by one or...

On reliable discovery of molecular signatures

Directory of Open Access Journals (Sweden)

Björkegren Johan

2009-01-01

Full Text Available Abstract Background Molecular signatures are sets of genes, proteins, genetic variants or other variables that can be used as markers for a particular phenotype. Reliable signature discovery methods could yield valuable insight into cell biology and mechanisms of human disease. However, it is currently not clear how to control error rates such as the false discovery rate (FDR in signature discovery. Moreover, signatures for cancer gene expression have been shown to be unstable, that is, difficult to replicate in independent studies, casting doubts on their reliability. Results We demonstrate that with modern prediction methods, signatures that yield accurate predictions may still have a high FDR. Further, we show that even signatures with low FDR may fail to replicate in independent studies due to limited statistical power. Thus, neither stability nor predictive accuracy are relevant when FDR control is the primary goal. We therefore develop a general statistical hypothesis testing framework that for the first time provides FDR control for signature discovery. Our method is demonstrated to be correct in simulation studies. When applied to five cancer data sets, the method was able to discover molecular signatures with 5% FDR in three cases, while two data sets yielded no significant findings. Conclusion Our approach enables reliable discovery of molecular signatures from genome-wide data with current sample sizes. The statistical framework developed herein is potentially applicable to a wide range of prediction problems in bioinformatics.

Sifat Fisik Pati Ganyong (Canna edulis Kerr. Termodifikasi dan Penambahan Gum Xanthan untuk Rerotian (Physical Characteristics of Modified Canna edulis Kerr. Starch and Gum Xanthan for Bakeries

Directory of Open Access Journals (Sweden)

Parwiyanti Parwiyanti

2016-12-01

Full Text Available Modification of Canna starch through heat-moisture treatment (HMT and gum xanthan (GX treatment was conducted to improve the disadvantage of natural Canna starch in order to expand its usage in food industry, especially for bakery products. The research was arranged in a factorial randomized complete block design with three factors (temperature, incubation time, and GX concentrations and three replications for each factor.  The modified Canna  starch by HMT possessed water content of 15 % as well as combination of temperature (80 °C and 100 °C, periods (8 and 16 hours and concentration of GX (0; 0.5; 1; 1.5 and 2 %. The observed variables were the swelling power, water solubility index, water absorption index, baking expantion, and bulk density of modified Canna starch. The result showed that the modification of Canna starch by temperature, time of HMT and concentration GX produced modified starch with physical properties that significantly differ among treatments and natural starch.  Modified Canna starch by treatments of 80 °C, 8 hours, and 1 % xanthan gum concentration showed had swelling power 16.90 ± 0.48 g/g, water solubility index 10.28 ± 0.25 %, water absorption index 112.58 ± 0.38 %, baking expantion 0.94 ± 0.11 mL/g and bulk density 0.73 ± 0.026 g/mL which alike with wheat flour so that it can be further developed as wheat flour substitute on bakery products.   ABSTRAK Penelitian modifikasi pati ganyong melalui perlakuan heat-moisture-treatment (HMT dan penambahan gum xanthan (GX dilakukan untuk memperbaiki kelemahan pati ganyong alami sehingga menjadi luas aplikasinya dalam industri pangan terutama produk rerotian.  Penelitian menggunakan rancangan acak kelompok faktorial dengan 3 perlakukan dan 3 ulangan.  Perlakuan yang diberikan adalah waktu (8 dan 16 jam, suhu (80 °C dan 100 °C, kadar air 15 % dan konsentrasi gum xanthan (0, 0,5; 1; 1,5; 2 %.  Data dianalisis dengan sidik ragam (ANOVA pada α = 0,05, dilanjutkan

10 CFR 2.709 - Discovery against NRC staff.

Science.gov (United States)

2010-01-01

... 10 Energy 1 2010-01-01 2010-01-01 false Discovery against NRC staff. 2.709 Section 2.709 Energy... Rules for Formal Adjudications § 2.709 Discovery against NRC staff. (a)(1) In a proceeding in which the NRC staff is a party, the NRC staff will make available one or more witnesses, designated by the...

Nanostructured gellan and xanthan hydrogel depot integrated within a baghdadite scaffold augments bone regeneration.

Science.gov (United States)

Sehgal, Rekha R; Roohani-Esfahani, S I; Zreiqat, Hala; Banerjee, Rinti

2017-04-01

Controlled delivery of biological cues through synthetic scaffolds to enhance the healing capacity of bone defects is yet to be realized clinically. The purpose of this study was development of a bioactive tissue-engineered scaffold providing the sustained delivery of an osteoinductive drug, dexamethasone disodium phosphate (DXP), encapsulated within chitosan nanoparticles (CN). Porous baghdadite (BD; Ca 3 ZrSi 2 O 9 ) scaffolds, a zirconia-modified calcium silicate ceramic, was coated with DXP-encapsulated CN nanoparticles (DXP-CN) using nanostructured gellan and xanthan hydrogel (GX). Crosslinker and GX polymer concentrations were optimized to achieve a homogeneous distribution of hydrogel coating within BD scaffolds. Dynamic laser scattering indicated an average size of 521 ± 21 nm for the DXP-CN nanoparticles. In vitro drug-release studies demonstrated that the developed DXP-CN-GX hydrogel-coated BD scaffolds (DXP-CN-GX-BD) resulted in a sustained delivery of DXP over the 5 days (78 ± 6% of drug release) compared with burst release over 1 h, seen from free DXP loaded in uncoated BD scaffolds (92 ± 8% release in 1 h). To estimate the influence of controlled delivery of DXP from the developed scaffolds, the effect on MG 63 cells was evaluated using various bone differentiation assays. Cell culture within DXP-CN-GX-BD scaffolds demonstrated a significant increase in the expression of early and late osteogenic markers of alkaline phosphatase activity, collagen type 1 and osteocalcin, compared to the uncoated BD scaffold. The results suggest that the DXP-releasing nanostructured hydrogel integrated within the BD scaffold caused sustained release of DXP, improving the potential for osteogenic differentiation. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.

Drug Discovery of Host CLK1 Inhibitors for Influenza Treatment

Directory of Open Access Journals (Sweden)

Mian Zu

2015-11-01

Full Text Available The rapid evolution of influenza virus makes antiviral drugs less effective, which is considered to be a major bottleneck in antiviral therapy. The key proteins in the host cells, which are related with the replication cycle of influenza virus, are regarded as potential drug targets due to their distinct advantage of lack of evolution and drug resistance. Cdc2-like kinase 1 (CLK1 in the host cells is responsible for alternative splicing of the M2 gene of influenza virus during influenza infection and replication. In this study, we carried out baculovirus-mediated expression and purification of CLK1 and established a reliable screening assay for CLK1 inhibitors. After a virtual screening of CLK1 inhibitors was performed, the activities of the selected compounds were evaluated. Finally, several compounds with strong inhibitory activity against CLK1 were discovered and their in vitro anti-influenza virus activities were validated using a cytopathic effect (CPE reduction assay. The assay results showed that clypearin, corilagin, and pinosylvine were the most potential anti-influenza virus compounds as CLK1 inhibitors among the compounds tested. These findings will provide important information for new drug design and development in influenza treatment, and CLK1 may be a potent drug target for anti-influenza drug screening and discovery.

SERENDIPITOUS DISCOVERY OF A MASSIVE cD GALAXY AT z = 1.096: IMPLICATIONS FOR THE EARLY FORMATION AND LATE EVOLUTION OF cD GALAXIES

Energy Technology Data Exchange (ETDEWEB)

Liu, F. S. [College of Physical Science and Technology, Shenyang Normal University, Shenyang 110034 (China); Guo Yicheng; Koo, David C.; Trump, Jonathan R.; Barro, Guillermo; Yesuf, Hassen; Faber, S. M.; Cheung, Edmond [UCO/Lick Observatory, Department of Astronomy and Astrophysics, University of California, Santa Cruz, CA 95064 (United States); Giavalisco, M. [Department of Astronomy, University of Massachusetts, Amherst, MA 01003 (United States); Cassata, P. [Aix Marseille Universite, CNRS, LAM-Laboratoire d' Astrophysique de Marseille, F-13388 Marseille (France); Koekemoer, A. M.; Grogin, Norman A. [Space Telescope Science Institute, 3700 San Martin Boulevard, Baltimore, MD 21218 (United States); Pentericci, L.; Castellano, M. [INAF Osservatorio Astronomico di Roma, Via Frascati 33, I-00040 Monteporzio (RM) (Italy); Mao, Shude [National Astronomical Observatories, Chinese Academy of Sciences, A20 Datun Road, Beijing 100012 (China); Xia, X. Y. [Tianjin Astrophysics Center, Tianjin Normal University, Tianjin 300387 (China); Hathi, Nimish P. [Observatories of the Carnegie Institution for Science, Pasadena, CA 91101 (United States); Huang, Kuang-Han [Johns Hopkins University, 3400 North Charles Street, Baltimore, MD 21218 (United States); Kocevski, Dale [Department of Physics and Astronomy, University of Kentucky, Lexington, KY 40506-0055 (United States); McGrath, Elizabeth J., E-mail: fengshan@ucolick.org [Department of Physics and Astronomy, Colby College, Mayflower Hill Drive, Waterville, ME 0490 (United States); and others

2013-06-01

We have made a serendipitous discovery of a massive ({approx}5 Multiplication-Sign 10{sup 11} M{sub Sun }) cD galaxy at z = 1.096 in a candidate-rich cluster in the Hubble Ultra Deep Field (HUDF) area of GOODS-South. This brightest cluster galaxy (BCG) is the most distant cD galaxy confirmed to date. Ultra-deep HST/WFC3 images reveal an extended envelope starting from {approx}10 kpc and reaching {approx}70 kpc in radius along the semimajor axis. The spectral energy distributions indicate that both its inner component and outer envelope are composed of an old, passively evolving (specific star formation rate <10{sup -4} Gyr{sup -1}) stellar population. The cD galaxy lies on the same mass-size relation as the bulk of quiescent galaxies at similar redshifts. The cD galaxy has a higher stellar mass surface density ({approx}M{sub *}/R{sub 50}{sup 2}) but a similar velocity dispersion ({approx}{radical}(M{sub *}/R{sub 50})) to those of more massive, nearby cDs. If the cD galaxy is one of the progenitors of today's more massive cDs, its size (R{sub 50}) and stellar mass have had to increase on average by factors of 3.4 {+-} 1.1 and 3.3 {+-} 1.3 over the past {approx}8 Gyr, respectively. Such increases in size and stellar mass without being accompanied by significant increases in velocity dispersion are consistent with evolutionary scenarios driven by both major and minor dissipationless (dry) mergers. If such cD envelopes originate from dry mergers, our discovery of even one example proves that some BCGs entered the dry merger phase at epochs earlier than z = 1. Our data match theoretical models which predict that the continuance of dry mergers at z < 1 can result in structures similar to those of massive cD galaxies seen today. Moreover, our discovery is a surprise given that the extreme depth of the HUDF is essential to reveal such an extended cD envelope at z > 1 and, yet, the HUDF covers only a minuscule region of sky ({approx}3.1 Multiplication-Sign 10{sup -8

Statistics and Discoveries at the LHC (1/4)

CERN Multimedia

CERN. Geneva

2010-01-01

The lectures will give an introduction to statistics as applied in particle physics and will provide all the necessary basics for data analysis at the LHC. Special emphasis will be placed on the the problems and questions that arise when searching for new phenomena, including p-values, discovery significance, limit setting procedures, treatment of small signals in the presence of large backgrounds. Specific issues that will be addressed include the advantages and drawbacks of different statistical test procedures (cut-based, likelihood-ratio, etc.), the look-elsewhere effect and treatment of systematic uncertainties.

Modulators of the human CCR5 receptor. Part 1: Discovery and initial SAR of 1-(3,3-diphenylpropyl)-piperidinyl amides and ureas.

Science.gov (United States)

Burrows, Jeremy N; Cumming, John G; Fillery, Shaun M; Hamlin, Gordon A; Hudson, Julian A; Jackson, Ruth J; McLaughlin, Sharon; Shaw, John S

2005-01-03

Investigation of weak screening hits led to the identification of N-alkyl-N-[1-(3,3-diphenylpropyl)piperidin-4-yl]-2-phenylacetamides and N-alkyl-N-[1-(3,3-diphenylpropyl)piperidin-4-yl]-N'-benzylureas as potent, selective ligands for the human CCR5 chemokine receptor.

Usability of Discovery Portals

OpenAIRE

Bulens, J.D.; Vullings, L.A.E.; Houtkamp, J.M.; Vanmeulebrouk, B.

2013-01-01

As INSPIRE progresses to be implemented in the EU, many new discovery portals are built to facilitate finding spatial data. Currently the structure of the discovery portals is determined by the way spatial data experts like to work. However, we argue that the main target group for discovery portals are not spatial data experts but professionals with limited spatial knowledge, and a focus outside the spatial domain. An exploratory usability experiment was carried out in which three discovery p...

EXPOSE-E: an ESA astrobiology mission 1.5 years in space.

Science.gov (United States)

Rabbow, Elke; Rettberg, Petra; Barczyk, Simon; Bohmeier, Maria; Parpart, André; Panitz, Corinna; Horneck, Gerda; von Heise-Rotenburg, Ralf; Hoppenbrouwers, Tom; Willnecker, Rainer; Baglioni, Pietro; Demets, René; Dettmann, Jan; Reitz, Guenther

2012-05-01

The multi-user facility EXPOSE-E was designed by the European Space Agency to enable astrobiology research in space (low-Earth orbit). On 7 February 2008, EXPOSE-E was carried to the International Space Station (ISS) on the European Technology Exposure Facility (EuTEF) platform in the cargo bay of Space Shuttle STS-122 Atlantis. The facility was installed at the starboard cone of the Columbus module by extravehicular activity, where it remained in space for 1.5 years. EXPOSE-E was returned to Earth with STS-128 Discovery on 12 September 2009 for subsequent sample analysis. EXPOSE-E provided accommodation in three exposure trays for a variety of astrobiological test samples that were exposed to selected space conditions: either to space vacuum, solar electromagnetic radiation at >110 nm and cosmic radiation (trays 1 and 3) or to simulated martian surface conditions (tray 2). Data on UV radiation, cosmic radiation, and temperature were measured every 10 s and downlinked by telemetry. A parallel mission ground reference (MGR) experiment was performed on ground with a parallel set of hardware and samples under simulated space conditions. EXPOSE-E performed a successful 1.5-year mission in space.

A historical sketch of the discovery and development of HIV-1 integrase inhibitors.

Science.gov (United States)

Savarino, Andrea

2006-12-01

The long process of HIV-1 integrase inhibitor discovery and development can be attributed to both the complexity of HIV-1 integration and poor 'integration' of these researches into mainstream investigations on antiretroviral therapy in the mid-1990s. Of note, some fungal extracts investigated during this period contain the beta-hydroxyketo group, later recognised to be a key structural requirement for keto-enol acids (also referred to as diketo acids) and other integrase inhibitors. This review reconstructs (in the general context of the history of AIDS research) the principal steps that led to the integrase inhibitors currently in clinical trials, and discusses possible future directions.

Discovery of gigantic molecular nanostructures using a flow reaction array as a search engine.

Science.gov (United States)

Zang, Hong-Ying; de la Oliva, Andreu Ruiz; Miras, Haralampos N; Long, De-Liang; McBurney, Roy T; Cronin, Leroy

2014-04-28

The discovery of gigantic molecular nanostructures like coordination and polyoxometalate clusters is extremely time-consuming since a vast combinatorial space needs to be searched, and even a systematic and exhaustive exploration of the available synthetic parameters relies on a great deal of serendipity. Here we present a synthetic methodology that combines a flow reaction array and algorithmic control to give a chemical 'real-space' search engine leading to the discovery and isolation of a range of new molecular nanoclusters based on [Mo(2)O(2)S(2)](2+)-based building blocks with either fourfold (C4) or fivefold (C5) symmetry templates and linkers. This engine leads us to isolate six new nanoscale cluster compounds: 1, {Mo(10)(C5)}; 2, {Mo(14)(C4)4(C5)2}; 3, {Mo(60)(C4)10}; 4, {Mo(48)(C4)6}; 5, {Mo(34)(C4)4}; 6, {Mo(18)(C4)9}; in only 200 automated experiments from a parameter space spanning ~5 million possible combinations.

Discovery of a Probable 4-5 Jupiter-mass Exoplanet to HD 95086 by Direct Imaging

Science.gov (United States)

Rameau, J.; Chauvin, G.; Lagrange, A.-M.; Boccaletti, A.; Quanz, S. P.; Bonnefoy, M.; Girard, J. H.; Delorme, P.; Desidera, S.; Klahr, H.; Mordasini, C.; Dumas, C.; Bonavita, M.

2013-08-01

Direct imaging has only begun to inventory the population of gas giant planets on wide orbits around young stars in the solar neighborhood. Following this approach, we carried out a deep imaging survey in the near-infrared using VLT/NaCo to search for substellar companions. Here we report the discovery of a probable companion orbiting the young (10-17 Myr), dusty, early-type (A8) star HD 95086 at 56 AU in L' (3.8 μm) images. This discovery is based on observations with more than a year time lapse. Our first epoch clearly revealed the source at ~= 10σ, while our second epoch lacks good observing conditions, yielding a ~= 3σ detection. Various tests were thus made to rule out possible artifacts. This recovery is consistent with the signal at the first epoch but requires cleaner confirmation. Nevertheless, our astrometric precision suggests that the companion is comoving with the star with a 3σ confidence level. The planetary nature of the source is reinforced by a non-detection in the Ks-band (2.18 μm) images according to its possible extremely red Ks-L' color. Conversely, background contamination is rejected with good confidence level. The luminosity yields a predicted mass of about 4-5 M Jup (at 10-17 Myr) using "hot-start" evolutionary models, making HD 95086 b the exoplanet with the lowest mass ever imaged around a star. Based on observations collected at the European Organisation for Astronomical Research in the Southern Hemisphere, Chile, under program Nos. 087.C-0292, 088.C.0085, 090.C-0538, 090.C-0698, and 090.C-0728.

1,3,5-Triazine-based analogues of purine: from isosteres to privileged scaffolds in medicinal chemistry.

Science.gov (United States)

Lim, Felicia Phei Lin; Dolzhenko, Anton V

2014-10-06

Purines can be considered as the most ubiquitous and functional N-heterocyclic compounds in nature. Structural modifications of natural purines, particularly using isosteric ring systems, have been in the focus of many drug discovery programs. Fusion of 1,3,5-triazine ring with pyrrole, pyrazole, imidazole, 1,2,3-triazole or 1,2,4-triazole results in seven bicyclic heterocyclic systems isosteric to purine. Application of the isosterism concept for the development of new compounds with therapeutic potential in areas involving purinergic regulation or purine metabolism led to significant advances in medicinal chemistry of the azolo[1,3,5]triazines. These 1,3,5-triazine-based purine-like scaffolds significantly increase level of molecular diversity and allow covering chemical space in the important areas of medicinal chemistry. Some of these azolo[1,3,5]triazine systems have become privileged scaffolds in the development of inhibitors of various kinases, phosphodiesterase, xanthine oxidase, and thymidine phosphorylase, antagonists of adenosine and corticotropin-releasing hormone receptors, anticancer and antiviral agents. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Reviewing Hit Discovery Literature for Difficult Targets: Glutathione Transferase Omega-1 as an Example.

Science.gov (United States)

Xie, Yiyue; Dahlin, Jayme L; Oakley, Aaron J; Casarotto, Marco G; Board, Philip G; Baell, Jonathan B

2018-05-10

Early stage drug discovery reporting on relatively new or difficult targets is often associated with insufficient hit triage. Literature reviews of such targets seldom delve into the detail required to critically analyze the associated screening hits reported. Here we take the enzyme glutathione transferase omega-1 (GSTO1-1) as an example of a relatively difficult target and review the associated literature involving small-molecule inhibitors. As part of this process we deliberately pay closer-than-usual attention to assay interference and hit quality aspects. We believe this Perspective will be a useful guide for future development of GSTO1-1 inhibitors, as well serving as a template for future review formats of new or difficult targets.

Discovery and study of novel protein tyrosine phosphatase 1B inhibitors

Science.gov (United States)

Zhang, Qian; Chen, Xi; Feng, Changgen

2017-10-01

Protein tyrosine phosphatase 1B (PTP1B) is considered to be a target for therapy of type II diabetes and obesity. So it is of great significance to take advantage of a computer aided drug design protocol involving the structured-based virtual screening with docking simulations for fast searching small molecule PTP1B inhibitors. Based on optimized complex structure of PTP1B bound with specific inhibitor of IX1, structured-based virtual screening against a library of natural products containing 35308 molecules, which was constructed based on Traditional Chinese Medicine database@ Taiwan (TCM database@ Taiwan), was conducted to determine the occurrence of PTP1B inhibitors using the Lubbock module and CDOCKER module from Discovery Studio 3.1 software package. The results were further filtered by predictive ADME simulation and predictive toxic simulation. As a result, 2 good drug-like molecules, namely para-benzoquinone compound 1 and Clavepictine analogue 2 were identified ultimately with the dock score of original inhibitor (IX1) and the receptor as a threshold. Binding model analyses revealed that these two candidate compounds have good interactions with PTP1B. The PTP1B inhibitory activity of compound 2 hasn't been reported before. The optimized compound 2 has higher scores and deserves further study.

Delineamentos (1/5(5³ Desings (1/5(5³

Directory of Open Access Journals (Sweden)

Armando Conagin

1977-01-01

Full Text Available É descrita a análise estatística de um grupo especial de fatoriais fracionados (1/5 (5³, utilizando os modelos quadráticos e com raiz quadrada; tal estudo foi desenvolvido pelos autores visando principalmente sua aplicação em experimentos agronômicos com fertilizantes. Estes delineamentos fatoriais se originaram da superposição de três dos quatro quadrados latinos ortogonais 5x5, sendo obtidos três conjuntos básicos, designados por Tipo I, II, III, Tipo I, II, IV e Tipo I, III, IV; o último deles é apresentado: 111 245 324 453 532 222 351 435 514 143 333 412 541 125 254 444 523 152 231 315 555 134 213 342 42 O modelo quadrático com dez parâmetros é dado por: Yijk = b0x0 +b li x li + b lj x lj + b lk x lk + b2i x2i + b2j x2j + b2k x2k + + b lilj x lilj + b lilk x lilk + b ljlk x ljlk + x ijk em que x lm = a1 + Xm, x2m = a2 + g2Xm + X²m , com m= i,j,k; os níveis em cada fator variam de 1 a 5; com as condições de ortogonalidade Sx lm=0, Sx2m=0, Sx lm x2m=0, resulta Sxlm=-3+Xm e Sx2m= 7-6Xm+X²m, de onde se tem: x l1=-2; x l2=-1; x l3=0; x l4=1; x l5=2; x21=2; x22=-1; x23=-2; x24=-1; x25=2, para cada índice i,j,k. O coeficiente linear para cada fator pode ser estimado independentemente; os coeficientes quadráticos e das interações linear x linear são estimados a partir de uma matriz simétrica completa 6x6. Consequentemente, na análise da variância as somas de quadrados dos componentes lineares são independentes, mas as somas de quadrados dos componentes quadráticos e das interações são confundidas e, por isso, testadas conjuntamente. Se a contribuição de um fator e sua interação com os outros são negligíveis, podem ser calculadas estimativas independentes dos coeficientes linear e quadrático dos outros dois fatores e sua interação correspondente. Por outro lado, se todos os fatores são importantes mas suas interações são negligíveis, os coeficientes lineares e quadráticos de cada fator são estimados

19 CFR 354.10 - Discovery.

Science.gov (United States)

2010-04-01

... 19 Customs Duties 3 2010-04-01 2010-04-01 false Discovery. 354.10 Section 354.10 Customs Duties... ANTIDUMPING OR COUNTERVAILING DUTY ADMINISTRATIVE PROTECTIVE ORDER § 354.10 Discovery. (a) Voluntary discovery. All parties are encouraged to engage in voluntary discovery procedures regarding any matter, not...

36 CFR 1150.63 - Discovery.

Science.gov (United States)

2010-07-01

... 36 Parks, Forests, and Public Property 3 2010-07-01 2010-07-01 false Discovery. 1150.63 Section... PRACTICE AND PROCEDURES FOR COMPLIANCE HEARINGS Prehearing Conferences and Discovery § 1150.63 Discovery. (a) Parties are encouraged to engage in voluntary discovery procedures. For good cause shown under...

78 FR 52787 - Kevin Dennis, M.D., Decision and Order

Science.gov (United States)

2013-08-26

... phentermine to family members, including his sister, wife and mother-in-law. Id. at 41. However, the ALJ also... May 23, 2008. GX 15, at 9-16. Each of the prescriptions included Respondent's cell-phone number, id... phentermine 37.5mg, to family members including his wife, sister, and mother-in-law. See GX 19, at 12-13, 17...

Usability of Discovery Portals

NARCIS (Netherlands)

Bulens, J.D.; Vullings, L.A.E.; Houtkamp, J.M.; Vanmeulebrouk, B.

2013-01-01

As INSPIRE progresses to be implemented in the EU, many new discovery portals are built to facilitate finding spatial data. Currently the structure of the discovery portals is determined by the way spatial data experts like to work. However, we argue that the main target group for discovery portals

SERENDIPITOUS DISCOVERY OF A PROJECTED PAIR OF QSOs SEPARATED BY 4.5 arcsec ON THE SKY

Energy Technology Data Exchange (ETDEWEB)

Heintz, K. E.; Fynbo, J. P. U.; Krogager, J.-K.; Vestergaard, M. [Dark Cosmology Centre, Niels Bohr Institute, University of Copenhagen, Juliane Maries Vej 30, DK-2100 Copenhagen O (Denmark); Møller, P.; Arabsalmani, M. [European Southern Observatory, Karl-Schwarzschildstrasse 2, D-85748 Garching (Germany); Geier, S. [Gran Telescopio Canarias (GRANTECAN), Cuesta de San José s/n, E-38712, Breña Baja, La Palma (Spain); Noterdaeme, P. [Institut d’Astrophysique de Paris, CNRS-UPMC, UMR7095, 98bis bd Arago, F-75014 Paris (France); Ledoux, C. [European Southern Observatory, Alonso de Crdova 3107, Vitacura, Casilla 19001, Santiago 19 (Chile); Saturni, F. G. [University of Rome “La Sapienza”, p.le A. Moro 5, I-00185 Rome (Italy); Venemans, B., E-mail: heintz@dark-cosmology.dk [Max-Planck Institute for Astronomy, Königstuhl 17, D-69117 Heidelberg (Germany)

2016-07-01

We present the serendipitous discovery of a projected pair of quasi-stellar objects (QSOs) with an angular separation of Δ θ = 4.50 arcsec. The redshifts of the two QSOs are widely different: one, our program target, is a QSO with a spectrum consistent with being a narrow line Seyfert 1 active galactic nucleus at z = 2.05. For this target we detect Ly α , C iv, and C iii]. The other QSO, which by chance was included on the spectroscopic slit, is a Type 1 QSO at a redshift of z = 1.68, for which we detect C iv, C iii], and Mg ii. We compare this system to previously detected projected QSO pairs and find that only about a dozen previously known pairs have smaller angular separation.

28 CFR 76.21 - Discovery.

Science.gov (United States)

2010-07-01

... 28 Judicial Administration 2 2010-07-01 2010-07-01 false Discovery. 76.21 Section 76.21 Judicial... POSSESSION OF CERTAIN CONTROLLED SUBSTANCES § 76.21 Discovery. (a) Scope. Discovery under this part covers... as a general guide for discovery practices in proceedings before the Judge. However, unless otherwise...

Preclinical discovery and development of maraviroc for the treatment of HIV.

Science.gov (United States)

Veljkovic, Nevena; Vucicevic, Jelica; Tassini, Sabrina; Glisic, Sanja; Veljkovic, Veljko; Radi, Marco

2015-06-01

Maraviroc is a first-in-class antiretroviral (ARV) drug acting on a host cell target (CCR5), which blocks the entry of the HIV virus into the cell. Maraviroc is currently indicated for combination ARV treatment in adults infected only with CCR5-tropic HIV-1. This drug discovery case history focuses on the key studies that led to the discovery and approval of maraviroc, as well as on post-launch clinical reports. The article is based on the data reported in published preclinical and clinical studies, conference posters and on drug package data. The profound understanding of HIV's entry mechanisms has provided a strong biological rationale for targeting the chemokine receptor CCR5. The CCR5-antagonist mariviroc, with its unique mode of action and excellent safety profile, is an important therapeutic option for HIV patients. In general, the authors believe that targeting host factors is a useful approach for combating new and re-emerging transmissible diseases, as well as pathogens that easily become resistant to common antiviral drugs. Maraviroc, offering a potent and safe cellular receptor-mediated pharmacological response to HIV, has paved the way for the development of a new generation of host-targeting antivirals.

49 CFR 604.38 - Discovery.

Science.gov (United States)

2010-10-01

... 49 Transportation 7 2010-10-01 2010-10-01 false Discovery. 604.38 Section 604.38 Transportation... TRANSPORTATION CHARTER SERVICE Hearings. § 604.38 Discovery. (a) Permissible forms of discovery shall be within the discretion of the PO. (b) The PO shall limit the frequency and extent of discovery permitted by...

15 CFR 719.10 - Discovery.

Science.gov (United States)

2010-01-01

... 15 Commerce and Foreign Trade 2 2010-01-01 2010-01-01 false Discovery. 719.10 Section 719.10... Discovery. (a) General. The parties are encouraged to engage in voluntary discovery regarding any matter... the Federal Rules of Civil Procedure relating to discovery apply to the extent consistent with this...

49 CFR 1503.633 - Discovery.

Science.gov (United States)

2010-10-01

... 49 Transportation 9 2010-10-01 2010-10-01 false Discovery. 1503.633 Section 1503.633... Rules of Practice in TSA Civil Penalty Actions § 1503.633 Discovery. (a) Initiation of discovery. Any party may initiate discovery described in this section, without the consent or approval of the ALJ, at...

29 CFR 1955.32 - Discovery.

Science.gov (United States)

2010-07-01

... 29 Labor 9 2010-07-01 2010-07-01 false Discovery. 1955.32 Section 1955.32 Labor Regulations...) PROCEDURES FOR WITHDRAWAL OF APPROVAL OF STATE PLANS Preliminary Conference and Discovery § 1955.32 Discovery... allow discovery by any other appropriate procedure, such as by interrogatories upon a party or request...

Discovery of native autoantigens via antigen surrogate technology: application to type 1 diabetes.

Science.gov (United States)

Doran, Todd M; Simanski, Scott; Kodadek, Thomas

2015-02-20

A fundamental goal in understanding the mechanisms of autoimmune disease is the characterization of autoantigens that are targeted by autoreactive antibodies and T cells. Unfortunately, the identification of autoantigens is a difficult problem. We have begun to explore a novel route to the discovery of autoantibody/autoantigen pairs that involves comparative screening of combinatorial libraries of unnatural, synthetic molecules for compounds that bind antibodies present at much higher levels in the serum of individuals with a given autoimmune disease than in the serum of control individuals. We have shown that this approach can yield "antigen surrogates" capable of capturing disease-specific autoantibodies from serum. In this report, we demonstrate that the synthetic antigen surrogates can be used to affinity purify the autoantibodies from serum and that these antibodies can then be used to identify their cognate autoantigen in an appropriate tissue lysate. Specifically, we report the discovery of a peptoid able to bind autoantibodies present in about one-third of nonobese diabetic (NOD) mice. The peptoid-binding autoantibodies were highly enriched through peptoid affinity chromatography and employed to probe mouse pancreatic and brain lysates. This resulted in identification of murine GAD65 as the native autoantigen. GAD65 is a known humoral autoantigen in human type 1 diabetes mellitus (T1DM), but its existence in mice had been controversial. This study demonstrates the potential of this chemical approach for the unbiased identification of autoantigen/autoantibody complexes.

Comprehensive Clinical Phenotyping and Genetic Mapping for the Discovery of Autism Susceptibility Genes

Science.gov (United States)

2013-03-14

behavioral teaching strategies and best practice for teaching students with autism spectrum disorders 4.52 Learn strategies for incorporating IEP goals...AFRL-SA-WP-TR-2013-0013 Comprehensive Clinical Phenotyping and Genetic Mapping for the Discovery of Autism Susceptibility Genes...Genetic Mapping for the Discovery of Autism Susceptibility Genes 5a. CONTRACT NUMBER N/A 5b. GRANT NUMBER N/A 5c. PROGRAM ELEMENT NUMBER N/A 6

Genomic selection improves response to selection in resilience by exploiting genotype by environment interactions

Directory of Open Access Journals (Sweden)

Han Mulder

2016-10-01

Full Text Available Genotype by environment interactions (GxE are very common in livestock and hamper genetic improvement. On the other hand, GxE is a source of genetic variation: genetic variation in response to environment, e.g. environmental perturbations such as heat stress or disease. In livestock breeding, there is tendency to ignore GxE because of increased complexity of models for genetic evaluations and lack of accuracy in extreme environments. GxE, however, creates opportunities to increase resilience of animals towards environmental perturbations. The main aim of the paper is to investigate to which extent GxE can be exploited with traditional and genomic selection methods. Furthermore, we investigated the benefit of reaction norm models compared to conventional methods ignoring GxE. The questions were addressed with selection index theory. GxE was modelled according to a linear reaction norm model in which the environmental gradient is the contemporary group mean. Economic values were based on linear and non-linear profit equations.Accuracies of environment-specific (GEBV were highest in intermediate environments and lowest in extreme environments. Reaction norm models had higher accuracies of (GEBV in extreme environments than conventional models ignoring GxE. Genomic selection always resulted in higher response to selection in all environments than sib or progeny testing schemes. The increase in response was with genomic selection between 9% and 140% compared to sib testing and between 11% and 114% compared to progeny testing when the reference population consisted of 1 million animals across all environments. When the aim was to decrease environmental sensitivity, the response in slope of the reaction norm model with genomic selection was between 1.09 and 319 times larger than with sib or progeny testing and in the right direction in contrast to sib and progeny testing that still increased environmental sensitivity. This shows that genomic selection

49 CFR 1121.2 - Discovery.

Science.gov (United States)

2010-10-01

... 49 Transportation 8 2010-10-01 2010-10-01 false Discovery. 1121.2 Section 1121.2 Transportation... TRANSPORTATION RULES OF PRACTICE RAIL EXEMPTION PROCEDURES § 1121.2 Discovery. Discovery shall follow the procedures set forth at 49 CFR part 1114, subpart B. Discovery may begin upon the filing of the petition for...

38 CFR 42.21 - Discovery.

Science.gov (United States)

2010-07-01

... 38 Pensions, Bonuses, and Veterans' Relief 2 2010-07-01 2010-07-01 false Discovery. 42.21 Section... IMPLEMENTING THE PROGRAM FRAUD CIVIL REMEDIES ACT § 42.21 Discovery. (a) The following types of discovery are... creation of a document. (c) Unless mutually agreed to by the parties, discovery is available only as...

15 CFR 766.9 - Discovery.

Science.gov (United States)

2010-01-01

... 15 Commerce and Foreign Trade 2 2010-01-01 2010-01-01 false Discovery. 766.9 Section 766.9... PROCEEDINGS § 766.9 Discovery. (a) General. The parties are encouraged to engage in voluntary discovery... provisions of the Federal Rules of Civil Procedure relating to discovery apply to the extent consistent with...

The discovery of radioactivity and its aftermath : this article celebrates the 100th anniversary of the discovery of radioactivity by Becquerel

International Nuclear Information System (INIS)

Newbold, B.T.

1996-01-01

The year 1996 marks the 100th anniversary of the discovery of natural radioactivity by the French physicist Antoine Henri Becquerel while studying the behaviour of a fluorescent uranium salt on exposure to sunlight. The great importance of this development has been underlined by Bagnall who stated that 'The scientific scene at the dawn of the 20th century was dominated by the excitement generated from Becquerel's discovery ... ' [1]. However, the discovery of radioactivity did not attract much attention initially when compared with that accorded to the more penetrating X rays found by the German physicist Wilhelm Konrad Roentgen in 1895. Roentgen received the 1901 Nobel Prize for physics for his outstanding discovery. Fortunately, the significance of Becquerel's contribution was quickly realized and in 1903 he was also awarded the Nobel Prize for physics, which he shared with Pierre Curie and Marie Skoldowska Curie, who were honoured for their research on the radiation phenomenon reported by Becquerel. 9 refs., 1 tab

The discovery of radioactivity and its aftermath : this article celebrates the 100th anniversary of the discovery of radioactivity by Becquerel

Energy Technology Data Exchange (ETDEWEB)

Newbold, B T [Moncton Univ., NB (Canada). Dept. of Chemistry and Biochemistry

1996-09-01

The year 1996 marks the 100th anniversary of the discovery of natural radioactivity by the French physicist Antoine Henri Becquerel while studying the behaviour of a fluorescent uranium salt on exposure to sunlight. The great importance of this development has been underlined by Bagnall who stated that `The scientific scene at the dawn of the 20th century was dominated by the excitement generated from Becquerel`s discovery ... ` [1]. However, the discovery of radioactivity did not attract much attention initially when compared with that accorded to the more penetrating X rays found by the German physicist Wilhelm Konrad Roentgen in 1895. Roentgen received the 1901 Nobel Prize for physics for his outstanding discovery. Fortunately, the significance of Becquerel`s contribution was quickly realized and in 1903 he was also awarded the Nobel Prize for physics, which he shared with Pierre Curie and Marie Skoldowska Curie, who were honoured for their research on the radiation phenomenon reported by Becquerel. 9 refs., 1 tab.

Get Involved in Planetary Discoveries through New Worlds, New Discoveries

Science.gov (United States)

Shupla, Christine; Shipp, S. S.; Halligan, E.; Dalton, H.; Boonstra, D.; Buxner, S.; SMD Planetary Forum, NASA

2013-01-01

"New Worlds, New Discoveries" is a synthesis of NASA’s 50-year exploration history which provides an integrated picture of our new understanding of our solar system. As NASA spacecraft head to and arrive at key locations in our solar system, "New Worlds, New Discoveries" provides an integrated picture of our new understanding of the solar system to educators and the general public! The site combines the amazing discoveries of past NASA planetary missions with the most recent findings of ongoing missions, and connects them to the related planetary science topics. "New Worlds, New Discoveries," which includes the "Year of the Solar System" and the ongoing celebration of the "50 Years of Exploration," includes 20 topics that share thematic solar system educational resources and activities, tied to the national science standards. This online site and ongoing event offers numerous opportunities for the science community - including researchers and education and public outreach professionals - to raise awareness, build excitement, and make connections with educators, students, and the public about planetary science. Visitors to the site will find valuable hands-on science activities, resources and educational materials, as well as the latest news, to engage audiences in planetary science topics and their related mission discoveries. The topics are tied to the big questions of planetary science: how did the Sun’s family of planets and bodies originate and how have they evolved? How did life begin and evolve on Earth, and has it evolved elsewhere in our solar system? Scientists and educators are encouraged to get involved either directly or by sharing "New Worlds, New Discoveries" and its resources with educators, by conducting presentations and events, sharing their resources and events to add to the site, and adding their own public events to the site’s event calendar! Visit to find quality resources and ideas. Connect with educators, students and the public to

2011 HM{sub 102}: DISCOVERY OF A HIGH-INCLINATION L5 NEPTUNE TROJAN IN THE SEARCH FOR A POST-PLUTO NEW HORIZONS TARGET

Energy Technology Data Exchange (ETDEWEB)

Parker, Alex H.; Holman, Matthew J.; McLeod, Brian A. [Harvard-Smithsonian Center for Astrophysics, 60 Garden Street, Cambridge, MA 02138 (United States); Buie, Marc W.; Borncamp, David M.; Spencer, John R.; Stern, S. Alan [Southwest Research Institute, 6220 Culebra Road, San Antonio, TX 78238 (United States); Osip, David J. [Carnegie Observatories, Las Campanas Observatory, Casilla 601, La Serena (Chile); Gwyn, Stephen D. J.; Fabbro, Sebastian; Kavelaars, J. J. [Canadian Astronomy Data Centre, National Research Council of Canada, 5071 W. Saanich Road, Victoria, BC V9E 2E7 (Canada); Benecchi, Susan D.; Sheppard, Scott S. [Department of Terrestrial Magnetism, Carnegie Institute of Washington, 5251 Broad Branch Road NW, Washington, DC 20015 (United States); Binzel, Richard P.; DeMeo, Francesca E. [Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139 (United States); Fuentes, Cesar I.; Trilling, David E. [Department of Physics and Astronomy, Northern Arizona University, S San Francisco St, Flagstaff, AZ 86011 (United States); Gay, Pamela L. [Center for Science, Technology, Engineering and Mathematics (STEM) Research, Education, and Outreach, Southern Illinois University, 1220 Lincoln Dr, Carbondale, IL 62901 (United States); Petit, Jean-Marc [CNRS, UTINAM, Universite de Franche Comte, Route de Gray, F-25030 Besancon Cedex, (France); Tholen, David J., E-mail: aparker@cfa.harvard.edu [Institute for Astronomy, University of Hawaii, 2680 Woodlawn Dr, Honolulu, HI 96822 (United States); and others

2013-04-15

We present the discovery of a long-term stable L5 (trailing) Neptune Trojan in data acquired to search for candidate trans-Neptunian objects for the New Horizons spacecraft to fly by during an extended post-Pluto mission. This Neptune Trojan, 2011 HM{sub 102}, has the highest inclination (29. Degree-Sign 4) of any known member of this population. It is intrinsically brighter than any single L5 Jupiter Trojan at H{sub V} {approx} 8.18. We have determined its gri colors (a first for any L5 Neptune Trojan), which we find to be similar to the moderately red colors of the L4 Neptune Trojans, suggesting similar surface properties for members of both Trojan clouds. We also present colors derived from archival data for two L4 Neptune Trojans (2006 RJ{sub 103} and 2007 VL{sub 305}), better refining the overall color distribution of the population. In this document we describe the discovery circumstances, our physical characterization of 2011 HM{sub 102}, and this object's implications for the Neptune Trojan population overall. Finally, we discuss the prospects for detecting 2011 HM{sub 102} from the New Horizons spacecraft during its close approach in mid- to late-2013.

Inseparability of science history and discovery

Directory of Open Access Journals (Sweden)

J. M. Herndon

2010-04-01

Full Text Available Science is very much a logical progression through time. Progressing along a logical path of discovery is rather like following a path through the wilderness. Occasionally the path splits, presenting a choice; the correct logical interpretation leads to further progress, the wrong choice leads to confusion. By considering deeply the relevant science history, one might begin to recognize past faltering in the logical progression of observations and ideas and, perhaps then, to discover new, more precise understanding. The following specific examples of science faltering are described from a historical perspective: (1 Composition of the Earth's inner core; (2 Giant planet internal energy production; (3 Physical impossibility of Earth-core convection and Earth-mantle convection, and; (4 Thermonuclear ignition of stars. For each example, a revised logical progression is described, leading, respectively, to: (1 Understanding the endo-Earth's composition; (2 The concept of nuclear georeactor origin of geo- and planetary magnetic fields; (3 The invalidation and replacement of plate tectonics; and, (4 Understanding the basis for the observed distribution of luminous stars in galaxies. These revised logical progressions clearly show the inseparability of science history and discovery. A different and more fundamental approach to making scientific discoveries than the frequently discussed variants of the scientific method is this: An individual ponders and through tedious efforts arranges seemingly unrelated observations into a logical sequence in the mind so that causal relationships become evident and new understanding emerges, showing the path for new observations, for new experiments, for new theoretical considerations, and for new discoveries. Science history is rich in "seemingly unrelated observations" just waiting to be logically and causally related to reveal new discoveries.

40 CFR 22.52 - Information exchange and discovery.

Science.gov (United States)

2010-07-01

... Procedure Act § 22.52 Information exchange and discovery. Respondent's information exchange pursuant to § 22.19(a) shall include information on any economic benefit resulting from any activity or failure to act... 40 Protection of Environment 1 2010-07-01 2010-07-01 false Information exchange and discovery. 22...

SDSS J074511.56+194926.5: Discovery of a metal-rich and tidally distorted extremely low mass white dwarf

Energy Technology Data Exchange (ETDEWEB)

Gianninas, A.; Barber, Sara D.; Kilic, Mukremin [Homer L. Dodge Department of Physics and Astronomy, University of Oklahoma, 440 W. Brooks St., Norman, OK 73019 (United States); Hermes, J. J.; Harrold, Samuel T. [Department of Astronomy, University of Texas at Austin, Austin, TX 78712 (United States); Brown, Warren R.; Kenyon, Scott J. [Smithsonian Astrophysical Observatory, 60 Garden St., Cambridge, MA 02138 (United States); Dufour, P., E-mail: alexg@nhn.ou.edu [Département de Physique, Université de Montréal, C.P. 6128, Succ. Centre-Ville, Montréal, Québec H3C 3J7 (Canada)

2014-02-01

We present the discovery of an unusual, tidally distorted extremely low mass white dwarf (WD) with nearly solar metallicity. Radial velocity measurements confirm that this is a compact binary with an orbital period of 2.6975 hr and a velocity semi-amplitude of K = 108.7 km s{sup –1}. Analysis of the hydrogen Balmer lines yields an effective temperature of T {sub eff} = 8380 K and a surface gravity of log g = 6.21 that in turn indicate a mass of M = 0.16 M {sub ☉} and a cooling age of 4.2 Gyr. In addition, a detailed analysis of the observed metal lines yields abundances of log (Mg/H) = –3.90, log (Ca/H) = –5.80, log (Ti/H) = –6.10, log (Cr/H) = –5.60, and log (Fe/H) = –4.50, similar to the sun. We see no evidence of a debris disk from which these metals would be accreted, though the possibility cannot entirely be ruled out. Other potential mechanisms to explain the presence of heavy elements are discussed. Finally, we expect this system to ultimately undergo unstable mass transfer and merge to form a ∼0.3-0.6 M {sub ☉} WD in a few Gyr.

Discovery of pulsations from NGC 300 ULX1 and its fast period evolution

Science.gov (United States)

Carpano, S.; Haberl, F.; Maitra, C.; Vasilopoulos, G.

2018-05-01

The supernova impostor SN 2010da located in the nearby galaxy NGC 300, later identified as a likely supergiant B[e] high-mass X-ray binary, was simultaneously observed by NuSTAR and XMM-Newton between 2016 December 16 and 20, over a total time span of ˜310 ks. We report the discovery of a strong periodic modulation in the X-ray flux with a pulse period of 31.6 s and a very rapid spin-up, and confirm therefore that the compact object is a neutron star. We find that the spin period is changing from 31.71 s to 31.54 s over that period, with a spin-up rate of -5.56 × 10-7 s s-1, likely the largest ever observed from an accreting neutron star. The spectrum is described by a power-law and a disc blackbody model, leading to a 0.3-30 keV unabsorbed luminosity of 4.7 × 1039 erg s-1. Applying our best-fitting model successfully to the spectra of an XMM-Newton observation from 2010, suggests that the lower fluxes of NGC 300 ULX1 reported from observations around that time are caused by a large amount of absorption, while the intrinsic luminosity was similar as seen in 2016. A more constant luminosity level is also consistent with the long-term pulse period evolution approaching an equilibrium value asymptotically. We conclude that the source is another candidate for the new class of ultraluminous X-ray pulsars.

Benthic boundary layer - IOS Observational Programme: Discovery Gap measurements, March 1984

International Nuclear Information System (INIS)

Saunders, P.M.

1984-01-01

A narrow gap in the East Azores Fracture Zone provides a channel for the exchange of the bottom water between the Madeira and Iberian abyssal basins. It is named Discovery Gap and a detailed survey defines its length, morphology and sills. Year-long measurements of flow are made from six moorings and ten current meters. This data is supplemented by numerous measurements of temperature made from ship-lowered instruments. A persistent S-N flow is found in Discovery Gap and an estimate of the flux of water colder than 2.05 deg C (potential temperature) is made. This discharge spreads over a region beyond the Gap exit where it is warmed both by the geothermal heating from the seabed and also by mixing with the overlying warm water. An estimate of approximately 2 cm 2 s -1 for the through density surface diffusion is derived, quite similar to two values determined from much larger channels in the Western Atlantic. It is not known whether most of the mixing takes place near the sea-bed or not. The values are in quite striking contrast to those derived for diffusion along a density surface: in Discovery Gap values are estimated to be about 5 x 10 6 cm 2 s -1 . (author)

MODEL DISCOVERY LEARNING DENGAN PENDEKATAN SAINTIFIK BERMUATAN KARAKTER UNTUK MENINGKATKAN KEMAMPUAN BERPIKIR KREATIF

Directory of Open Access Journals (Sweden)

Hendra Erik Rudyanto

2016-11-01

Full Text Available This Study aims to produce a model learning device discovery learning with scientific approach to improve the character charged valid creative thinking, practical and effective. The model refers to a model of learning development includes activities Plomp initial investigation, design, realization/contruction, testing, evaluation and revision. The results showed that (1 learning tools developed valid; syllabus ehit an average of 3,3 (very good; RPP with an average of 3,2 (good; LKS with an average of 3,2 (good; textbook student with an average of 3,3 (very good; and TKBK with an average of 3,5 (good.; (2 the stated learning practical , namely: 1 the activity of student on both criteria, an average score 74,1%; 2 the activity of the teacher are very good on the criterion, the average score of 98,25; 3 positive teacher response, a score of 97,14; 4 positive students response, average 89,73.; (3 the learning of mathematics is declared effective the indicator 1 traffic to think creatively achieve mastery with the average value of 71,55 and a classical completeness reaches 90%; 2 the average grade of creative thinking ability model of discovery learning with scientific approachis better than ekspositori class; 3 the character of the curiosity and skills to communicate a positive influence on the ability to think creatively; and 4 an increase in the ability to think creatively in class models discovery learning with scientific approach.   Keywords: discovery learning, scientific approach, creative thinking ability.

Bioinformatics for discovery of microbiome variation

DEFF Research Database (Denmark)

Brejnrod, Asker Daniel

of various molecular methods to build hypotheses about the impact of a copper contaminated soil. The introduction is a broad introduction to the field of microbiome research with a focus on the technologies that enable these discoveries and how some of the broader issues have related to this thesis......Sequencing based tools have revolutionized microbiology in recent years. Highthroughput DNA sequencing have allowed high-resolution studies on microbial life in many different environments and at unprecedented low cost. These culture-independent methods have helped discovery of novel bacteria...... 1 ,“Large-scale benchmarking reveals false discoveries and count transformation sensitivity in 16S rRNA gene amplicon data analysis methods used in microbiome studies”, benchmarked the performance of a variety of popular statistical methods for discovering differentially abundant bacteria . between...

Current Landscape of Antiviral Drug Discovery [version 1; referees: 2 approved

Directory of Open Access Journals (Sweden)

Wade Blair

2016-02-01

Full Text Available Continued discovery and development of new antiviral medications are paramount for global human health, particularly as new pathogens emerge and old ones evolve to evade current therapeutic agents. Great success has been achieved in developing effective therapies to suppress human immunodeficiency virus (HIV and hepatitis B virus (HBV; however, the therapies are not curative and therefore current efforts in HIV and HBV drug discovery are directed toward longer-acting therapies and/or developing new mechanisms of action that could potentially lead to cure, or eradication, of the virus. Recently, exciting early clinical data have been reported for novel antivirals targeting respiratory syncytial virus (RSV and influenza (flu. Preclinical data suggest that these new approaches may be effective in treating high-risk patients afflicted with serious RSV or flu infections. In this review, we highlight new directions in antiviral approaches for HIV, HBV, and acute respiratory virus infections.

DISCOVERY OF TeV GAMMA-RAY EMISSION TOWARD SUPERNOVA REMNANT SNR G78.2+2.1

Energy Technology Data Exchange (ETDEWEB)

Aliu, E. [Department of Physics and Astronomy, Barnard College, Columbia University, NY 10027 (United States); Archambault, S. [Physics Department, McGill University, Montreal, QC H3A 2T8 (Canada); Arlen, T.; Aune, T. [Department of Physics and Astronomy, University of California, Los Angeles, CA 90095 (United States); Beilicke, M.; Buckley, J. H.; Bugaev, V.; Dickherber, R. [Department of Physics, Washington University, St. Louis, MO 63130 (United States); Benbow, W. [Fred Lawrence Whipple Observatory, Harvard-Smithsonian Center for Astrophysics, Amado, AZ 85645 (United States); Bird, R.; Cannon, A.; Collins-Hughes, E. [School of Physics, University College Dublin, Belfield, Dublin 4 (Ireland); Bouvier, A. [Santa Cruz Institute for Particle Physics and Department of Physics, University of California, Santa Cruz, CA 95064 (United States); Bradbury, S. M. [School of Physics and Astronomy, University of Leeds, Leeds, LS2 9JT (United Kingdom); Byrum, K. [Argonne National Laboratory, 9700 S. Cass Avenue, Argonne, IL 60439 (United States); Cesarini, A.; Connolly, M. P. [School of Physics, National University of Ireland Galway, University Road, Galway (Ireland); Ciupik, L. [Astronomy Department, Adler Planetarium and Astronomy Museum, Chicago, IL 60605 (United States); Cui, W. [Department of Physics, Purdue University, West Lafayette, IN 47907 (United States); Duke, C., E-mail: amandajw@iastate.edu [Department of Physics, Grinnell College, Grinnell, IA 50112-1690 (United States); and others

2013-06-20

We report the discovery of an unidentified, extended source of very-high-energy gamma-ray emission, VER J2019+407, within the radio shell of the supernova remnant SNR G78.2+2.1, using 21.4 hr of data taken by the VERITAS gamma-ray observatory in 2009. These data confirm the preliminary indications of gamma-ray emission previously seen in a two-year (2007-2009) blind survey of the Cygnus region by VERITAS. VER J2019+407, which is detected at a post-trials significance of 7.5 standard deviations in the 2009 data, is localized to the northwestern rim of the remnant in a region of enhanced radio and X-ray emission. It has an intrinsic extent of 0.23 Degree-Sign .23 {+-} 0. Degree-Sign 03{sub stat-0 Degree-Sign .02sys}{sup +0 Degree-Sign .04} and its spectrum is well-characterized by a differential power law (dN/dE = N{sub 0} Multiplication-Sign (E/TeV){sup -{Gamma}}) with a photon index of {Gamma} = 2.37 {+-} 0.14{sub stat} {+-} 0.20{sub sys} and a flux normalization of N{sub 0} = 1.5 {+-} 0.2{sub stat} {+-} 0.4{sub sys} Multiplication-Sign 10{sup -12} photon TeV{sup -1} cm{sup -2} s{sup -1}. This yields an integral flux of 5.2 {+-} 0.8{sub stat} {+-} 1.4{sub sys} Multiplication-Sign 10{sup -12} photon cm{sup -2} s{sup -1} above 320 GeV, corresponding to 3.7% of the Crab Nebula flux. We consider the relationship of the TeV gamma-ray emission with the GeV gamma-ray emission seen from SNR G78.2+2.1 as well as that seen from a nearby cocoon of freshly accelerated cosmic rays. Multiple scenarios are considered as possible origins for the TeV gamma-ray emission, including hadronic particle acceleration at the SNR shock.

Decades of Discovery

Science.gov (United States)

2011-06-01

For the past two-and-a-half decades, the Office of Science at the U.S. Department of Energy has been at the forefront of scientific discovery. Over 100 important discoveries supported by the Office of Science are represented in this document.

Discovery and the atom

International Nuclear Information System (INIS)

1989-01-01

''Discovery and the Atom'' tells the story of the founding of nuclear physics. This programme looks at nuclear physics up to the discovery of the neutron in 1932. Animation explains the science of the classic experiments, such as the scattering of alpha particles by Rutherford and the discovery of the nucleus. Archive film shows the people: Lord Rutherford, James Chadwick, Marie Curie. (author)

Macro cell assisted cell discovery method for 5G mobile networks

DEFF Research Database (Denmark)

Marcano, Andrea; Christiansen, Henrik Lehrmann

2016-01-01

, and requires a new system design. The aspects concerning the impact of using mmWave frequencies on the medium access (MAC) layer are one of the topics that need to be further analyzed. In this article we focus on the cell discovery process of the MAC laywe for mmWave communications. A new approach assuming...... a joint search of the user equipment (UE) between the mmWave small cell (SC) and the macro cell (MC) is proposed. The performance of this method is analyzed and compared with existing methods. The results show that using the MC as aid during the search process can allow for up to 99% improvement in terms...

Structure-based drug discovery for combating influenza virus by targeting the PA-PB1 interaction.

Science.gov (United States)

Watanabe, Ken; Ishikawa, Takeshi; Otaki, Hiroki; Mizuta, Satoshi; Hamada, Tsuyoshi; Nakagaki, Takehiro; Ishibashi, Daisuke; Urata, Shuzo; Yasuda, Jiro; Tanaka, Yoshimasa; Nishida, Noriyuki

2017-08-25

Influenza virus infections are serious public health concerns throughout the world. The development of compounds with novel mechanisms of action is urgently required due to the emergence of viruses with resistance to the currently-approved anti-influenza viral drugs. We performed in silico screening using a structure-based drug discovery algorithm called Nagasaki University Docking Engine (NUDE), which is optimised for a GPU-based supercomputer (DEstination for Gpu Intensive MAchine; DEGIMA), by targeting influenza viral PA protein. The compounds selected by NUDE were tested for anti-influenza virus activity using a cell-based assay. The most potent compound, designated as PA-49, is a medium-sized quinolinone derivative bearing a tetrazole moiety, and it inhibited the replication of influenza virus A/WSN/33 at a half maximal inhibitory concentration of 0.47 μM. PA-49 has the ability to bind PA and its anti-influenza activity was promising against various influenza strains, including a clinical isolate of A(H1N1)pdm09 and type B viruses. The docking simulation suggested that PA-49 interrupts the PA-PB1 interface where important amino acids are mostly conserved in the virus strains tested, suggesting the strain independent utility. Because our NUDE/DEGIMA system is rapid and efficient, it may help effective drug discovery against the influenza virus and other emerging viruses.

Discovery and History of Amino Acid Fermentation.

Science.gov (United States)

Hashimoto, Shin-Ichi

There has been a strong demand in Japan and East Asia for L-glutamic acid as a seasoning since monosodium glutamate was found to present umami taste in 1907. The discovery of glutamate fermentation by Corynebacterium glutamicum in 1956 enabled abundant and low-cost production of the amino acid, creating a large market. The discovery also prompted researchers to develop fermentative production processes for other L-amino acids, such as lysine. Currently, the amino acid fermentation industry is so huge that more than 5 million metric tons of amino acids are manufactured annually all over the world, and this number continues to grow. Research on amino acid fermentation fostered the notion and skills of metabolic engineering which has been applied for the production of other compounds from renewable resources. The discovery of glutamate fermentation has had revolutionary impacts on both the industry and science. In this chapter, the history and development of glutamate fermentation, including the very early stage of fermentation of other amino acids, are reviewed.

Developmentally Sensitive Interaction Effects of Genes and the Social Environment on Total and Subcortical Brain Volumes.

Directory of Open Access Journals (Sweden)

Jennifer S Richards

Full Text Available Smaller total brain and subcortical volumes have been linked to psychopathology including attention-deficit/hyperactivity disorder (ADHD. Identifying mechanisms underlying these alterations, therefore, is of great importance. We investigated the role of gene-environment interactions (GxE in interindividual variability of total gray matter (GM, caudate, and putamen volumes. Brain volumes were derived from structural magnetic resonance imaging scans in participants with (N = 312 and without ADHD (N = 437 from N = 402 families (age M = 17.00, SD = 3.60. GxE effects between DAT1, 5-HTT, and DRD4 and social environments (maternal expressed warmth and criticism; positive and deviant peer affiliation as well as the possible moderating effect of age were examined using linear mixed modeling. We also tested whether findings depended on ADHD severity. Deviant peer affiliation was associated with lower caudate volume. Participants with low deviant peer affiliations had larger total GM volumes with increasing age. Likewise, developmentally sensitive GxE effects were found on total GM and putamen volume. For total GM, differential age effects were found for DAT1 9-repeat and HTTLPR L/L genotypes, depending on the amount of positive peer affiliation. For putamen volume, DRD4 7-repeat carriers and DAT1 10/10 homozygotes showed opposite age relations depending on positive peer affiliation and maternal criticism, respectively. All results were independent of ADHD severity. The presence of differential age-dependent GxE effects might explain the diverse and sometimes opposing results of environmental and genetic effects on brain volumes observed so far.

Developmentally Sensitive Interaction Effects of Genes and the Social Environment on Total and Subcortical Brain Volumes.

Science.gov (United States)

Richards, Jennifer S; Arias Vásquez, Alejandro; Franke, Barbara; Hoekstra, Pieter J; Heslenfeld, Dirk J; Oosterlaan, Jaap; Faraone, Stephen V; Buitelaar, Jan K; Hartman, Catharina A

2016-01-01

Smaller total brain and subcortical volumes have been linked to psychopathology including attention-deficit/hyperactivity disorder (ADHD). Identifying mechanisms underlying these alterations, therefore, is of great importance. We investigated the role of gene-environment interactions (GxE) in interindividual variability of total gray matter (GM), caudate, and putamen volumes. Brain volumes were derived from structural magnetic resonance imaging scans in participants with (N = 312) and without ADHD (N = 437) from N = 402 families (age M = 17.00, SD = 3.60). GxE effects between DAT1, 5-HTT, and DRD4 and social environments (maternal expressed warmth and criticism; positive and deviant peer affiliation) as well as the possible moderating effect of age were examined using linear mixed modeling. We also tested whether findings depended on ADHD severity. Deviant peer affiliation was associated with lower caudate volume. Participants with low deviant peer affiliations had larger total GM volumes with increasing age. Likewise, developmentally sensitive GxE effects were found on total GM and putamen volume. For total GM, differential age effects were found for DAT1 9-repeat and HTTLPR L/L genotypes, depending on the amount of positive peer affiliation. For putamen volume, DRD4 7-repeat carriers and DAT1 10/10 homozygotes showed opposite age relations depending on positive peer affiliation and maternal criticism, respectively. All results were independent of ADHD severity. The presence of differential age-dependent GxE effects might explain the diverse and sometimes opposing results of environmental and genetic effects on brain volumes observed so far.

Performance modeling of neighbor discovery in proactive routing protocols

Directory of Open Access Journals (Sweden)

Andres Medina

2011-07-01

Full Text Available It is well known that neighbor discovery is a critical component of proactive routing protocols in wireless ad hoc networks. However there is no formal study on the performance of proposed neighbor discovery mechanisms. This paper provides a detailed model of key performance metrics of neighbor discovery algorithms, such as node degree and the distribution of the distance to symmetric neighbors. The model accounts for the dynamics of neighbor discovery as well as node density, mobility, radio and interference. The paper demonstrates a method for applying these models to the evaluation of global network metrics. In particular, it describes a model of network connectivity. Validation of the models shows that the degree estimate agrees, within 5% error, with simulations for the considered scenarios. The work presented in this paper serves as a basis for the performance evaluation of remaining performance metrics of routing protocols, vital for large scale deployment of ad hoc networks.

29 CFR 2700.56 - Discovery; general.

Science.gov (United States)

2010-07-01

...(c) or 111 of the Act has been filed. 30 U.S.C. 815(c) and 821. (e) Completion of discovery... 29 Labor 9 2010-07-01 2010-07-01 false Discovery; general. 2700.56 Section 2700.56 Labor... Hearings § 2700.56 Discovery; general. (a) Discovery methods. Parties may obtain discovery by one or more...

Plantics-GX: a biodegradable and cost-effective thermoset plastic that is 100% plant-based

NARCIS (Netherlands)

Alberts, A.H.; Rothenberg, G.

2017-01-01

We recount here the story of the discovery and invention of a family of thermoset resins that are fully biodegradable and plant-based. The resin is prepared by polymerising glycerol, the simplest trialcohol, with citric acid, the simplest abundantly available triacid. Mixing these two chemicals at

Application of encoded library technology (ELT) to a protein-protein interaction target: discovery of a potent class of integrin lymphocyte function-associated antigen 1 (LFA-1) antagonists.

Science.gov (United States)

Kollmann, Christopher S; Bai, Xiaopeng; Tsai, Ching-Hsuan; Yang, Hongfang; Lind, Kenneth E; Skinner, Steven R; Zhu, Zhengrong; Israel, David I; Cuozzo, John W; Morgan, Barry A; Yuki, Koichi; Xie, Can; Springer, Timothy A; Shimaoka, Motomu; Evindar, Ghotas

2014-04-01

The inhibition of protein-protein interactions remains a challenge for traditional small molecule drug discovery. Here we describe the use of DNA-encoded library technology for the discovery of small molecules that are potent inhibitors of the interaction between lymphocyte function-associated antigen 1 and its ligand intercellular adhesion molecule 1. A DNA-encoded library with a potential complexity of 4.1 billion compounds was exposed to the I-domain of the target protein and the bound ligands were affinity selected, yielding an enriched small-molecule hit family. Compounds representing this family were synthesized without their DNA encoding moiety and found to inhibit the lymphocyte function-associated antigen 1/intercellular adhesion molecule-1 interaction with submicromolar potency in both ELISA and cell adhesion assays. Re-synthesized compounds conjugated to DNA or a fluorophore were demonstrated to bind to cells expressing the target protein. Copyright © 2014 Elsevier Ltd. All rights reserved.

Socratic Questioning-Guided Discovery

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M. Hakan Türkçapar

2012-04-01

Full Text Available “Socratic Method” is a way of teaching philosophical thinking and knowledge by asking questions which was used by antique period greek philosopher Socrates. Socrates was teaching knowledge to his followers by asking questions and the conversation between them was named “Socratic Dialogues”. In this meaning, no novel knowledge is taught to the individual but only what is formerly known is reminded and rediscovered. The form of socratic questioning which is used during the process of cognitive behavioral therapy is known as Guided Discovery. In this method it is aimed to make the client notice the piece of knowledge which he could notice but is not aware with a series of questions. Socratic method or guided discovery consists of several steps which are: Identifying the problem by listening to the client and making reflections, finding alternatives by examining and evaluating, reidentification by using the newly found information and questioning the old distorted belief and reaching to a conclusion and applying it. Question types used during these procedures are, questions for gaining information, questions revealing the meanings, questions revealing the beliefs, questions about behaviours during the similar past experiences, analyse questions and analytic synthesis questions. In order to make the patient feel understood it is important to be empathetic and summarising the problem during the interview. In this text, steps of Socratic Questioning-Guided Discovery will be reviewed with sample dialogues after eachstep. [JCBPR 2012; 1(1.000: 15-20

Non-replication of the association between 5HTTLPR and response to psychological therapy for child anxiety disorders

Science.gov (United States)

Lester, Kathryn J.; Roberts, Susanna; Keers, Robert; Coleman, Jonathan R. I.; Breen, Gerome; Wong, Chloe C. Y.; Xu, Xiaohui; Arendt, Kristian; Blatter-Meunier, Judith; Bögels, Susan; Cooper, Peter; Creswell, Cathy; Heiervang, Einar R.; Herren, Chantal; Hogendoorn, Sanne M.; Hudson, Jennifer L.; Krause, Karen; Lyneham, Heidi J.; McKinnon, Anna; Morris, Talia; Nauta, Maaike H.; Rapee, Ronald M.; Rey, Yasmin; Schneider, Silvia; Schneider, Sophie C.; Silverman, Wendy K.; Smith, Patrick; Thastum, Mikael; Thirlwall, Kerstin; Waite, Polly; Wergeland, Gro Janne; Eley, Thalia C.

2016-01-01

Background We previously reported an association between 5HTTLPR genotype and outcome following cognitive–behavioural therapy (CBT) in child anxiety (Cohort 1). Children homozygous for the low-expression short-allele showed more positive outcomes. Other similar studies have produced mixed results, with most reporting no association between genotype and CBT outcome. Aims To replicate the association between 5HTTLPR and CBT outcome in child anxiety from the Genes for Treatment study (GxT Cohort 2, n = 829). Method Logistic and linear mixed effects models were used to examine the relationship between 5HTTLPR and CBT outcomes. Mega-analyses using both cohorts were performed. Results There was no significant effect of 5HTTLPR on CBT outcomes in Cohort 2. Mega-analyses identified a significant association between 5HTTLPR and remission from all anxiety disorders at follow-up (odds ratio 0.45, P = 0.014), but not primary anxiety disorder outcomes. Conclusions The association between 5HTTLPR genotype and CBT outcome did not replicate. Short-allele homozygotes showed more positive treatment outcomes, but with small, non-significant effects. Future studies would benefit from utilising whole genome approaches and large, homogenous samples. PMID:26294368

The discovery of tropane-derived CCR5 receptor antagonists.

Science.gov (United States)

Armour, Duncan R; de Groot, Marcel J; Price, David A; Stammen, Blanda L C; Wood, Anthony; Perros, Manos; Burt, Catherine

2006-04-01

The development of compound 1, a piperidine-based CCR5 receptor antagonist with Type I CYP2D6 inhibition, into the tropane-derived analogue 5, is described. This compound, which is devoid of CYP2D6 liabilities, is a highly potent ligand for the CCR5 receptor and has broad-spectrum activity against a range of clinically relevant HIV isolates. The identification of human ether a-go-go-related gene channel inhibition within this series is described and the potential for QTc interval prolongation discussed. Furthermore, structure activity relationship (SAR) around the piperidine moiety is also described.

Fluorescent glycosidase inhibiting 1,5-dideoxy-1,5-iminoalditols

DEFF Research Database (Denmark)

Greimel, Peter; Häusler, Herwig; Lundt, Inge

2006-01-01

1,5-Dideoxy-1,5-iminoalditols of various configurations as well as isofagomine were N-alkylated with non-polar straight chain spacer-arms by a set of simple standard procedures. The spacer-arms’ terminal functional groups, primary amines, were employed to introduce fluorescent tags such as dansyl...

Discovery of IPV6 Router Interface Addresses via Heuristic Methods

Science.gov (United States)

2015-09-01

NAVAL POSTGRADUATE SCHOOL MONTEREY, CALIFORNIA THESIS DISCOVERY OF IPV6 ROUTER INTERFACE ADDRESSES VIA HEURISTIC METHODS by Matthew D. Gray September...AND SUBTITLE DISCOVERY OF IPV6 ROUTER INTERFACE ADDRESSES VIA HEURISTIC METHODS 5. FUNDING NUMBERS CNS-1111445 6. AUTHOR(S) Matthew D. Gray 7...Internet Assigned Numbers Authority, there is continued pressure for widespread IPv6 adoption. Because the IPv6 address space is orders of magnitude

Discovery of a Probable Nova in M81 and Photometry of Three M81 Novae

Science.gov (United States)

Hornoch, K.; Errmann, R.; Carlisle, Ch.; Vaduvescu, O.

2015-02-01

We report the discovery of a probable nova in M81 on a co-added 1600-s narrow-band H-alpha CCD image taken with the 2.5-m Isaac Newton Telescope (INT) + WFC at La Palma under ~1.6" seeing on 2015 Jan.

A Tale of Two Discoveries: Comparing the Usability of Summon and EBSCO Discovery Service

Science.gov (United States)

Foster, Anita K.; MacDonald, Jean B.

2013-01-01

Web-scale discovery systems are gaining momentum among academic libraries as libraries seek a means to provide their users with a one-stop searching experience. Illinois State University's Milner Library found itself in the unique position of having access to two distinct discovery products, EBSCO Discovery Service and Serials Solutions' Summon.…

5-[(3,5-Dimethyl-1-phenyl-1H-pyrazol-4-ylmethylene]-1,3-diethyl-2-thioxodihydropyrimidine-4,6(1H,5H-dione

Directory of Open Access Journals (Sweden)

Salman A. Khan

2010-03-01

Full Text Available The title compound, 5-[(3,5-dimethyl-1-phenyl-1H-pyrazol-4-ylmethylene]-1,3-diethyl-2-thioxodihydropyrimidine-4,6(1H,5H-dione, has been synthesized by condensation of 1,3-diethyl-2-thiobarbituric acid and 3,5-dimethyl-1-phenylpyrazole-4-carbaldehyde in ethanol in the presence of pyridine. The structure of this new compound was confirmed by elemental analysis, IR, 1H-NMR, 13C-NMR and EI-MS spectral analysis.

Gene expression profiling leads to discovery of correlation of matrix metalloproteinase 11 and heparanase 2 in breast cancer progression

International Nuclear Information System (INIS)

Fu, Junjie; Khaybullin, Ravil; Zhang, Yanping; Xia, Amy; Qi, Xin

2015-01-01

In order to identify biomarkers involved in breast cancer, gene expression profiling was conducted using human breast cancer tissues. Total RNAs were extracted from 150 clinical patient tissues covering three breast cancer subtypes (Luminal A, Luminal B, and Triple negative) as well as normal tissues. The expression profiles of a total of 50,739 genes were established from a training set of 32 samples using the Agilent Sure Print G3 Human Gene Expression Microarray technology. Data were analyzed using Agilent Gene Spring GX 12.6 software. The expression of several genes was validated using real-time RT-qPCR. Data analysis with Agilent GeneSpring GX 12.6 software showed distinct expression patterns between cancer and normal tissue samples. A group of 28 promising genes were identified with ≥ 10-fold changes of expression level and p-values < 0.05. In particular, MMP11 and HPSE2 were closely examined due to the important roles they play in cancer cell growth and migration. Real-time RT-qPCR analyses of both training and testing sets validated the gene expression profiles of MMP11 and HPSE2. Our findings identified these 2 genes as a novel breast cancer biomarker gene set, which may facilitate the diagnosis and treatment in breast cancer clinical therapies

The Fruiting Bodies, Submerged Culture Biomass, and Acidic Polysaccharide Glucuronoxylomannan of Yellow Brain Mushroom Tremella mesenterica Modulate the Immunity of Peripheral Blood Leukocytes and Splenocytes in Rats with Impaired Glucose Tolerance

Directory of Open Access Journals (Sweden)

Tai-Hao Hsu

2014-01-01

Full Text Available The prevalence of diabetes mellitus (DM, a chronic disease with hyperglycemia and impaired immune function, is increasing worldwide. Progression from impaired glucose tolerance (IGT to type 2 DM has recently become a target for early intervention. The fruiting bodies (FB and submerged culture mycelium (CM of Tremella mesenterica, an edible and medicinal mushroom, have been demonstrated to have antihyperglycemic and immunomodulatory activities in type 1 DM rats. Herein, we investigated the effects of acidic polysaccharide glucuronoxylomannan (GX extracted from CM on the immunocyte responses. Male Wistar rats were injected with streptozotocin (65 mg/kg plus nicotinamide (200 mg/kg for the induction of IGT, and gavaged daily with vehicle, FB, CM, or GX (1 g/kg/day. Rats injected with saline and gavaged vehicle were used as controls. Two weeks later, peripheral blood leukocytes (PBLs and splenocytes were collected. Ingestion of FB, CM, and GX significantly decreased blood glucose levels in the postprandial period and in oral glucose tolerance test, and partially reversed T-splenocytic proliferation in IGT rats. CM significantly decreased T-helper lymphocytes in the PBLs and B-splenocytes. In addition, FB, CM, and GX significantly reversed the IGT-induced decreases in tumor necrosis factor-α production; GX significantly increased interleukin-6 production in T-lymphocytes in the PBLs and splenocytes; and CM and GX significantly reversed IGT-induced decrease in interferon-γ production in T-lymphocytes in the spleen. In conclusion, FB, CM, and acidic polysaccharide GX of T. mesenterica may increase T-cell immunity via the elevation of proinflammatory and T-helper cytokine production in rats with impaired glucose tolerance.

Perspectives of biomolecular NMR in drug discovery: the blessing and curse of versatility

International Nuclear Information System (INIS)

Jahnke, Wolfgang

2007-01-01

The versatility of NMR and its broad applicability to several stages in the drug discovery process is well known and generally considered one of the major strengths of NMR (Pellecchia et al., Nature Rev Drug Discov 1:211-219, 2002; Stockman and Dalvit, Prog Nucl Magn Reson Spectrosc 41:187-231, 2002; Lepre et al., Comb Chem High throughput screen 5:583-590, 2002; Wyss et al., Curr Opin Drug Discov Devel 5:630-647, 2002; Jahnke and Widmer, Cell Mol Life Sci 61:580-599, 2004; Huth et al., Methods Enzymol 394:549-571, 2005b; Klages et al., Mol Biosyst 2:318-332, 2006; Takeuchi and Wagner, Curr Opin Struct Biol 16:109-117, 2006; Zartler and Shapiro, Curr Pharm Des 12:3963-3972, 2006). Indeed, NMR is the only biophysical technique which can detect and quantify molecular interactions, and at the same time provide detailed structural information with atomic level resolution. NMR should therefore be ideally suited and widely requested as a tool for drug discovery research, and numerous examples of drug discovery projects which have substantially benefited from NMR contributions or were even driven by NMR have been described in the literature. However, not all pharmaceutical companies have rigorously implemented NMR as integral tool of their research processes. Some companies invest with limited resources, and others do not use biomolecular NMR at all. This discrepancy in assessing the value of a technology is striking, and calls for clarification-under which circumstances can NMR provide added value to the drug discovery process? What kind of contributions can NMR make, and how is it implemented and integrated for maximum impact? This perspectives article suggests key areas of impact for NMR, and a model of integrating NMR with other technologies to realize synergies and maximize their value for drug discovery

The rays of life, centennial of discovery of Radium

International Nuclear Information System (INIS)

Constantin, Enrique; Plazas, Maria C.

1999-01-01

The authors make a recount from the discovery of the rays X for William Conrad Roentgen, in November of 1.985, until our days of the main discoveries and advances in medicine, having like base the radium and their importance in the treatment of the cancer

Discovery of 4-anilino-N-methylthieno[3,2-d]pyrimidines and 4-anilino-N-methylthieno[2,3-d]pyrimidines as potent apoptosis inducers.

Science.gov (United States)

Kemnitzer, William; Sirisoma, Nilantha; May, Chris; Tseng, Ben; Drewe, John; Cai, Sui Xiong

2009-07-01

We report the discovery of N-((benzo[d][1,3]dioxol-5-yl)methyl)-6-phenylthieno[3,2-d]pyrimidin-4-amine (2a) as an apoptosis inducer using our proprietary cell- and caspase-based ASAP HTS assay, and SAR study of HTS hit 2a which led to the discovery of 4-anilino-N-methylthieno[3,2-d]pyrimidines and 4-anilino-N-methylthieno[2,3-d]pyrimidines as potent apoptosis inducers. Compounds 5d and 5e were the most potent with EC(50) values of 0.008 and 0.004microM in T47D human breast cancer cells, respectively. Compound 5d was found to be highly active in the MX-1 breast cancer model. Functionally, compounds 5d and 5e both induced apoptosis through inhibition of tubulin polymerization.

1 CFR 5.1 - Publication policy.

Science.gov (United States)

2010-01-01

... 1 General Provisions 1 2010-01-01 2010-01-01 false Publication policy. 5.1 Section 5.1 General Provisions ADMINISTRATIVE COMMITTEE OF THE FEDERAL REGISTER THE FEDERAL REGISTER GENERAL § 5.1 Publication... Federal Register shall publish a serial publication called the Federal Register to contain the following...

Identification of a Novel Enterovirus Species in Rhesus Macaque in China.

Science.gov (United States)

Ao, Yuan-Yun; Yu, Jie-Mei; Zhang, Cui-Yuan; Xin, Yun-Yun; Li, Li-Li; Duan, Zhao-Jun

2016-06-22

Recent studies of Enterovirus (EV) in nonhuman primates (NHPs), which could act as a source of future emerging human viral diseases, have boosted interest in the search for novel EVs. Here, a highly divergent strain of EV, tentatively named SEV-gx, was identified by viral metagenomic analysis from stool samples of rhesus macaques in China. In total, 27 of 280 (9.6%) faecal samples from rhesus macaques were positive for SEV-gx. Its complete genomic sequence is 7,367 nucleotide (nt). Genomic analyses showed that it has a standard genomic organisation for EVs, being more closely related to EV-J strains (approximately 54.0%, 43.0-44.1%, 52.3-55.2%, 61.1-62.7% and 64.0% amino acids identity in polyprotein, P1, P2 and P3 and combined 2C/3CD regions, respectively). It was also shown to have genome characteristics typical of EVs. Phylogenetic analysis of P1, 2C and 3CD aa indicated that SEV-gx can be classified as a distinct cluster in the EVs. All of this evidence demonstrates SEV-gx is a novel species (tentatively named EV-K) in the EV genus, which contributes to our understanding of the genetic diversity and evolution of EVs. Further studies are needed to investigate the potential pathogenicity of SEV-gx in NHPs and humans.

Discovery of PF-04620110, a Potent, Selective, and Orally Bioavailable Inhibitor of DGAT-1.

Science.gov (United States)

Dow, Robert L; Li, Jian-Cheng; Pence, Michael P; Gibbs, E Michael; LaPerle, Jennifer L; Litchfield, John; Piotrowski, David W; Munchhof, Michael J; Manion, Tara B; Zavadoski, William J; Walker, Gregory S; McPherson, R Kirk; Tapley, Susan; Sugarman, Eliot; Guzman-Perez, Angel; DaSilva-Jardine, Paul

2011-05-12

Acyl-CoA:diacylglycerol acyltransferase-1 (DGAT-1) catalyzes the final committed step in the biosynthesis of triglycerides. DGAT-1 knockout mice have been shown to be resistant to diet-induced obesity and have increased insulin sensitivity. Thus, inhibition of DGAT-1 may represent an attractive target for the treatment of obesity or type II diabetes. Herein, we report the discovery and characterization of a potent and selective DGAT-1 inhibitor PF-04620110 (3). Compound 3 inhibits DGAT-1 with an IC50 of 19 nM and shows high selectivity versus a broad panel of off-target pharmacologic end points. In vivo DGAT-1 inhibition has been demonstrated through reduction of plasma triglyceride levels in rodents at doses of ≥0.1 mg/kg following a lipid challenge. On the basis of this pharmacologic and pharmacokinetic profile, compound 3 has been advanced to human clinical studies.

29 CFR 2200.208 - Discovery.

Science.gov (United States)

2010-07-01

... 29 Labor 9 2010-07-01 2010-07-01 false Discovery. 2200.208 Section 2200.208 Labor Regulations Relating to Labor (Continued) OCCUPATIONAL SAFETY AND HEALTH REVIEW COMMISSION RULES OF PROCEDURE Simplified Proceedings § 2200.208 Discovery. Discovery, including requests for admissions, will only be...

47 CFR 65.105 - Discovery.

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2010-10-01

... 47 Telecommunication 3 2010-10-01 2010-10-01 false Discovery. 65.105 Section 65.105... OF RETURN PRESCRIPTION PROCEDURES AND METHODOLOGIES Procedures § 65.105 Discovery. (a) Participants... evidence. (c) Discovery requests pursuant to § 65.105(b), including written interrogatories, shall be filed...

49 CFR 209.313 - Discovery.

Science.gov (United States)

2010-10-01

... 49 Transportation 4 2010-10-01 2010-10-01 false Discovery. 209.313 Section 209.313 Transportation... TRANSPORTATION RAILROAD SAFETY ENFORCEMENT PROCEDURES Disqualification Procedures § 209.313 Discovery. (a... parties. Discovery is designed to enable a party to obtain relevant information needed for preparation of...

Pan-STARRS1 DISCOVERY OF TWO ULTRALUMINOUS SUPERNOVAE AT z Almost-Equal-To 0.9

Energy Technology Data Exchange (ETDEWEB)

Chomiuk, L. [National Radio Astronomy Observatory, P.O. Box O, Socorro, NM 87801 (United States); Chornock, R.; Soderberg, A. M.; Berger, E.; Foley, R. J.; Kirshner, R. P.; Czekala, I. [Harvard-Smithsonian Center for Astrophysics, 60 Garden Street, Cambridge, MA 02138 (United States); Chevalier, R. A. [Department of Astronomy, University of Virginia, P.O. Box 400325, Charlottesville, VA 22904-4325 (United States); Huber, M. E.; Gezari, S.; Riess, A.; Rodney, S. A. [Department of Physics and Astronomy, Johns Hopkins University, 3400 North Charles Street, Baltimore, MD 21218 (United States); Narayan, G.; Stubbs, C. W. [Department of Physics, Harvard University, Cambridge, MA 02138 (United States); Rest, A. [Space Telescope Science Institute, 3700 San Martin Drive, Baltimore, MD 21218 (United States); Smartt, S. J. [Astrophysics Research Centre, School of Mathematics and Physics, Queen' s University Belfast, Belfast BT7 1NN (United Kingdom); Tonry, J. L.; Burgett, W. S.; Chambers, K. C. [Institute for Astronomy, University of Hawaii at Manoa, Honolulu, HI 96822 (United States); Wood-Vasey, W. M., E-mail: lchomiuk@cfa.harvard.edu [Department of Physics and Astronomy, University of Pittsburgh, 3941 O' Hara Street, Pittsburgh, PA 15260 (United States); and others

2011-12-20

We present the discovery of two ultraluminous supernovae (SNe) at z Almost-Equal-To 0.9 with the Pan-STARRS1 Medium Deep Survey. These SNe, PS1-10ky and PS1-10awh, are among the most luminous SNe ever discovered, comparable to the unusual transients SN 2005ap and SCP 06F6. Like SN 2005ap and SCP 06F6, they show characteristic high luminosities (M{sub bol} Almost-Equal-To -22.5 mag), blue spectra with a few broad absorption lines, and no evidence for H or He. We have constructed a full multi-color light curve sensitive to the peak of the spectral energy distribution in the rest-frame ultraviolet, and we have obtained time series spectroscopy for these SNe. Given the similarities between the SNe, we combine their light curves to estimate a total radiated energy over the course of explosion of (0.9-1.4) Multiplication-Sign 10{sup 51} erg. We find photospheric velocities of 12,000-19,000 km s{sup -1} with no evidence for deceleration measured across {approx}3 rest-frame weeks around light curve peak, consistent with the expansion of an optically thick massive shell of material. We show that, consistent with findings for other ultraluminous SNe in this class, radioactive decay is not sufficient to power PS1-10ky, and we discuss two plausible origins for these events: the initial spin-down of a newborn magnetar in a core-collapse SN, or SN shock breakout from the dense circumstellar wind surrounding a Wolf-Rayet star.

1,4-Bis(5-(naphthalen-1-yl)thiophen-2-yl)naphthalene, a small molecule, functions as a novel anti-HIV-1 inhibitor targeting the interaction between integrase and cellular Lens epithelium-derived growth factor.

Science.gov (United States)

Gu, Wan-gang; Ip, Denis Tsz-Ming; Liu, Si-jie; Chan, Joseph H; Wang, Yan; Zhang, Xuan; Zheng, Yong-tang; Wan, David Chi-Cheong

2014-04-25

Translocation of viral integrase (IN) into the nucleus is a critical precondition of integration during the life cycle of HIV, a causative agent of Acquired Immunodeficiency Syndromes (AIDS). As the first discovered cellular factor to interact with IN, Lens epithelium-derived growth factor (LEDGF/p75) plays an important role in the process of integration. Disruption of the LEDGF/p75-IN interaction has provided a great interest for anti-HIV agent discovery. In this work, we reported that one small molecular compound, 1,4-bis(5-(naphthalen-1-yl)thiophen-2-yl)naphthalene(Compound 15), potently inhibit the IN-LEDGF/p75 interaction and affect the HIV-1 IN nuclear distribution at 1 μM. The putative binding mode of Compound 15 was constructed by a molecular docking simulation to provide structural insights into the ligand-binding mechanism. Compound 15 suppressed viral replication by measuring p24 antigen production in HIV-1IIIB acute infected C8166 cells with EC50 value of 11.19 μM. Compound 15 might supply useful structural information for further anti-HIV agent discovery. Copyright © 2014. Published by Elsevier Ireland Ltd.

Quantifying the Ease of Scientific Discovery.

Science.gov (United States)

Arbesman, Samuel

2011-02-01

It has long been known that scientific output proceeds on an exponential increase, or more properly, a logistic growth curve. The interplay between effort and discovery is clear, and the nature of the functional form has been thought to be due to many changes in the scientific process over time. Here I show a quantitative method for examining the ease of scientific progress, another necessary component in understanding scientific discovery. Using examples from three different scientific disciplines - mammalian species, chemical elements, and minor planets - I find the ease of discovery to conform to an exponential decay. In addition, I show how the pace of scientific discovery can be best understood as the outcome of both scientific output and ease of discovery. A quantitative study of the ease of scientific discovery in the aggregate, such as done here, has the potential to provide a great deal of insight into both the nature of future discoveries and the technical processes behind discoveries in science.

Sustained Accelerated Idioventricular Rhythm in a Centrifuge-Simulated Suborbital Spaceflight.

Science.gov (United States)

Suresh, Rahul; Blue, Rebecca S; Mathers, Charles; Castleberry, Tarah L; Vanderploeg, James M

2017-08-01

Hypergravitational exposures during human centrifugation are known to provoke dysrhythmias, including sinus dysrhythmias/tachycardias, premature atrial/ventricular contractions, and even atrial fibrillations or flutter patterns. However, events are generally short-lived and resolve rapidly after cessation of acceleration. This case report describes a prolonged ectopic ventricular rhythm in response to high G exposure. A previously healthy 30-yr-old man voluntarily participated in centrifuge trials as a part of a larger study, experiencing a total of 7 centrifuge runs over 48 h. Day 1 consisted of two +Gz runs (peak +3.5 Gz, run 2) and two +Gx runs (peak +6.0 Gx, run 4). Day 2 consisted of three runs approximating suborbital spaceflight profiles (combined +Gx and +Gz). Hemodynamic data collected included blood pressure, heart rate, and continuous three-lead electrocardiogram. Following the final acceleration exposure of the last Day 2 run (peak +4.5 Gx and +4.0 Gz combined, resultant +6.0 G), during a period of idle resting centrifuge activity (resultant vector +1.4 G), the subject demonstrated a marked change in his three-lead electrocardiogram from normal sinus rhythm to a wide-complex ectopic ventricular rhythm at a rate of 91-95 bpm, consistent with an accelerated idioventricular rhythm (AIVR). This rhythm was sustained for 2 m, 24 s before reversion to normal sinus. The subject reported no adverse symptoms during this time. While prolonged, the dysrhythmia was asymptomatic and self-limited. AIVR is likely a physiological response to acceleration and can be managed conservatively. Vigilance is needed to ensure that AIVR is correctly distinguished from other, malignant rhythms to avoid inappropriate treatment and negative operational impacts.Suresh R, Blue RS, Mathers C, Castleberry TL, Vanderploeg JM. Sustained accelerated idioventricular rhythm in a centrifuge-simulated suborbital spaceflight. Aerosp Med Hum Perform. 2017; 88(8):789-793.

Biocatalytic ammonolysis of (5S)-4,5-dihydro-1H-pyrrole-1,5-dicarboxylic acid, 1-(1,1-dimethylethyl)-5-ethyl ester: preparation of an intermediate to the dipeptidyl peptidase IV inhibitor Saxagliptin.

Science.gov (United States)

Gill, Iqbal; Patel, Ramesh

2006-02-01

An efficient biocatalytic method has been developed for the conversion of (5S)-4,5-dihydro-1H-pyrrole-1,5-dicarboxylic acid, 1-(1,1-dimethylethyl)-5-ethyl ester (1) into the corresponding amide (5S)-5-aminocarbonyl-4,5-dihydro-1H-pyrrole-1-carboxylic acid, 1-(1,1-dimethylethyl)ester (2), which is a critical intermediate in the synthesis of the dipeptidyl peptidase IV (DPP4) inhibitor Saxagliptin (3). Candida antartica lipase B mediates ammonolysis of the ester with ammonium carbamate as ammonia donor to yield up to 71% of the amide. The inclusion of Ascarite and calcium chloride as adsorbents for carbon dioxide and ethanol byproducts, respectively, increases the yield to 98%, thereby offering an efficient and practical alternative to chemical routes which yield 57-64%.

Results obtained so far with the production of turbine and valve casings made of the new 9% Cr cast steel types G-X 12 CrMoWVNbN 10 11 and G-X 12 CrMoVNbN 91; Erfahrungsbericht ueber die Herstellung von Turbinen- und Ventilgehaeusen aus den neuen 9% Cr-Stahlgusssorten G-X 12 CrMoWVNbN 10 1 1 und G-X 12 CrMoVNbN 91

Energy Technology Data Exchange (ETDEWEB)

Schuster, F.; Buberl, A.; Hanus, R. [VOEST-ALPINE STAHL LINZ GmbH, Linz (Austria); Cerjak, H. [Technische Univ., Graz (Austria)

1996-12-31

In the course of production start-up of new 9-10% Cr cast steel types, and application of R and D results to practice, the following examinations and modifications have been performed: 1. Reduction of average chromium content from 10.5 to 9.5% in order to suppress delta ferrite segregation, and adjustment of austenite and ferrite stabilizing alloying constituents. 2. Analysis of typical defects in castings, and modification of casting and feeding techniques in compliance with the saturation behaviour of the new 9-10% Cr steels. These measures achieved a reduction of feeding-based flaws (shrinkage) in the last few cast pieces. 3. The good weldability was proven of the new 9-10% Cr steels by means of welding tests and crack-free production and construction welds made in cast pieces. (orig./MM) [Deutsch] Im Zuge der Produktionsaufnahme neuer 9-10% Cr-Stahlgusssorten und der Ueberleitung der F and E Ergebnisse in die betriebliche Praxis wurden folgende Untersuchungen und Anpassungen vorgenommen: 1. Um die Deltaferritausscheidung zu unterdruecken, wurde der mittlere Chromgehalt von 10,5 auf 9,5% abgesenkt und die austenit- und ferritstabilisierenden Legierungselemente besser angepasst. 2. Die Analyse typischer Fehlererscheinungen an Gussstuecken machten eine Anpassung der Giess- und Speisungstechnik an das Saettigungsverhalten der neuen 9-10% Cr-Staehle erforderlich. Diese Massnahmen fuehrten zu einer Verringerung der Speisungsfehler (Lunker) bei den zuletzt abgegossenen Gussstuecken. 3. Bei Schweissversuchen und an Gussstuecken rissfrei ausgefuehrten Fertigungs- und Konstruktionsschweissungen konnte die gute Schweisseignung der neuen 9-10% Cr-Staehle nachgewiesen werden. (orig./MM)

SERENDIPITOUS DISCOVERY OF A MASSIVE cD GALAXY AT z = 1.096: IMPLICATIONS FOR THE EARLY FORMATION AND LATE EVOLUTION OF cD GALAXIES

International Nuclear Information System (INIS)

Liu, F. S.; Guo Yicheng; Koo, David C.; Trump, Jonathan R.; Barro, Guillermo; Yesuf, Hassen; Faber, S. M.; Cheung, Edmond; Giavalisco, M.; Cassata, P.; Koekemoer, A. M.; Grogin, Norman A.; Pentericci, L.; Castellano, M.; Mao, Shude; Xia, X. Y.; Hathi, Nimish P.; Huang, Kuang-Han; Kocevski, Dale; McGrath, Elizabeth J.

2013-01-01

We have made a serendipitous discovery of a massive (∼5 × 10 11 M ☉ ) cD galaxy at z = 1.096 in a candidate-rich cluster in the Hubble Ultra Deep Field (HUDF) area of GOODS-South. This brightest cluster galaxy (BCG) is the most distant cD galaxy confirmed to date. Ultra-deep HST/WFC3 images reveal an extended envelope starting from ∼10 kpc and reaching ∼70 kpc in radius along the semimajor axis. The spectral energy distributions indicate that both its inner component and outer envelope are composed of an old, passively evolving (specific star formation rate –4 Gyr –1 ) stellar population. The cD galaxy lies on the same mass-size relation as the bulk of quiescent galaxies at similar redshifts. The cD galaxy has a higher stellar mass surface density (∼M * /R 50 2 ) but a similar velocity dispersion (∼√(M * /R 50 )) to those of more massive, nearby cDs. If the cD galaxy is one of the progenitors of today's more massive cDs, its size (R 50 ) and stellar mass have had to increase on average by factors of 3.4 ± 1.1 and 3.3 ± 1.3 over the past ∼8 Gyr, respectively. Such increases in size and stellar mass without being accompanied by significant increases in velocity dispersion are consistent with evolutionary scenarios driven by both major and minor dissipationless (dry) mergers. If such cD envelopes originate from dry mergers, our discovery of even one example proves that some BCGs entered the dry merger phase at epochs earlier than z = 1. Our data match theoretical models which predict that the continuance of dry mergers at z 1 and, yet, the HUDF covers only a minuscule region of sky (∼3.1 × 10 –8 ). Adding that cDs are rare, our serendipitous discovery hints that such cDs may be more common than expected, perhaps even ubiquitous. Images reaching HUDF depths of more area (especially with cluster BCGs at z > 1) are needed to confirm this conjecture.

46 CFR 550.502 - Discovery.

Science.gov (United States)

2010-10-01

... 46 Shipping 9 2010-10-01 2010-10-01 false Discovery. 550.502 Section 550.502 Shipping FEDERAL... Proceedings § 550.502 Discovery. The Commission may authorize a party to a proceeding to use depositions, written interrogatories, and discovery procedures that, to the extent practicable, are in conformity with...

15 CFR 785.8 - Discovery.

Science.gov (United States)

2010-01-01

... 15 Commerce and Foreign Trade 2 2010-01-01 2010-01-01 false Discovery. 785.8 Section 785.8... INDUSTRY AND SECURITY, DEPARTMENT OF COMMERCE ADDITIONAL PROTOCOL REGULATIONS ENFORCEMENT § 785.8 Discovery. (a) General. The parties are encouraged to engage in voluntary discovery regarding any matter, not...

KNODWAT: a scientific framework application for testing knowledge discovery methods for the biomedical domain.

Science.gov (United States)

Holzinger, Andreas; Zupan, Mario

2013-06-13

Professionals in the biomedical domain are confronted with an increasing mass of data. Developing methods to assist professional end users in the field of Knowledge Discovery to identify, extract, visualize and understand useful information from these huge amounts of data is a huge challenge. However, there are so many diverse methods and methodologies available, that for biomedical researchers who are inexperienced in the use of even relatively popular knowledge discovery methods, it can be very difficult to select the most appropriate method for their particular research problem. A web application, called KNODWAT (KNOwledge Discovery With Advanced Techniques) has been developed, using Java on Spring framework 3.1. and following a user-centered approach. The software runs on Java 1.6 and above and requires a web server such as Apache Tomcat and a database server such as the MySQL Server. For frontend functionality and styling, Twitter Bootstrap was used as well as jQuery for interactive user interface operations. The framework presented is user-centric, highly extensible and flexible. Since it enables methods for testing using existing data to assess suitability and performance, it is especially suitable for inexperienced biomedical researchers, new to the field of knowledge discovery and data mining. For testing purposes two algorithms, CART and C4.5 were implemented using the WEKA data mining framework.

Some historical glimpses on the discovery of x-rays and radioactivity

International Nuclear Information System (INIS)

Patil, S.K.

1996-01-01

In the last decade of the nineteenth century, a cascade of a number of scientific discoveries of great importance took place. The first of these was the discovery of x-rays which marked the beginning of a new era in physics and this was soon followed by the discovery of radioactivity. Both x-rays and radioactivity have wide applications in basic science, technology and medicine. Some glimpses on the historical aspects of the discovery of x-rays and radioactivity are presented. (author). 72 refs., 1 fig

45 CFR 1386.103 - Discovery.

Science.gov (United States)

2010-10-01

... 45 Public Welfare 4 2010-10-01 2010-10-01 false Discovery. 1386.103 Section 1386.103 Public... Hearing Procedures § 1386.103 Discovery. The Department and any party named in the Notice issued pursuant to § 1386.90 has the right to conduct discovery (including depositions) against opposing parties as...

Fragment-Based Discovery of Pyrimido[1,2-b]indazole PDE10A Inhibitors.

Science.gov (United States)

Chino, Ayaka; Seo, Ryushi; Amano, Yasushi; Namatame, Ichiji; Hamaguchi, Wataru; Honbou, Kazuya; Mihara, Takuma; Yamazaki, Mayako; Tomishima, Masaki; Masuda, Naoyuki

2018-01-01

In this study, we report the identification of potent pyrimidoindazoles as phosphodiesterase10A (PDE10A) inhibitors by using the method of fragment-based drug discovery (FBDD). The pyrazolopyridine derivative 2 was found to be a fragment hit compound which could occupy a part of the binding site of PDE10A enzyme by using the method of the X-ray co-crystal structure analysis. On the basis of the crystal structure of compound 2 and PDE10A protein, a number of compounds were synthesized and evaluated, by means of structure-activity relationship (SAR) studies, which culminated in the discovery of a novel pyrimidoindazole derivative 13 having good physicochemical properties.

Repeated 1-cm Resolution Topographic and 2.5-mm Resolution Photomosiac Surveys of Benthic Communities and Fine Scale Bedforms in Monterey Canyon

Science.gov (United States)

Caress, D. W.; Hobson, B.; Thomas, H. J.; Henthorn, R.; Martin, E. J.; Bird, L.; Risi, M.; Troni, G.; Paull, C. K.; Rock, S.; Padial, J. A.; Hammond, M. M.

2014-12-01

The Monterey Bay Aquarium Research Institute has developed a low altitude, ROV-based seafloor mapping system that combines lidar laser ranging, multibeam sonar, and stereo photographic imagery. When operated at a 3-m altitude, this system maps seafloor topography with a 1-cm lateral resolution and simultaneously collects 2.5-mm resolution color photography. We have twice mapped an 80-m by 80-m area of a chemosynthetic clam community located at 2850-m depth in the Monterey Canyon axis. Both the topography and the photomosaics resolve changes in the clam community over a six-month interval. Many individual animals have moved, and tracks of those animals are visible in the lidar topography. No other changes in the seafloor at this site can be discerned. We have also performed single surveys of bedforms and scours at both 1850-m and 2850-m depths in Monterey Canyon. The highest resolution bathymetry data are collected using a 3DatDepth SL1 lidar laser scanner. This system has a 30° field of view and ranges continuously, achieving a 1 cm sounding spacing at a 3 m altitude and 0.3 m/s speed. Bathymetry data are also collected using a 400-kHz Reson 7125 multibeam sonar. This configuration produces 512 beams across a 135° wide swath; each beam has a 0.5° acrosstrack by 1.0° alongtrack angular width. At a 3-m altitude, the nadir beams have a 2.5 cm acrosstrack and 5 cm alongtrack footprint. Dual Prosilica GX1920 2.4 Mpixel color cameras provide color stereo photography of the seafloor. Illumination is provided by dual xenon strobes. The camera housings have been fitted with corrective optics achieving a 90° field of view with less than 1% distortion. At a 3-m altitude the raw image pixels have a 2.5 mm resolution. Position and attitude data are provided by a Kearfott SeaDevil Inertial Navigation System (INS) integrated with a 300 kHz Teledyne RD Instruments Doppler velocity log (DVL). A separate Paroscientific pressure sensor is mounted adjacent to the INS. The INS

29 CFR 1603.210 - Discovery.

Science.gov (United States)

2010-07-01

... 29 Labor 4 2010-07-01 2010-07-01 false Discovery. 1603.210 Section 1603.210 Labor Regulations... GOVERNMENT EMPLOYEE RIGHTS ACT OF 1991 Hearings § 1603.210 Discovery. (a) Unless otherwise ordered by the administrative law judge, discovery may begin as soon as the complaint has been transmitted to the administrative...

12 CFR 1780.26 - Discovery.

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2010-01-01

... 12 Banks and Banking 7 2010-01-01 2010-01-01 false Discovery. 1780.26 Section 1780.26 Banks and... OF PRACTICE AND PROCEDURE RULES OF PRACTICE AND PROCEDURE Prehearing Proceedings § 1780.26 Discovery. (a) Limits on discovery. Subject to the limitations set out in paragraphs (b), (d), and (e) of this...

42 CFR 430.86 - Discovery.

Science.gov (United States)

2010-10-01

... 42 Public Health 4 2010-10-01 2010-10-01 false Discovery. 430.86 Section 430.86 Public Health... Plans and Practice to Federal Requirements § 430.86 Discovery. CMS and any party named in the notice issued under § 430.70 has the right to conduct discovery (including depositions) against opposing parties...

Dysrhythmias in Laypersons During Centrifuge-Simulated Suborbital Spaceflight.

Science.gov (United States)

Suresh, Rahul; Blue, Rebecca S; Mathers, Charles H; Castleberry, Tarah L; Vanderploeg, James M

2017-11-01

There are limited data on cardiac dysrhythmias in laypersons during hypergravity exposure. We report layperson electrocardiograph (ECG) findings and tolerance of dysrhythmias during centrifuge-simulated suborbital spaceflight. Volunteers participated in varied-length centrifuge training programs of 2-7 centrifuge runs over 0.5-2 d, culminating in two simulated suborbital spaceflights of combined +Gz and +Gx (peak +4.0 Gz, +6.0 Gx, duration 5 s). Monitors recorded pre- and post-run mean arterial blood pressure (MAP), 6-s average heart rate (HR) collected at prespecified points during exposures, documented dysrhythmias observed on continuous 3-lead ECG, self-reported symptoms, and objective signs of intolerance on real-time video monitoring. Participating in the study were 148 subjects (43 women). Documented dysrhythmias included sinus pause (N = 5), couplet premature ventricular contractions (N = 4), bigeminy (N = 3), accelerated idioventricular rhythm (N = 1), and relative bradycardia (RB, defined as a transient HR drop of >20 bpm; N = 63). None were associated with subjective symptoms or objective signs of acceleration intolerance. Episodes of RB occurred only during +Gx exposures. Subjects had a higher post-run vs. pre-run MAP after all exposures, but demonstrated no difference in pre- and post-run HR. RB was more common in men, younger individuals, and subjects experiencing more centrifuge runs. Dysrhythmias in laypersons undergoing simulated suborbital spaceflight were well tolerated, though RB was frequently noted during short-duration +Gx exposure. No subjects demonstrated associated symptoms or objective hemodynamic sequelae from these events. Even so, heightened caution remains warranted when monitoring dysrhythmias in laypersons with significant cardiopulmonary disease or taking medications that modulate cardiac conduction.Suresh R, Blue RS, Mathers CH, Castleberry TL, Vanderploeg JM. Dysrhythmias in laypersons during centrifuge-stimulated suborbital

Discovery Driven Growth

DEFF Research Database (Denmark)

Bukh, Per Nikolaj

2009-01-01

Anmeldelse af Discovery Driven Growh : A breakthrough process to reduce risk and seize opportunity, af Rita G. McGrath & Ian C. MacMillan, Boston: Harvard Business Press. Udgivelsesdato: 14 august......Anmeldelse af Discovery Driven Growh : A breakthrough process to reduce risk and seize opportunity, af Rita G. McGrath & Ian C. MacMillan, Boston: Harvard Business Press. Udgivelsesdato: 14 august...

20 CFR 498.207 - Discovery.

Science.gov (United States)

2010-04-01

... 20 Employees' Benefits 2 2010-04-01 2010-04-01 false Discovery. 498.207 Section 498.207 Employees... § 498.207 Discovery. (a) For the purpose of inspection and copying, a party may make a request to...) Any form of discovery other than that permitted under paragraph (a) of this section, such as requests...

Computational methods in drug discovery

Directory of Open Access Journals (Sweden)

Sumudu P. Leelananda

2016-12-01

Full Text Available The process for drug discovery and development is challenging, time consuming and expensive. Computer-aided drug discovery (CADD tools can act as a virtual shortcut, assisting in the expedition of this long process and potentially reducing the cost of research and development. Today CADD has become an effective and indispensable tool in therapeutic development. The human genome project has made available a substantial amount of sequence data that can be used in various drug discovery projects. Additionally, increasing knowledge of biological structures, as well as increasing computer power have made it possible to use computational methods effectively in various phases of the drug discovery and development pipeline. The importance of in silico tools is greater than ever before and has advanced pharmaceutical research. Here we present an overview of computational methods used in different facets of drug discovery and highlight some of the recent successes. In this review, both structure-based and ligand-based drug discovery methods are discussed. Advances in virtual high-throughput screening, protein structure prediction methods, protein–ligand docking, pharmacophore modeling and QSAR techniques are reviewed.

Identification of Novel 5,6-Dimethoxyindan-1-one Derivatives as Antiviral Agents.

Science.gov (United States)

Patil, Siddappa A; Patil, Vikrant; Patil, Renukadevi; Beaman, Kenneth; Patil, Shivaputra A

2017-01-01

Discovery of novel antiviral agents is essential because viral infection continues to threaten human life globally. Various heterocyclic small molecules have been developed as antiviral agents. The 5,6-dimethoxyindan-1-on nucleus is of considerable interest as this ring is the key constituent in a range of bioactive compounds, both naturally occurring and synthetic, and often of considerable complexity. The main purpose of this research was to discover and develop small molecule heterocycles as broad-spectrum of antiviral agents. A focused small set of 5,6-dimethoxyindan-1-one analogs (6-8) along with a thiopene derivative (9) was screened for selected viruses (Vaccinia virus - VACA, Human papillomavirus - HPV, Zika virus - ZIKV, Dengue virus - DENV, Measles virus - MV, Poliovirus 3 - PV, Rift Valley fever virus - RVFV, Tacaribe virus - TCRV, Venezuelan equine encephalitis virus - VEEV, Herpes simplex virus 1 -HSV-1 and Human cytomegalovirus - HCMV) using the National Institute of Allergy and Infectious Diseases (NIAID)'s Division of Microbiology and Infectious Diseases (DMID) antiviral screening program. These molecules demonstrated moderate to excellent antiviral activity towards variety of viruses. The 5,6-dimethoxyindan-1-one analog (7) demonstrated high efficacy towards vaccinia virus (EC50: 30.00 µM) in secondary plaque reduction assay. The thiophene analog (9) has shown very good viral inhibition towards several viruses such as Human papillomavirus, Measles virus, Rift Valley fever virus, Tacaribe virus and Herpes simplex virus 1. Our research identified a novel 5,6-dimethoxyindan-1-one analog (compound 7), as a potent antiviral agent for vaccinia virus, and heterocyclic chalcone analog (compound 9) as a broad spectrum antiviral agent. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

The discovery of the tau lepton: Part 1, The early history through 1975; Part 2, Confirmation of the discovery and measurement of major properties, 1976--1982

International Nuclear Information System (INIS)

Perl, M.L.

1994-08-01

Several previous papers have given the history of the discovery of the τ lepton at the Stanford Linear Accelerator Center (SLAC). These papers emphasized (a) the experiments which led to our 1975 publication of the first evidence for the existence of the τ, (b) the subsequent experiments which confirmed the existence of the r, and (c) the experiments which elucidated the major properties of the τ. That history will be summarized in Part 2 of this talk. In this Part 1, I describe the earlier thoughts and work of myself and my colleagues at SLAC in the 1960's and early 1970's which led to the discovery. I also describe the theoretical and experimental events in particle physics in the 1960's in which our work was immersed. I will also try to describe for the younger generations of particle physicists, the atmosphere in the 1960's. That was before the elucidation of the quark model of hadrons, before the development of the concept of particle generations The experimental paths to program we hot as clear as they are today and we had to cast a wide experimental net

The Discovery of the Tau Lepton: Part 1, The Early History Through 1975; Part 2, Confirmation of the Discovery and Measurement of Major Properties, 1976--1982

Science.gov (United States)

Perl, M. L.

1994-08-01

Several previous papers have given the history of the discovery of the {tau} lepton at the Stanford Linear Accelerator Center (SLAC). These papers emphasized (a) the experiments which led to our 1975 publication of the first evidence for the existence of the {tau}, (b) the subsequent experiments which confirmed the existence of the r, and (c) the experiments which elucidated the major properties of the {tau}. That history will be summarized in Part 2 of this talk. In this Part 1, I describe the earlier thoughts and work of myself and my colleagues at SLAC in the 1960's and early 1970's which led to the discovery. I also describe the theoretical and experimental events in particle physics in the 1960's in which our work was immersed. I will also try to describe for the younger generations of particle physicists, the atmosphere in the 1960's. That was before the elucidation of the quark model of hadrons, before the development of the concept of particle generations The experimental paths to program we hot as clear as they are today and we had to cast a wide experimental net.

Aptamer-based multiplexed proteomic technology for biomarker discovery.

Directory of Open Access Journals (Sweden)

Larry Gold

2010-12-01

Full Text Available The interrogation of proteomes ("proteomics" in a highly multiplexed and efficient manner remains a coveted and challenging goal in biology and medicine.We present a new aptamer-based proteomic technology for biomarker discovery capable of simultaneously measuring thousands of proteins from small sample volumes (15 µL of serum or plasma. Our current assay measures 813 proteins with low limits of detection (1 pM median, 7 logs of overall dynamic range (~100 fM-1 µM, and 5% median coefficient of variation. This technology is enabled by a new generation of aptamers that contain chemically modified nucleotides, which greatly expand the physicochemical diversity of the large randomized nucleic acid libraries from which the aptamers are selected. Proteins in complex matrices such as plasma are measured with a process that transforms a signature of protein concentrations into a corresponding signature of DNA aptamer concentrations, which is quantified on a DNA microarray. Our assay takes advantage of the dual nature of aptamers as both folded protein-binding entities with defined shapes and unique nucleotide sequences recognizable by specific hybridization probes. To demonstrate the utility of our proteomics biomarker discovery technology, we applied it to a clinical study of chronic kidney disease (CKD. We identified two well known CKD biomarkers as well as an additional 58 potential CKD biomarkers. These results demonstrate the potential utility of our technology to rapidly discover unique protein signatures characteristic of various disease states.We describe a versatile and powerful tool that allows large-scale comparison of proteome profiles among discrete populations. This unbiased and highly multiplexed search engine will enable the discovery of novel biomarkers in a manner that is unencumbered by our incomplete knowledge of biology, thereby helping to advance the next generation of evidence-based medicine.

Aptamer-based multiplexed proteomic technology for biomarker discovery.

Science.gov (United States)

Gold, Larry; Ayers, Deborah; Bertino, Jennifer; Bock, Christopher; Bock, Ashley; Brody, Edward N; Carter, Jeff; Dalby, Andrew B; Eaton, Bruce E; Fitzwater, Tim; Flather, Dylan; Forbes, Ashley; Foreman, Trudi; Fowler, Cate; Gawande, Bharat; Goss, Meredith; Gunn, Magda; Gupta, Shashi; Halladay, Dennis; Heil, Jim; Heilig, Joe; Hicke, Brian; Husar, Gregory; Janjic, Nebojsa; Jarvis, Thale; Jennings, Susan; Katilius, Evaldas; Keeney, Tracy R; Kim, Nancy; Koch, Tad H; Kraemer, Stephan; Kroiss, Luke; Le, Ngan; Levine, Daniel; Lindsey, Wes; Lollo, Bridget; Mayfield, Wes; Mehan, Mike; Mehler, Robert; Nelson, Sally K; Nelson, Michele; Nieuwlandt, Dan; Nikrad, Malti; Ochsner, Urs; Ostroff, Rachel M; Otis, Matt; Parker, Thomas; Pietrasiewicz, Steve; Resnicow, Daniel I; Rohloff, John; Sanders, Glenn; Sattin, Sarah; Schneider, Daniel; Singer, Britta; Stanton, Martin; Sterkel, Alana; Stewart, Alex; Stratford, Suzanne; Vaught, Jonathan D; Vrkljan, Mike; Walker, Jeffrey J; Watrobka, Mike; Waugh, Sheela; Weiss, Allison; Wilcox, Sheri K; Wolfson, Alexey; Wolk, Steven K; Zhang, Chi; Zichi, Dom

2010-12-07

The interrogation of proteomes ("proteomics") in a highly multiplexed and efficient manner remains a coveted and challenging goal in biology and medicine. We present a new aptamer-based proteomic technology for biomarker discovery capable of simultaneously measuring thousands of proteins from small sample volumes (15 µL of serum or plasma). Our current assay measures 813 proteins with low limits of detection (1 pM median), 7 logs of overall dynamic range (~100 fM-1 µM), and 5% median coefficient of variation. This technology is enabled by a new generation of aptamers that contain chemically modified nucleotides, which greatly expand the physicochemical diversity of the large randomized nucleic acid libraries from which the aptamers are selected. Proteins in complex matrices such as plasma are measured with a process that transforms a signature of protein concentrations into a corresponding signature of DNA aptamer concentrations, which is quantified on a DNA microarray. Our assay takes advantage of the dual nature of aptamers as both folded protein-binding entities with defined shapes and unique nucleotide sequences recognizable by specific hybridization probes. To demonstrate the utility of our proteomics biomarker discovery technology, we applied it to a clinical study of chronic kidney disease (CKD). We identified two well known CKD biomarkers as well as an additional 58 potential CKD biomarkers. These results demonstrate the potential utility of our technology to rapidly discover unique protein signatures characteristic of various disease states. We describe a versatile and powerful tool that allows large-scale comparison of proteome profiles among discrete populations. This unbiased and highly multiplexed search engine will enable the discovery of novel biomarkers in a manner that is unencumbered by our incomplete knowledge of biology, thereby helping to advance the next generation of evidence-based medicine.

Discovery in a World of Mashups

Science.gov (United States)

King, T. A.; Ritschel, B.; Hourcle, J. A.; Moon, I. S.

2014-12-01

When the first digital information was stored electronically, discovery of what existed was through file names and the organization of the file system. With the advent of networks, digital information was shared on a wider scale, but discovery remained based on file and folder names. With a growing number of information sources, named based discovery quickly became ineffective. The keyword based search engine was one of the first types of a mashup in the world of Web 1.0. Embedded links from one document to another with prescribed relationships between files and the world of Web 2.0 was formed. Search engines like Google used the links to improve search results and a worldwide mashup was formed. While a vast improvement, the need for semantic (meaning rich) discovery was clear, especially for the discovery of scientific data. In response, every science discipline defined schemas to describe their type of data. Some core schemas where shared, but most schemas are custom tailored even though they share many common concepts. As with the networking of information sources, science increasingly relies on data from multiple disciplines. So there is a need to bring together multiple sources of semantically rich information. We explore how harvesting, conceptual mapping, facet based search engines, search term promotion, and style sheets can be combined to create the next generation of mashups in the emerging world of Web 3.0. We use NASA's Planetary Data System and NASA's Heliophysics Data Environment to illustrate how to create a multi-discipline mash-up.

10 CFR 205.198 - Discovery.

Science.gov (United States)

2010-01-01

... 10 Energy 3 2010-01-01 2010-01-01 false Discovery. 205.198 Section 205.198 Energy DEPARTMENT OF... of Proposed Disallowance, and Order of Disallowance § 205.198 Discovery. (a) If a person intends to file a Motion for Discovery, he must file it at the same time that he files his Statement of Objections...

12 CFR 908.46 - Discovery.

Science.gov (United States)

2010-01-01

... 12 Banks and Banking 7 2010-01-01 2010-01-01 false Discovery. 908.46 Section 908.46 Banks and... PRACTICE AND PROCEDURE IN HEARINGS ON THE RECORD Pre-Hearing Proceedings § 908.46 Discovery. (a) Limits on discovery. Subject to the limitations set out in paragraphs (b), (d), and (e) of this section, any party to...

Development of a New Structural Class of Broadly Acting HCV Non-Nucleoside Inhibitors Leading to the Discovery of MK-8876

Energy Technology Data Exchange (ETDEWEB)

McComas, Casey C.; Palani, Anandan; Chang, Wei; Holloway, M. Katharine; Lesburg, Charles A.; Li, Peng; Liverton, Nigel; Meinke, Peter T.; Olsen, David B.; Peng, Xuanjia; Soll, Richard M.; Ummat, Ajay; Wu, Jie; Wu, Jin; Zorn, Nicolas; Ludmerer, Steven W. (Merck); (WuXi App Tec)

2017-07-25

Studies directed at developing a broadly acting non-nucleoside inhibitor of HCV NS5B led to the discovery of a novel structural class of 5-aryl benzofurans that simultaneously interact with both the palm I and palm II binding regions. An initial candidate was potent in vitro against HCV GT1a and GT1b replicons, and induced multi-log reductions in HCV viral load when orally dosed to chronic GT1 infected chimpanzees. However, in vitro potency losses against clinically relevant GT1a variants prompted a further effort to develop compounds with sustained potency across a broader array of HCV genotypes and mutants. Ultimately, a biology and medicinal chemistry collaboration led to the discovery of the development candidate MK-8876. MK-8876 demonstrated a pan-genotypic potency profile and maintained potency against clinically relevant mutants. It demonstrated moderate bioavailability in rats and dogs, but showed low plasma clearance characteristics consistent with once-daily dosing. Herein we describe the efforts which led to the discovery of MK-8876, which advanced into Phase 1 monotherapy studies for evaluation and characterization as a component of an all-oral direct-acting drug regimen for the treatment of chronic HCV infection.

Polyamine conjugation of curcumin analogues toward the discovery of mitochondria-directed neuroprotective agents.

Science.gov (United States)

Simoni, Elena; Bergamini, Christian; Fato, Romana; Tarozzi, Andrea; Bains, Sandip; Motterlini, Roberto; Cavalli, Andrea; Bolognesi, Maria Laura; Minarini, Anna; Hrelia, Patrizia; Lenaz, Giorgio; Rosini, Michela; Melchiorre, Carlo

2010-10-14

Mitochondria-directed antioxidants 2-5 were designed by conjugating curcumin congeners with different polyamine motifs as vehicle tools. The conjugates emerged as efficient antioxidants in mitochondria and fibroblasts and also exerted a protecting role through heme oxygenase-1 activation. Notably, the insertion of a polyamine function into the curcumin-like moiety allowed an efficient intracellular uptake and mitochondria targeting. It also resulted in a significant decrease in the cytotoxicity effects. 2-5 are therefore promising molecules for neuroprotectant lead discovery.

A historical reflection on the discovery of human retroviruses.

Science.gov (United States)

Vahlne, Anders

2009-05-01

The discovery of HIV-1 as the cause of AIDS was one of the major scientific achievements during the last century. Here the events leading to this discovery are reviewed with particular attention to priority and actual contributions by those involved. Since I would argue that discovering HIV was dependent on the previous discovery of the first human retrovirus HTLV-I, the history of this discovery is also re-examined. The first human retroviruses (HTLV-I) was first reported by Robert C. Gallo and coworkers in 1980 and reconfirmed by Yorio Hinuma and coworkers in 1981. These discoveries were in turn dependent on the previous discovery by Gallo and coworkers in 1976 of interleukin 2 or T-cell growth factor as it was called then. HTLV-II was described by Gallo's group in 1982. A human retrovirus distinct from HTLV-I and HTLV-II in that it was shown to have the morphology of a lentivirus was in my mind described for the first time by Luc Montagnier in an oral presentation at Cold Spring Harbor in September of 1983. This virus was isolated from a patient with lymphadenopathy using the protocol previously described for HTLV by Gallo. The first peer reviewed paper by Montagnier's group of such a retrovirus, isolated from two siblings of whom one with AIDS, appeared in Lancet in April of 1984. However, the proof that a new human retrovirus (HIV-1) was the cause of AIDS was first established in four publications by Gallo's group in the May 4th issue of Science in 1984.

The circumstances of minor planet discovery

International Nuclear Information System (INIS)

Pilcher, F.

1989-01-01

The circumstances of discoveries of minor planets are presented in tabular form. Complete data are given for planets 2125-4044, together with notes pertaining to these planets. Information in the table includes the permanent number; the official name; for planets 330 and forward, the table includes the provisional designation attached to the discovery apparition and the year, month, the day of discovery, and the discovery place

Discovery and widespread occurrence of polyhalogenated 1,1'-dimethyl-2,2'-bipyrroles (PDBPs) in marine biota

International Nuclear Information System (INIS)

Hauler, Carolin; Martin, René; Knölker, Hans-Joachim; Gaus, Caroline; Mueller, Jochen F.; Vetter, Walter

2013-01-01

Polyhalogenated 1,1′-dimethyl-2,2′-bipyrroles (PDBPs) are halogenated natural products (HNPs) previously shown to bioaccumulate in marine mammals and birds. Since their discovery in 1999, six hexahalogenated and a few lesser halogenated congeners have been identified in diverse marine mammal samples. Here we report the identification of 17 additional hexahalogenated PDBPs in the blubber extract of a humpback dolphin (Sousa chinensis) from Queensland, Australia. Thirteen of these new PDBPs were also detected in an Australian sea cucumber (Holothuria sp.). Additional samples were also tested positive on several new PDBPs, including an Australian venus tuskfish (Choerodon venustus) as well as a white whale (Delphinapterus leucas) and a sperm whale (Physeter macrocephalus) from the Northern Hemisphere. GC/ECNI-MS-SIM quantification of the molecular ions was carried out with the help of synthesized standards. The sum concentration of PDBPs was 1.1 mg/kg lipid in the humpback dolphin and 0.48 mg/kg lipid in the sea cucumber. -- Highlights: •Polyhalogenated 1,1′-dimethyl-2,2′-bipyrroles (PDBPs) are natural products. •17 New hexahalogenated PDBPs were identified in marine biota from Australia. •A humpback dolphin (Sousa chinensis) contained 1.1 mg/kg lipid PDBPs. •New PDBPs were also detected in marine mammals from the Northern Hemisphere. -- Detection of new polyhalogenated 1,1′-dimethyl-2,2′-bipyrroles indicates a higher toxic risk of these halogenated natural products in the marine environment than previously known

Cross-Layer Service Discovery Mechanism for OLSRv2 Mobile Ad Hoc Networks

Directory of Open Access Journals (Sweden)

M. Isabel Vara

2015-07-01

Full Text Available Service discovery plays an important role in mobile ad hoc networks (MANETs. The lack of central infrastructure, limited resources and high mobility make service discovery a challenging issue for this kind of network. This article proposes a new service discovery mechanism for discovering and advertising services integrated into the Optimized Link State Routing Protocol Version 2 (OLSRv2. In previous studies, we demonstrated the validity of a similar service discovery mechanism integrated into the previous version of OLSR (OLSRv1. In order to advertise services, we have added a new type-length-value structure (TLV to the OLSRv2 protocol, called service discovery message (SDM, according to the Generalized MANET Packet/Message Format defined in Request For Comments (RFC 5444. Each node in the ad hoc network only advertises its own services. The advertisement frequency is a user-configurable parameter, so that it can be modified depending on the user requirements. Each node maintains two service tables, one to store information about its own services and another one to store information about the services it discovers in the network. We present simulation results, that compare our service discovery integrated into OLSRv2 with the one defined for OLSRv1 and with the integration of service discovery in Ad hoc On-demand Distance Vector (AODV protocol, in terms of service discovery ratio, service latency and network overhead.

Cross-Layer Service Discovery Mechanism for OLSRv2 Mobile Ad Hoc Networks.

Science.gov (United States)

Vara, M Isabel; Campo, Celeste

2015-07-20

Service discovery plays an important role in mobile ad hoc networks (MANETs). The lack of central infrastructure, limited resources and high mobility make service discovery a challenging issue for this kind of network. This article proposes a new service discovery mechanism for discovering and advertising services integrated into the Optimized Link State Routing Protocol Version 2 (OLSRv2). In previous studies, we demonstrated the validity of a similar service discovery mechanism integrated into the previous version of OLSR (OLSRv1). In order to advertise services, we have added a new type-length-value structure (TLV) to the OLSRv2 protocol, called service discovery message (SDM), according to the Generalized MANET Packet/Message Format defined in Request For Comments (RFC) 5444. Each node in the ad hoc network only advertises its own services. The advertisement frequency is a user-configurable parameter, so that it can be modified depending on the user requirements. Each node maintains two service tables, one to store information about its own services and another one to store information about the services it discovers in the network. We present simulation results, that compare our service discovery integrated into OLSRv2 with the one defined for OLSRv1 and with the integration of service discovery in Ad hoc On-demand Distance Vector (AODV) protocol, in terms of service discovery ratio, service latency and network overhead.

A Single-Amino-Acid Substitution at Position 225 in Hemagglutinin Alters the Transmissibility of Eurasian Avian-Like H1N1 Swine Influenza Virus in Guinea Pigs.

Science.gov (United States)

Wang, Zeng; Yang, Huanliang; Chen, Yan; Tao, Shiyu; Liu, Liling; Kong, Huihui; Ma, Shujie; Meng, Fei; Suzuki, Yasuo; Qiao, Chuanling; Chen, Hualan

2017-11-01

Efficient transmission from human to human is the prerequisite for an influenza virus to cause a pandemic; however, the molecular determinants of influenza virus transmission are still largely unknown. In this study, we explored the molecular basis for transmission of Eurasian avian-like H1N1 (EAH1N1) swine influenza viruses by comparing two viruses that are genetically similar but differ in their transmissibility in guinea pigs: the A/swine/Guangxi/18/2011 virus (GX/18) is highly transmissible by respiratory droplet in guinea pigs, whereas the A/swine/Heilongjiang/27/2012 virus (HLJ/27) does not transmit in this animal model. We used reverse genetics to generate a series of reassortants and mutants in the GX/18 background and tested their transmissibility in guinea pigs. We found that a single-amino-acid substitution of glycine (G) for glutamic acid (E) at position 225 (E225G) in the HA1 protein completely abolished the respiratory droplet transmission of GX/18, whereas the substitution of E for G at the same position (G225E) in HA1 enabled HLJ/27 to transmit in guinea pigs. We investigated the underlying mechanism and found that viruses bearing 225E in HA1 replicated more rapidly than viruses bearing 225G due to differences in assembly and budding efficiencies. Our study indicates that the amino acid 225E in HA1 plays a key role in EAH1N1 swine influenza virus transmission and provides important information for evaluating the pandemic potential of field influenza virus strains. IMPORTANCE Efficient transmission among humans is a prerequisite for a novel influenza virus to cause a human pandemic. Transmissibility of influenza viruses is a polygenic trait, and understanding the genetic determinants for transmissibility will provide useful insights for evaluating the pandemic potential of influenza viruses in the field. Several amino acids in the hemagglutinin (HA) protein of influenza viruses have been shown to be important for transmissibility, usually by

Toxins and drug discovery.

Science.gov (United States)

Harvey, Alan L

2014-12-15

Components from venoms have stimulated many drug discovery projects, with some notable successes. These are briefly reviewed, from captopril to ziconotide. However, there have been many more disappointments on the road from toxin discovery to approval of a new medicine. Drug discovery and development is an inherently risky business, and the main causes of failure during development programmes are outlined in order to highlight steps that might be taken to increase the chances of success with toxin-based drug discovery. These include having a clear focus on unmet therapeutic needs, concentrating on targets that are well-validated in terms of their relevance to the disease in question, making use of phenotypic screening rather than molecular-based assays, and working with development partners with the resources required for the long and expensive development process. Copyright © 2014 The Author. Published by Elsevier Ltd.. All rights reserved.

mHealth Visual Discovery Dashboard.

Science.gov (United States)

Fang, Dezhi; Hohman, Fred; Polack, Peter; Sarker, Hillol; Kahng, Minsuk; Sharmin, Moushumi; al'Absi, Mustafa; Chau, Duen Horng

2017-09-01

We present Discovery Dashboard, a visual analytics system for exploring large volumes of time series data from mobile medical field studies. Discovery Dashboard offers interactive exploration tools and a data mining motif discovery algorithm to help researchers formulate hypotheses, discover trends and patterns, and ultimately gain a deeper understanding of their data. Discovery Dashboard emphasizes user freedom and flexibility during the data exploration process and enables researchers to do things previously challenging or impossible to do - in the web-browser and in real time. We demonstrate our system visualizing data from a mobile sensor study conducted at the University of Minnesota that included 52 participants who were trying to quit smoking.

Automated Supernova Discovery (Abstract)

Science.gov (United States)

Post, R. S.

2015-12-01

(Abstract only) We are developing a system of robotic telescopes for automatic recognition of Supernovas as well as other transient events in collaboration with the Puckett Supernova Search Team. At the SAS2014 meeting, the discovery program, SNARE, was first described. Since then, it has been continuously improved to handle searches under a wide variety of atmospheric conditions. Currently, two telescopes are used to build a reference library while searching for PSN with a partial library. Since data is taken every night without clouds, we must deal with varying atmospheric and high background illumination from the moon. Software is configured to identify a PSN, reshoot for verification with options to change the run plan to acquire photometric or spectrographic data. The telescopes are 24-inch CDK24, with Alta U230 cameras, one in CA and one in NM. Images and run plans are sent between sites so the CA telescope can search while photometry is done in NM. Our goal is to find bright PSNs with magnitude 17.5 or less which is the limit of our planned spectroscopy. We present results from our first automated PSN discoveries and plans for PSN data acquisition.

Service discovery at home

NARCIS (Netherlands)

Sundramoorthy, V.; Scholten, Johan; Jansen, P.G.; Hartel, Pieter H.

2003-01-01

Service discovery is a fairly new field that kicked off since the advent of ubiquitous computing and has been found essential in the making of intelligent networks by implementing automated discovery and remote control between devices. This paper provides an overview and comparison of several

Open Drug Discovery Toolkit (ODDT): a new open-source player in the drug discovery field.

Science.gov (United States)

Wójcikowski, Maciej; Zielenkiewicz, Piotr; Siedlecki, Pawel

2015-01-01

There has been huge progress in the open cheminformatics field in both methods and software development. Unfortunately, there has been little effort to unite those methods and software into one package. We here describe the Open Drug Discovery Toolkit (ODDT), which aims to fulfill the need for comprehensive and open source drug discovery software. The Open Drug Discovery Toolkit was developed as a free and open source tool for both computer aided drug discovery (CADD) developers and researchers. ODDT reimplements many state-of-the-art methods, such as machine learning scoring functions (RF-Score and NNScore) and wraps other external software to ease the process of developing CADD pipelines. ODDT is an out-of-the-box solution designed to be easily customizable and extensible. Therefore, users are strongly encouraged to extend it and develop new methods. We here present three use cases for ODDT in common tasks in computer-aided drug discovery. Open Drug Discovery Toolkit is released on a permissive 3-clause BSD license for both academic and industrial use. ODDT's source code, additional examples and documentation are available on GitHub (https://github.com/oddt/oddt).

Thermochemical studies of 1-hydroxyisoquinoline, 5-hydroxyisoquinoline and 1,5-dihydroxyisoquinoline

International Nuclear Information System (INIS)

Ribeiro da Silva, Manuel A.V.; Matos, Maria Agostinha R.; Amaral, Luisa M.P.F.

2005-01-01

The standard (p 0 =0.1MPa) molar enthalpies of formation, Δ f H m 0 , for crystalline 1-hydroxyisoquinoline, 5-hydroxyisoquinoline and 1,5-diidroxyisoquinoline, were derived from the standard molar enthalpies of combustion, in oxygen, at the temperature 298.15K, measured by static bomb-combustion calorimetry. The standard molar enthalpies of sublimation, Δ cr g H m 0 , at T=298.15K, were determined by Calvet microcalorimetry. The results were as follows: -Δ c H m 0 (cr)/kJ.mol -1 Δ cr g H m 0 /kJ.mol -1 1-Hydroxyisoquinoline4395.1+/-1.5113.6+/-2.25-Hydroxyisoquinoline 4455.2+/-1.9109.6+/-2.11,5-Dihydroxyisoquinoline4194.1+/-2.2123.6+/-2.2 The derived standard molar enthalpies of formation, in the gaseous state, are analysed in terms of enthalpic increments and interpreted in terms of molecular structure

Discovery of peptidic anti-­myotoxins

DEFF Research Database (Denmark)

Bjärtun, Johanna; Laustsen, Andreas Hougaard; Munk, Andreas

More than 2.5 millions envenomations and 125.000 death occur each year due to snakebite. Current antivenoms consist of immunoglobulinesderived from animals, and they are therefore associated with a high risk of adverse reactions in humans. The use of synthetic peptidic antitoxinsmay lead to safer...... and more effective antivenoms. This research reports the discovery of peptidic antitoxins against myotoxin II from B. asper....

A role for physicians in ethnopharmacology and drug discovery.

Science.gov (United States)

Raza, Mohsin

2006-04-06

Ethnopharmacology investigations classically involved traditional healers, botanists, anthropologists, chemists and pharmacologists. The role of some groups of researchers but not of physician has been highlighted and well defined in ethnopharmacological investigations. Historical data shows that discovery of several important modern drugs of herbal origin owe to the medical knowledge and clinical expertise of physicians. Current trends indicate negligible role of physicians in ethnopharmacological studies. Rising cost of modern drug development is attributed to the lack of classical ethnopharmacological approach. Physicians can play multiple roles in the ethnopharmacological studies to facilitate drug discovery as well as to rescue authentic traditional knowledge of use of medicinal plants. These include: (1) Ethnopharmacological field work which involves interviewing healers, interpreting traditional terminologies into their modern counterparts, examining patients consuming herbal remedies and identifying the disease for which an herbal remedy is used. (2) Interpretation of signs and symptoms mentioned in ancient texts and suggesting proper use of old traditional remedies in the light of modern medicine. (3) Clinical studies on herbs and their interaction with modern medicines. (4) Advising pharmacologists to carryout laboratory studies on herbs observed during field studies. (5) Work in collaboration with local healers to strengthen traditional system of medicine in a community. In conclusion, physician's involvement in ethnopharmacological studies will lead to more reliable information on traditional use of medicinal plants both from field and ancient texts, more focused and cheaper natural product based drug discovery, as well as bridge the gap between traditional and modern medicine.

77 FR 17505 - Morris W. Cochran, M.D.: Revocation of Registration

Science.gov (United States)

2012-03-26

... abnormal. Id. Respondent did not document having taken JC1's vital signs. Id. At this visit, Respondent... withdrawal, was agitated/moody, had insomnia, and had a positive MDQ (Mood Disorder Questionnaire). Id... pain, substance abuse, and bipolar disorder. GX 5, at 3. While Respondent checked ``YES'' for whether...

The in silico drug discovery toolbox: applications in lead discovery and optimization.

Science.gov (United States)

Bruno, Agostino; Costantino, Gabriele; Sartori, Luca; Radi, Marco

2017-11-06

Discovery and development of a new drug is a long lasting and expensive journey that takes around 15 years from starting idea to approval and marketing of new medication. Despite the R&D expenditures have been constantly increasing in the last few years, number of new drugs introduced into market has been steadily declining. This is mainly due to preclinical and clinical safety issues, which still represent about 40% of drug discontinuation. From this point of view, it is clear that if we want to increase drug-discovery success rate and reduce costs associated with development of a new drug, a comprehensive evaluation/prediction of potential safety issues should be conducted as soon as possible during early drug discovery phase. In the present review, we will analyse the early steps of drug-discovery pipeline, describing the sequence of steps from disease selection to lead optimization and focusing on the most common in silico tools used to assess attrition risks and build a mitigation plan. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Academic Drug Discovery Centres

DEFF Research Database (Denmark)

Kirkegaard, Henriette Schultz; Valentin, Finn

2014-01-01

Academic drug discovery centres (ADDCs) are seen as one of the solutions to fill the innovation gap in early drug discovery, which has proven challenging for previous organisational models. Prior studies of ADDCs have identified the need to analyse them from the angle of their economic...

Service Discovery At Home

NARCIS (Netherlands)

Sundramoorthy, V.; Scholten, Johan; Jansen, P.G.; Hartel, Pieter H.

Service discovery is a fady new field that kicked off since the advent of ubiquitous computing and has been found essential in the making of intelligent networks by implementing automated discovery and remote control between deviies. This paper provides an ovewiew and comparison of several prominent

A historical reflection on the discovery of human retroviruses

Directory of Open Access Journals (Sweden)

Vahlne Anders

2009-05-01

Full Text Available Abstract The discovery of HIV-1 as the cause of AIDS was one of the major scientific achievements during the last century. Here the events leading to this discovery are reviewed with particular attention to priority and actual contributions by those involved. Since I would argue that discovering HIV was dependent on the previous discovery of the first human retrovirus HTLV-I, the history of this discovery is also re-examined. The first human retroviruses (HTLV-I was first reported by Robert C. Gallo and coworkers in 1980 and reconfirmed by Yorio Hinuma and coworkers in 1981. These discoveries were in turn dependent on the previous discovery by Gallo and coworkers in 1976 of interleukin 2 or T-cell growth factor as it was called then. HTLV-II was described by Gallo's group in 1982. A human retrovirus distinct from HTLV-I and HTLV-II in that it was shown to have the morphology of a lentivirus was in my mind described for the first time by Luc Montagnier in an oral presentation at Cold Spring Harbor in September of 1983. This virus was isolated from a patient with lymphadenopathy using the protocol previously described for HTLV by Gallo. The first peer reviewed paper by Montagnier's group of such a retrovirus, isolated from two siblings of whom one with AIDS, appeared in Lancet in April of 1984. However, the proof that a new human retrovirus (HIV-1 was the cause of AIDS was first established in four publications by Gallo's group in the May 4th issue of Science in 1984.

Synthetic biology of antimicrobial discovery.

Science.gov (United States)

Zakeri, Bijan; Lu, Timothy K

2013-07-19

Antibiotic discovery has a storied history. From the discovery of penicillin by Sir Alexander Fleming to the relentless quest for antibiotics by Selman Waksman, the stories have become like folklore used to inspire future generations of scientists. However, recent discovery pipelines have run dry at a time when multidrug-resistant pathogens are on the rise. Nature has proven to be a valuable reservoir of antimicrobial agents, which are primarily produced by modularized biochemical pathways. Such modularization is well suited to remodeling by an interdisciplinary approach that spans science and engineering. Herein, we discuss the biological engineering of small molecules, peptides, and non-traditional antimicrobials and provide an overview of the growing applicability of synthetic biology to antimicrobials discovery.

Discovery of Hard Nonthermal Pulsed X-Ray Emission from the Anomalous X-Ray Pulsar 1E 1841-045

NARCIS (Netherlands)

Kuiper, L.; Hermsen, W.; Méndez, R.M.

2004-01-01

We report the discovery of nonthermal pulsed X-ray/soft gamma-ray emission up to ~150 keV from the anomalous 11.8 s X-ray pulsar AXP 1E 1841-045 located near the center of supernova remnant Kes 73 using Rossi X-Ray Timing Explorer (RXTE) Proportional Counter Array and High Energy X-Ray Timing

DISCOVERY AND CHARACTERIZATION OF WIDE BINARY SYSTEMS WITH A VERY LOW MASS COMPONENT

Energy Technology Data Exchange (ETDEWEB)

Baron, Frédérique; Lafrenière, David; Artigau, Étienne; Doyon, René; Gagné, Jonathan; Robert, Jasmin; Nadeau, Daniel [Département de Physique, Université de Montréal, C.P. 6128 Succ. Centre-ville, Montréal, Qc H3C 3J7 (Canada); Davison, Cassy L. [Department of Physics and Astronomy, Georgia State University, Atlanta, GA 30303 (United States); Malo, Lison [Canada-France-Hawaii Telescope, 65–1238 Mamalahoa Hwy, Kamuela, HI 96743 (United States); Reylé, Céline, E-mail: baron@astro.umontreal.ca [Institut Utinam, CNRS UMR6213, Université de Franche-Comté, OSU THETA Franche-Comté-Bourgogne, Observatoire de Besançon, BP 1615, F-25010 Besançon Cedex (France)

2015-03-20

We report the discovery of 14 low-mass binary systems containing mid-M to mid-L dwarf companions with separations larger than 250 AU. We also report the independent discovery of nine other systems with similar characteristics that were recently discovered in other studies. We have identified these systems by searching for common proper motion sources in the vicinity of known high proper motion stars, based on a cross-correlation of wide area near-infrared surveys (2MASS, SDSS, and SIMP). An astrometric follow-up, for common proper motion confirmation, was made with SIMON and/or CPAPIR at the Observatoire du Mont Mégantic 1.6 m and CTIO 1.5 m telescopes for all the candidates identified. A spectroscopic follow-up was also made with GMOS or GNIRS at Gemini to determine the spectral types of 11 of our newly identified companions and 10 of our primaries. Statistical arguments are provided to show that all of the systems we report here are very likely to be physical binaries. One of the new systems reported features a brown dwarf companion: LSPM J1259+1001 (M5) has an L4.5 (2M1259+1001) companion at ∼340 AU. This brown dwarf was previously unknown. Seven other systems have a companion of spectral type L0–L1 at a separation in the 250–7500 AU range. Our sample includes 14 systems with a mass ratio below 0.3.

DISCOVERY AND CHARACTERIZATION OF WIDE BINARY SYSTEMS WITH A VERY LOW MASS COMPONENT

International Nuclear Information System (INIS)

Baron, Frédérique; Lafrenière, David; Artigau, Étienne; Doyon, René; Gagné, Jonathan; Robert, Jasmin; Nadeau, Daniel; Davison, Cassy L.; Malo, Lison; Reylé, Céline

2015-01-01

We report the discovery of 14 low-mass binary systems containing mid-M to mid-L dwarf companions with separations larger than 250 AU. We also report the independent discovery of nine other systems with similar characteristics that were recently discovered in other studies. We have identified these systems by searching for common proper motion sources in the vicinity of known high proper motion stars, based on a cross-correlation of wide area near-infrared surveys (2MASS, SDSS, and SIMP). An astrometric follow-up, for common proper motion confirmation, was made with SIMON and/or CPAPIR at the Observatoire du Mont Mégantic 1.6 m and CTIO 1.5 m telescopes for all the candidates identified. A spectroscopic follow-up was also made with GMOS or GNIRS at Gemini to determine the spectral types of 11 of our newly identified companions and 10 of our primaries. Statistical arguments are provided to show that all of the systems we report here are very likely to be physical binaries. One of the new systems reported features a brown dwarf companion: LSPM J1259+1001 (M5) has an L4.5 (2M1259+1001) companion at ∼340 AU. This brown dwarf was previously unknown. Seven other systems have a companion of spectral type L0–L1 at a separation in the 250–7500 AU range. Our sample includes 14 systems with a mass ratio below 0.3

Discovery of an Apparent Nova in M81

Science.gov (United States)

Hornoch, K.; Alfaro, M. Diaz; Ordonez-Etxeberria, I.; Vaduvescu, O.

2015-01-01

We report the discovery of an apparent nova in M81 on a co-added 1600-s narrow-band H-alpha CCD image taken with the 2.5-m Isaac Newton Telescope (INT) + WFC at La Palma under ~2.4" seeing on 2015 Jan. 15.126 UT.

Discovery of AG-120 (Ivosidenib): A First-in-Class Mutant IDH1 Inhibitor for the Treatment of IDH1 Mutant Cancers.

Science.gov (United States)

Popovici-Muller, Janeta; Lemieux, René M; Artin, Erin; Saunders, Jeffrey O; Salituro, Francesco G; Travins, Jeremy; Cianchetta, Giovanni; Cai, Zhenwei; Zhou, Ding; Cui, Dawei; Chen, Ping; Straley, Kimberly; Tobin, Erica; Wang, Fang; David, Muriel D; Penard-Lacronique, Virginie; Quivoron, Cyril; Saada, Véronique; de Botton, Stéphane; Gross, Stefan; Dang, Lenny; Yang, Hua; Utley, Luke; Chen, Yue; Kim, Hyeryun; Jin, Shengfang; Gu, Zhiwei; Yao, Gui; Luo, Zhiyong; Lv, Xiaobing; Fang, Cheng; Yan, Liping; Olaharski, Andrew; Silverman, Lee; Biller, Scott; Su, Shin-San M; Yen, Katharine

2018-04-12

Somatic point mutations at a key arginine residue (R132) within the active site of the metabolic enzyme isocitrate dehydrogenase 1 (IDH1) confer a novel gain of function in cancer cells, resulting in the production of d-2-hydroxyglutarate (2-HG), an oncometabolite. Elevated 2-HG levels are implicated in epigenetic alterations and impaired cellular differentiation. IDH1 mutations have been described in an array of hematologic malignancies and solid tumors. Here, we report the discovery of AG-120 (ivosidenib), an inhibitor of the IDH1 mutant enzyme that exhibits profound 2-HG lowering in tumor models and the ability to effect differentiation of primary patient AML samples ex vivo. Preliminary data from phase 1 clinical trials enrolling patients with cancers harboring an IDH1 mutation indicate that AG-120 has an acceptable safety profile and clinical activity.

A practical drug discovery project at the undergraduate level.

Science.gov (United States)

Fray, M Jonathan; Macdonald, Simon J F; Baldwin, Ian R; Barton, Nick; Brown, Jack; Campbell, Ian B; Churcher, Ian; Coe, Diane M; Cooper, Anthony W J; Craven, Andrew P; Fisher, Gail; Inglis, Graham G A; Kelly, Henry A; Liddle, John; Maxwell, Aoife C; Patel, Vipulkumar K; Swanson, Stephen; Wellaway, Natalie

2013-12-01

In this article, we describe a practical drug discovery project for third-year undergraduates. No previous knowledge of medicinal chemistry is assumed. Initial lecture workshops cover the basic principles; then students, in teams, seek to improve the profile of a weakly potent, insoluble phosphatidylinositide 3-kinase delta (PI3Kδ) inhibitor (1) through compound array design, molecular modelling, screening data analysis and the synthesis of target compounds in the laboratory. The project benefits from significant industrial support, including lectures, student mentoring and consumables. The aim is to make the learning experience as close as possible to real-life industrial situations. In total, 48 target compounds were prepared, the best of which (5b, 5j, 6b and 6ap) improved the potency and aqueous solubility of the lead compound (1) by 100-1000 fold and ≥tenfold, respectively. Copyright © 2013 Elsevier Ltd. All rights reserved.

Discovery and structure-activity relationships of (2-(arylthio)benzylideneamino)guanidines as a novel series of potent apoptosis inducers.

Science.gov (United States)

Zhang, Han-Zhong; Crogan-Grundy, Candace; May, Chris; Drewe, John; Tseng, Ben; Cai, Sui Xiong

2009-04-01

1-(2-(2,5-Dimethoxyphenylthio)benzylidene)semicarbazide (2a) was discovered as a potent apoptosis inducer through our cell based HTS assay. SAR study led to the discovery of a more aqueous soluble analog (2-(2,5-dimethoxyphenylthio)-6-methoxybenzylideneamino)guanidine (5e) with EC(50) value of 60 nM in the caspase activation assay and GI(50) value of 62 nM in the growth inhibition assay in T47D cells. Compound 5e was found to be an inhibitor of tubulin polymerization and efficacious in a MX-1 breast tumor model.

The discovery of radioactivity: the centenary

International Nuclear Information System (INIS)

Patil, S.K.

1995-01-01

In the last decade of the nineteenth century, a number of fundamental discoveries of outstanding importance were made unexpectedly which marked the beginning of a new era in physics. A cascade of spectacular discoveries began with the announcement of the discovery of x-rays by Roentgen followed by the discoveries, in quick succession, of radioactivity by Becquerel, of Zeeman effect, of electron by J.J. Thomson, and of polonium and radium by the Curies. Both x-rays and radioactivity have wide applications in scientific, medical and industrial fields and have made outstanding contribution to the advancement of human knowledge and welfare. Radioactivity is well known and no other discovery in the field of physics or chemistry has had a more profound effect on our fundamental knowledge of nature. Present article, on the occasion of the centenary of the discovery of radioactivity, makes an attempt to describe some glimpses of the history of radioactivity. (author). 59 refs

The π discovery

International Nuclear Information System (INIS)

Fowler, P.H.

1988-01-01

The paper traces the discovery of the Π meson. The discovery was made by exposure of nuclear emulsions to cosmic radiation at high altitudes, with subsequent scanning of the emulsions for meson tracks. Disintegration of nuclei by a negative meson, and the decay of a Π meson were both observed. Further measurements revealed the mass of the meson. The studies carried out on the origin of the Π-mesons, and their mode of decay, are both described. (U.K.)

Designing for Discovery Learning of Complexity Principles of Congestion by Driving Together in the TrafficJams Simulation

Science.gov (United States)

Levy, Sharona T.; Peleg, Ran; Ofeck, Eyal; Tabor, Naamit; Dubovi, Ilana; Bluestein, Shiri; Ben-Zur, Hadar

2018-01-01

We propose and evaluate a framework supporting collaborative discovery learning of complex systems. The framework blends five design principles: (1) individual action: amidst (2) social interactions; challenged with (3) multiple tasks; set in (4) a constrained interactive learning environment that draws attention to (5) highlighted target…

Drug discovery for alopecia: gone today, hair tomorrow.

Science.gov (United States)

Santos, Zenildo; Avci, Pinar; Hamblin, Michael R

2015-03-01

Hair loss or alopecia affects the majority of the population at some time in their life, and increasingly, sufferers are demanding treatment. Three main types of alopecia (androgenic [AGA], areata [AA] and chemotherapy-induced [CIA]) are very different, and have their own laboratory models and separate drug-discovery efforts. In this article, the authors review the biology of hair, hair follicle (HF) cycling, stem cells and signaling pathways. AGA, due to dihydrotesterone, is treated by 5-α reductase inhibitors, androgen receptor blockers and ATP-sensitive potassium channel-openers. AA, which involves attack by CD8(+)NK group 2D-positive (NKG2D(+)) T cells, is treated with immunosuppressives, biologics and JAK inhibitors. Meanwhile, CIA is treated by apoptosis inhibitors, cytokines and topical immunotherapy. The desire to treat alopecia with an easy topical preparation is expected to grow with time, particularly with an increasing aging population. The discovery of epidermal stem cells in the HF has given new life to the search for a cure for baldness. Drug discovery efforts are being increasingly centered on these stem cells, boosting the hair cycle and reversing miniaturization of HF. Better understanding of the molecular mechanisms underlying the immune attack in AA will yield new drugs. New discoveries in HF neogenesis and low-level light therapy will undoubtedly have a role to play.

Synthetic biology of antimicrobial discovery

Science.gov (United States)

Zakeri, Bijan; Lu, Timothy K.

2012-01-01

Antibiotic discovery has a storied history. From the discovery of penicillin by Sir Alexander Fleming to the relentless quest for antibiotics by Selman Waksman, the stories have become like folklore, used to inspire future generations of scientists. However, recent discovery pipelines have run dry at a time when multidrug resistant pathogens are on the rise. Nature has proven to be a valuable reservoir of antimicrobial agents, which are primarily produced by modularized biochemical pathways. Such modularization is well suited to remodeling by an interdisciplinary approach that spans science and engineering. Herein, we discuss the biological engineering of small molecules, peptides, and non-traditional antimicrobials and provide an overview of the growing applicability of synthetic biology to antimicrobials discovery. PMID:23654251

'The Lusiads', poem of discovery

Directory of Open Access Journals (Sweden)

Natasha Furlan Felizi

2016-07-01

Full Text Available The article proposes reading Os Lusíadas as a discovery journey. Discovery here read as aletheia or “revelation”, as proposed by Sophia de Mello Brey­ner Andresen in 1980. Using Martin Heidegger’s notion of aletheia in the book Parmenides along with Jorge de Sena and Sophia de Mello Breyner Andresen reflections on Camões, I’ll seek to point out alternative readings for Os Lusíadas as a “discovery journey”.

Computational methods in drug discovery

OpenAIRE

Sumudu P. Leelananda; Steffen Lindert

2016-01-01

The process for drug discovery and development is challenging, time consuming and expensive. Computer-aided drug discovery (CADD) tools can act as a virtual shortcut, assisting in the expedition of this long process and potentially reducing the cost of research and development. Today CADD has become an effective and indispensable tool in therapeutic development. The human genome project has made available a substantial amount of sequence data that can be used in various drug discovery project...

Choosing Discovery: A Literature Review on the Selection and Evaluation of Discovery Layers

Science.gov (United States)

Moore, Kate B.; Greene, Courtney

2012-01-01

Within the next few years, traditional online public access catalogs will be replaced by more robust and interconnected discovery layers that can serve as primary public interfaces to simultaneously search many separate collections of resources. Librarians have envisioned this type of discovery tool since the 1980s, and research shows that…

Investigations into Library Web-Scale Discovery Services

Directory of Open Access Journals (Sweden)

Jason Vaughan

2008-03-01

Full Text Available Web-scale discovery services for libraries provide deep discovery to a library’s local and licensed content, and represent an evolution, perhaps a revolution, for end user information discovery as pertains to library collections.  This article frames the topic of web-scale discovery, and begins by illuminating web-scale discovery from an academic library’s perspective – that is, the internal perspective seeking widespread staff participation in the discovery conversation.  This included the creation of a discovery task force, a group which educated library staff, conducted internal staff surveys, and gathered observations from early adopters.  The article next addresses the substantial research conducted with library vendors which have developed these services.  Such work included drafting of multiple comprehensive question lists distributed to the vendors, onsite vendor visits, and continual tracking of service enhancements.  Together, feedback gained from library staff, insights arrived at by the Discovery Task Force, and information gathered from vendors collectively informed the recommendation of a service for the UNLV Libraries.

The Europa Ocean Discovery mission

Energy Technology Data Exchange (ETDEWEB)

Edwards, B.C. [Los Alamos National Lab., NM (United States); Chyba, C.F. [Univ. of Arizona, Tucson, AZ (United States); Abshire, J.B. [National Aeronautics and Space Administration, Greenbelt, MD (United States). Goddard Space Flight Center] [and others

1997-06-01

Since it was first proposed that tidal heating of Europa by Jupiter might lead to liquid water oceans below Europa`s ice cover, there has been speculation over the possible exobiological implications of such an ocean. Liquid water is the essential ingredient for life as it is known, and the existence of a second water ocean in the Solar System would be of paramount importance for seeking the origin and existence of life beyond Earth. The authors present here a Discovery-class mission concept (Europa Ocean Discovery) to determine the existence of a liquid water ocean on Europa and to characterize Europa`s surface structure. The technical goal of the Europa Ocean Discovery mission is to study Europa with an orbiting spacecraft. This goal is challenging but entirely feasible within the Discovery envelope. There are four key challenges: entering Europan orbit, generating power, surviving long enough in the radiation environment to return valuable science, and complete the mission within the Discovery program`s launch vehicle and budget constraints. The authors will present here a viable mission that meets these challenges.

DISCOVERY OF A MAKEMAKEAN MOON

Energy Technology Data Exchange (ETDEWEB)

Parker, Alex H.; Buie, Marc W. [Southwest Research Institute, 1050 Walnut Street, Suite 300, Boulder, CO 80302 (United States); Grundy, Will M. [Lowell Observatory, Flagstaff, AZ (United States); Noll, Keith S., E-mail: aparker@boulder.swri.edu [NASA Goddard Space Flight Center, Greenbelt, MD (United States)

2016-07-01

We describe the discovery of a satellite in orbit about the dwarf planet (136472) Makemake. This satellite, provisionally designated S/2015 (136472) 1, was detected in imaging data collected with the Hubble Space Telescope ’s Wide Field Camera 3 on UTC 2015 April 27 at 7.80 ± 0.04 mag fainter than Makemake and at a separation of 0.″57. It likely evaded detection in previous satellite searches due to a nearly edge-on orbital configuration, placing it deep within the glare of Makemake during a substantial fraction of its orbital period. This configuration would place Makemake and its satellite near a mutual event season. Insufficient orbital motion was detected to make a detailed characterization of its orbital properties, prohibiting a measurement of the system mass with the discovery data alone. Preliminary analysis indicates that if the orbit is circular, its orbital period must be longer than 12.4 days and must have a semimajor axis ≳21,000 km. We find that the properties of Makemake’s moon suggest that the majority of the dark material detected in the system by thermal observations may not reside on the surface of Makemake, but may instead be attributable to S/2015 (136472) 1 having a uniform dark surface. This “dark moon hypothesis” can be directly tested with future James Webb Space Telescope observations. We discuss the implications of this discovery for the spin state, figure, and thermal properties of Makemake and the apparent ubiquity of trans-Neptunian dwarf planet satellites.

Discovery of a Makemakean Moon

Science.gov (United States)

Parker, Alex H.; Buie, Marc W.; Grundy, Will M.; Noll, Keith S.

2016-01-01

We describe the discovery of a satellite in orbit about the dwarf planet (136472) Makemake. This satellite, provisionally designated S/2015 (136472) 1, was detected in imaging data collected with the Hubble Space Telescope's Wide Field Camera 3 on UTC 2015 April 27 at 7.80 +/- 0.04 mag fainter than Makemake and at a separation of 0farcs57. It likely evaded detection in previous satellite searches due to a nearly edge-on orbital configuration, placing it deep within the glare of Makemake during a substantial fraction of its orbital period. This configuration would place Makemake and its satellite near a mutual event season. Insufficient orbital motion was detected to make a detailed characterization of its orbital properties, prohibiting a measurement of the system mass with the discovery data alone. Preliminary analysis indicates that if the orbit is circular, its orbital period must be longer than 12.4 days and must have a semimajor axis > or approx. = 21,000 km. We find that the properties of Makemake's moon suggest that the majority of the dark material detected in the system by thermal observations may not reside on the surface of Makemake, but may instead be attributable to S/2015 (136472) 1 having a uniform dark surface. This dark moon hypothesis can be directly tested with future James Webb Space Telescope observations. We discuss the implications of this discovery for the spin state, figure, and thermal properties of Makemake and the apparent ubiquity of trans-Neptunian dwarf planet satellites.

First EURONEAR NEA discoveries from La Palma using the INT

Science.gov (United States)

Vaduvescu, O.; Hudin, L.; Tudor, V.; Char, F.; Mocnik, T.; Kwiatkowski, T.; de Leon, J.; Cabrera-Lavers, A.; Alvarez, C.; Popescu, M.; Cornea, R.; Díaz Alfaro, M.; Ordonez-Etxeberria, I.; Kamiński, K.; Stecklum, B.; Verdes-Montenegro, L.; Sota, A.; Casanova, V.; Martin Ruiz, S.; Duffard, R.; Zamora, O.; Gomez-Jimenez, M.; Micheli, M.; Koschny, D.; Busch, M.; Knofel, A.; Schwab, E.; Negueruela, I.; Dhillon, V.; Sahman, D.; Marchant, J.; Génova-Santos, R.; Rubiño-Martín, J. A.; Riddick, F. C.; Mendez, J.; Lopez-Martinez, F.; Gänsicke, B. T.; Hollands, M.; Kong, A. K. H.; Jin, R.; Hidalgo, S.; Murabito, S.; Font, J.; Bereciartua, A.; Abe, L.; Bendjoya, P.; Rivet, J. P.; Vernet, D.; Mihalea, S.; Inceu, V.; Gajdos, S.; Veres, P.; Serra-Ricart, M.; Abreu Rodriguez, D.

2015-05-01

Since 2006, the European Near Earth Asteroids Research (EURONEAR) project has been contributing to the research of near-Earth asteroids (NEAs) within a European network. One of the main aims is the amelioration of the orbits of NEAs, and starting in 2014 February we focus on the recovery of one-opposition NEAs using the Isaac Newton Telescope (INT) in La Palma in override mode. Part of this NEA recovery project, since 2014 June EURONEAR serendipitously started to discover and secure the first NEAs from La Palma and using the INT, thanks to the teamwork including amateurs and students who promptly reduce the data, report discoveries and secure new objects recovered with the INT and few other telescopes from the EURONEAR network. Five NEAs were discovered with the INT, including 2014 LU14, 2014 NL52 (one very fast rotator), 2014 OL339 (the fourth known Earth quasi-satellite), 2014 SG143 (a quite large NEA), and 2014 VP. Another very fast moving NEA was discovered but was unfortunately lost due to lack of follow-up time. Additionally, another 14 NEA candidates were identified based on two models, all being rapidly followed-up using the INT and another 11 telescopes within the EURONEAR network. They include one object discovered by Pan-STARRS, two Mars crossers, two Hungarias, one Jupiter trojan, and other few inner main belt asteroids (MBAs). Using the INT and Sierra Nevada 1.5 m for photometry, then the Gran Telescopio de Canarias for spectroscopy, we derived the very rapid rotation of 2014 NL52, then its albedo, magnitude, size, and its spectral class. Based on the total sky coverage in dark conditions, we evaluate the actual survey discovery rate using 2-m class telescopes. One NEA is possible to be discovered randomly within minimum 2.8 deg2 and maximum 5.5 deg2. These findings update our past statistics, being based on double sky coverage and taking into account the recent increase in discovery.

Fragrance material review on 1-(5,5-dimethylcyclohexen-1-yl)pent-4-en-1-one.

Science.gov (United States)

Scognamiglio, J; Letizia, C S; Api, A M

2013-12-01

A toxicologic and dermatologic review of 1-(5,5-dimethylcyclohexen-1-yl)pent-4-en-1-one when used as a fragrance ingredient is presented. 1-(5,5-Dimethylcyclohexen-1-yl)pent-4-en-1-one is a member of the fragrance structural group Alkyl Cyclic Ketones. These fragrances can be described as being composed of an alkyl, R1, and various substituted and bicyclic saturated or unsaturated cyclic hydrocarbons, R2, in which one of the rings may include up to 12 carbons. Alternatively, R2 may be a carbon bridge of C2-C4 carbon chain length between the ketone and cyclic hydrocarbon. This review contains a detailed summary of all published and unpublished toxicology and dermatology papers that are related to this individual fragrance ingredient and is not intended as a stand-alone document. Available data for 1-(5,5-dimethylcyclohexen-1-yl)pent-4-en-1-one were evaluated then summarized and includes physical properties, acute toxicity, skin irritation, mucous membrane (eye) irritation, skin sensitization, and photoallergy data. A safety assessment of the entire Alkyl Cyclic Ketones will be published simultaneously with this document; please refer to Belsito et al. (Belsito, D., Bickers, D., Bruze, M., Calow, P., Dagli, M., Fryer, A.D., Greim, H., Miyachi, Y., Saurat, J.H., Sipes, I.G., 2013. A Toxicologic and Dermatologic Assessment of Alkyl Cyclic Ketones When Used as Fragrance Ingredients (submitted for publication)) for an overall assessment of the safe use of this material and all Alkyl Cyclic Ketones in fragrances. Copyright © 2013 Elsevier Ltd. All rights reserved.

Secreted proteins as a fundamental source for biomarker discovery

Czech Academy of Sciences Publication Activity Database

Šťastná, Miroslava; Van Eyk, J.E.

2012-01-01

Roč. 12, 4-5 (2012), s. 722-735 ISSN 1615-9853 Institutional research plan: CEZ:AV0Z40310501 Keywords : conditioned media * secreted proteins * proteomics * biomarker discovery Subject RIV: CB - Analytical Chemistry, Separation Impact factor: 4.132, year: 2012

Discovery of the neutron (to the fiftieth anniversary of neutron discovery)

International Nuclear Information System (INIS)

Pasechnik, M.V.

1984-01-01

Development of neutron physics in the USSR for the recent 50 years from the moment of neutron discovery is considered. History of neutron discovery is presented in brief. Neutron properties and fundamental problems of physics: electric dipole neutron moment, neutron β-decay, neutron interaction with nuclei and potential of nucleon interaction not conserving spatial parity are discussed. Main aspects of neutron physics application in power engineering, nuclear technology and other branches of science and technique are set forth

STECH VOL5 (1) FEBRUARY, 2016

African Journals Online (AJOL)

Copyright 1AARR 2012-2016: www.afrrevjo.net

2016-02-11

Feb 11, 2016 ... This study investigated impact of prior knowledge of behavioural objectives on ... These discoveries and the level of technological advancement had led to the ... has a great deal to do with students' motivation and learning. ..... objectives on students' achievement and retention in social studies in Akwa.

Representation Discovery using Harmonic Analysis

CERN Document Server

Mahadevan, Sridhar

2008-01-01

Representations are at the heart of artificial intelligence (AI). This book is devoted to the problem of representation discovery: how can an intelligent system construct representations from its experience? Representation discovery re-parameterizes the state space - prior to the application of information retrieval, machine learning, or optimization techniques - facilitating later inference processes by constructing new task-specific bases adapted to the state space geometry. This book presents a general approach to representation discovery using the framework of harmonic analysis, in particu

Antibody informatics for drug discovery

DEFF Research Database (Denmark)

Shirai, Hiroki; Prades, Catherine; Vita, Randi

2014-01-01

to the antibody science in every project in antibody drug discovery. Recent experimental technologies allow for the rapid generation of large-scale data on antibody sequences, affinity, potency, structures, and biological functions; this should accelerate drug discovery research. Therefore, a robust bioinformatic...... infrastructure for these large data sets has become necessary. In this article, we first identify and discuss the typical obstacles faced during the antibody drug discovery process. We then summarize the current status of three sub-fields of antibody informatics as follows: (i) recent progress in technologies...... for antibody rational design using computational approaches to affinity and stability improvement, as well as ab-initio and homology-based antibody modeling; (ii) resources for antibody sequences, structures, and immune epitopes and open drug discovery resources for development of antibody drugs; and (iii...

Are 1,4- and 1,5-disubstituted 1,2,3-triazoles good pharmacophoric groups?

Science.gov (United States)

Massarotti, Alberto; Aprile, Silvio; Mercalli, Valentina; Del Grosso, Erika; Grosa, Giorgio; Sorba, Giovanni; Tron, Gian Cesare

2014-11-01

Over the last decade, 1,2,3-triazoles have received increasing attention in medicinal chemistry thanks to the discovery of the highly useful and widely applicable 1,3-dipolar cycloaddition reaction between azides and alkynes (click chemistry) catalyzed by copper salts and ruthenium complexes. After a decade of medicinal chemistry research on 1,2,3-triazoles, we feel that the time is ripe to demonstrate the real ability of this heterocycle to participate in important and pivotal binding interactions with biological targets while maintaining a good pharmacokinetic profile. In this study, we retrieved and analyzed X-ray crystal structures of complexes between 1,2,3-triazoles and either proteins or DNA to understand the pharmacophoric role of the triazole. Furthermore, the metabolic stability, the capacity to inhibit cytochromes, and the contribution of 1,2,3-triazoles to the overall aqueous solubility of compounds containing them have been analyzed. This information should furnish fresh insight for medicinal chemists in the design of novel bioactive molecules that contain the triazole nucleus. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

"Drug" Discovery with the Help of Organic Chemistry.

Science.gov (United States)

Itoh, Yukihiro; Suzuki, Takayoshi

2017-01-01

The first step in "drug" discovery is to find compounds binding to a potential drug target. In modern medicinal chemistry, the screening of a chemical library, structure-based drug design, and ligand-based drug design, or a combination of these methods, are generally used for identifying the desired compounds. However, they do not necessarily lead to success and there is no infallible method for drug discovery. Therefore, it is important to explore medicinal chemistry based on not only the conventional methods but also new ideas. So far, we have found various compounds as drug candidates. In these studies, some strategies based on organic chemistry have allowed us to find drug candidates, through 1) construction of a focused library using organic reactions and 2) rational design of enzyme inhibitors based on chemical reactions catalyzed by the target enzyme. Medicinal chemistry based on organic chemical reactions could be expected to supplement the conventional methods. In this review, we present drug discovery with the help of organic chemistry showing examples of our explorative studies on histone deacetylase inhibitors and lysine-specific demethylase 1 inhibitors.

45 CFR 213.23a - Discovery.

Science.gov (United States)

2010-10-01

... 45 Public Welfare 2 2010-10-01 2010-10-01 false Discovery. 213.23a Section 213.23a Public Welfare... Discovery. The Department and any party named in the notice issued pursuant to § 213.11 shall have the right to conduct discovery (including depositions) against opposing parties. Rules 26-37 of the Federal...

Serendipitous discovery of light-induced (In Situ) formation of an Azo-bridged dimeric sulfonated naphthol as a potent PTP1B inhibitor.

Science.gov (United States)

Bongard, Robert D; Lepley, Michael; Thakur, Khushabu; Talipov, Marat R; Nayak, Jaladhi; Lipinski, Rachel A Jones; Bohl, Chris; Sweeney, Noreena; Ramchandran, Ramani; Rathore, Rajendra; Sem, Daniel S

2017-05-31

Protein tyrosine phosphatases (PTPs) like dual specificity phosphatase 5 (DUSP5) and protein tyrosine phosphatase 1B (PTP1B) are drug targets for diseases that include cancer, diabetes, and vascular disorders such as hemangiomas. The PTPs are also known to be notoriously difficult targets for designing inihibitors that become viable drug leads. Therefore, the pipeline for approved drugs in this class is minimal. Furthermore, drug screening for targets like PTPs often produce false positive and false negative results. Studies presented herein provide important insights into: (a) how to detect such artifacts, (b) the importance of compound re-synthesis and verification, and (c) how in situ chemical reactivity of compounds, when diagnosed and characterized, can actually lead to serendipitous discovery of valuable new lead molecules. Initial docking of compounds from the National Cancer Institute (NCI), followed by experimental testing in enzyme inhibition assays, identified an inhibitor of DUSP5. Subsequent control experiments revealed that this compound demonstrated time-dependent inhibition, and also a time-dependent change in color of the inhibitor that correlated with potency of inhibition. In addition, the compound activity varied depending on vendor source. We hypothesized, and then confirmed by synthesis of the compound, that the actual inhibitor of DUSP5 was a dimeric form of the original inhibitor compound, formed upon exposure to light and oxygen. This compound has an IC 50 of 36 μM for DUSP5, and is a competitive inhibitor. Testing against PTP1B, for selectivity, demonstrated the dimeric compound was actually a more potent inhibitor of PTP1B, with an IC 50 of 2.1 μM. The compound, an azo-bridged dimer of sulfonated naphthol rings, resembles previously reported PTP inhibitors, but with 18-fold selectivity for PTP1B versus DUSP5. We report the identification of a potent PTP1B inhibitor that was initially identified in a screen for DUSP5, implying common

Tanzania Journal of Agricultural Sciences - Vol 2, No 1 (1999)

African Journals Online (AJOL)

Studies on genotype-environment interaction (GxE) in half-sib progenies of cashew (Anacardium occidentale L.) in Tanzania · EMAIL FREE FULL TEXT EMAIL FREE FULL TEXT · DOWNLOAD FULL TEXT DOWNLOAD FULL TEXT. PAL Masawe, EP Cundall, PDS Caligari ...

5-Hydroxypyrido[2,3-b]pyrazin-6(5H)-one derivatives as novel dual inhibitors of HIV-1 reverse transcriptase-associated ribonuclease H and integrase.

Science.gov (United States)

Sun, Lin; Gao, Ping; Dong, Guanyu; Zhang, Xujie; Cheng, Xiqiang; Ding, Xiao; Wang, Xueshun; Daelemans, Dirk; De Clercq, Erik; Pannecouque, Christophe; Menéndez-Arias, Luis; Zhan, Peng; Liu, Xinyong

2018-06-18

We reported herein the design, synthesis and biological evaluation of a series of 5-hydroxypyrido[2,3-b]pyrazin-6(5H)-one derivatives as HIV-1 reverse transcriptase (RT) ribonuclease H (RNase H) inhibitors using a privileged structure-guided scaffold refining strategy. In view of the similarities between the pharmacophore model of RNase H and integrase (IN) inhibitors as well as their catalytic sites, we also performed IN inhibition assays. Notably, the majority of these derivatives inhibited RNase H and IN at micromolar concentrations. Among them, compound 7a exhibited similar inhibitory activity against RNase H and IN (IC 50 RNase H  = 1.77 μM, IC 50 IN  = 1.18 μM, ratio = 1.50). To the best of our knowledge, this is the first reported dual HIV-1 RNase H-IN inhibitor based on a 5-hydroxypyrido[2,3-b]pyrazin-6(5H)-one structure. Molecular modeling has been used to predict the binding mode of 7a in complex with the catalytic cores of HIV-1 RNase H and IN. Taken together these results strongly support the feasibility of developing HIV-1 dual inhibitors from analog-based optimization of divalent metal ion chelators. Recently, the identification of dual inhibitors proved to be a highly effective strategy for novel antivirals discovery. Therefore, these compounds appear to be useful leads that can be further modified to develop more valuable anti-HIV-1 molecules with suitable drug profiles. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Discovery and Optimization of 5-Amino-1,2,3-triazole-4-carboxamide Series against Trypanosoma cruzi.

Science.gov (United States)

Brand, Stephen; Ko, Eun Jung; Viayna, Elisabet; Thompson, Stephen; Spinks, Daniel; Thomas, Michael; Sandberg, Lars; Francisco, Amanda F; Jayawardhana, Shiromani; Smith, Victoria C; Jansen, Chimed; De Rycker, Manu; Thomas, John; MacLean, Lorna; Osuna-Cabello, Maria; Riley, Jennifer; Scullion, Paul; Stojanovski, Laste; Simeons, Frederick R C; Epemolu, Ola; Shishikura, Yoko; Crouch, Sabrinia D; Bakshi, Tania S; Nixon, Christopher J; Reid, Iain H; Hill, Alan P; Underwood, Tim Z; Hindley, Sean J; Robinson, Sharon A; Kelly, John M; Fiandor, Jose M; Wyatt, Paul G; Marco, Maria; Miles, Timothy J; Read, Kevin D; Gilbert, Ian H

2017-09-14

Chagas' disease, caused by the protozoan parasite Trypanosoma cruzi, is the most common cause of cardiac-related deaths in endemic regions of Latin America. There is an urgent need for new safer treatments because current standard therapeutic options, benznidazole and nifurtimox, have significant side effects and are only effective in the acute phase of the infection with limited efficacy in the chronic phase. Phenotypic high content screening against the intracellular parasite in infected VERO cells was used to identify a novel hit series of 5-amino-1,2,3-triazole-4-carboxamides (ATC). Optimization of the ATC series gave improvements in potency, aqueous solubility, and metabolic stability, which combined to give significant improvements in oral exposure. Mitigation of a potential Ames and hERG liability ultimately led to two promising compounds, one of which demonstrated significant suppression of parasite burden in a mouse model of Chagas' disease.

The crystal structure of the mixed-layer Aurivillius phase Bi 5Ti 1.5W 1.5O 15

Science.gov (United States)

Tellier, J.; Boullay, Ph.; Créon, N.; Mercurio, D.

2005-09-01

The crystal structure of the 1+2 mixed-layer Aurivillius phase Bi 5Ti 1.5W 1.5O 15 (SG I2cm n o 46: -cba, Z=4, a=5.4092(3) Å, b=5.3843(3) Å and c=41.529(3) Å) consisting of the ordered intergrowth of one and two octahedra thick perovskite-type blocks separated by [Bi 2O 2] 2+ slabs is reported. Supported by an electron diffraction investigation and, using the Rietveld analysis, it is shown that this compound should be described using a I-centering lattice in agreement with the generalised structural model of the Aurivillius type compounds recently presented by the authors. The structure of this Bi 5Ti 1.5W 1.5O 15 phase is analyzed in comparison with the related simple members (Bi 2WO 6 and Bi 3Ti 1.5W 0.5O 9). The crystal structure of Bi 3Ti 1.5W 0.5O 9 is also reported.

Fragrance material review on 1-(2,4,4,5,5-pentamethyl-1-cyclopenten-1-yl)ethan-1-one.

Science.gov (United States)

Scognamiglio, J; Letizia, C S; Api, A M

2013-12-01

A toxicologic and dermatologic review of 1-(2,4,4,5,5-pentamethyl-1-cyclopenten-1-yl)ethan-1-one when used as a fragrance ingredient is presented. 1-(2,4,4,5,5-Pentamethyl-1-cyclopenten-1-yl)ethan-1-one is a member of the fragrance structural group Alkyl Cyclic Ketones. These fragrances can be described as being composed of an alkyl, R1, and various substituted and bicyclic saturated or unsaturated cyclic hydrocarbons, R2, in which one of the rings may include up to 12 carbons. Alternatively, R2 may be a carbon bridge of C2-C4 carbon chain length between the ketone and cyclic hydrocarbon. This review contains a detailed summary of all available toxicology and dermatology papers that are related to this individual fragrance ingredient and is not intended as a stand-alone document. Available data for 1-(2,4,4,5,5-pentamethyl-1-cyclopenten-1-yl)ethan-1-one were evaluated then summarized and includes physical properties, acute toxicity, skin irritation, mucous membrane (eye) irritation, skin sensitization, phototoxicity, and photoallergy data. A safety assessment of the entire Alkyl Cyclic Ketones will be published simultaneously with this document; please refer to Belsito et al. (Belsito, D., Bickers, D., Bruze, M., Calow, P., Dagli, M., Fryer, A.D., Greim, H., Miyachi, Y., Saurat, J.H., Sipes, I.G., 2013. A Toxicologic and Dermatologic Assessment of Alkyl Cyclic Ketones When Used as Fragrance Ingredients (submitted for publication)) for an overall assessment of the safe use of this material and all Alkyl Cyclic Ketones in fragrances. Copyright © 2013 Elsevier Ltd. All rights reserved.

Microstructure and magnetocaloric effect in cast LaFe11.5Si1.5Bx (x=0.5, 1.0)

International Nuclear Information System (INIS)

Zhang, H.; Long, Y.; Cao, Q.; Mudryk, Ya.; Zou, M.; Gschneidner, K.A.; Pecharsky, V.K.

2010-01-01

Phase formation, structure, and the magnetocaloric effect (MCE) in as-cast LaFe 11.5 Si 1.5 B x (x=0.5, 1.0) compounds have been studied. The Curie temperatures, T C , are ∼211 and 230 K for x=0.5 and 1.0, respectively, which are higher than that of annealed LaFe 11.5 Si 1.5 (T C =183 K), while the maximum magnetic entropy changes at the respective T C under a magnetic field change of 0-5 T are 7.8 and 5.8 J/(kg K). Wavelength dispersive spectrometry (WDS) analysis shows that only a small fraction of boron atoms is dissolved in the NaZn 13 -type structure phase, and that the compositions of the as-cast LaFe 11.5 Si 1.5 B x (x=0.5, 1.0) alloys are much different from the intended nominal compositions. These as-cast alloys exhibit second-order magnetic phase transitions and low MCEs. However, based on the relative cooling power, the as-cast LaFe 11.5 Si 1.5 B x alloys are promising candidates for magnetic refrigerants over a wide temperature range.

Comparison of discovery limits for extra Z bosons at future colliders

International Nuclear Information System (INIS)

Godfrey, S.

1995-01-01

We study and compare the discovery potential for heavy neutral gauge bosons (Z') at various e + e - and pp (-) colliders that are planned or have been proposed. Typical discovery limits are for the Fermilab Tevatron ∼1 TeV, Di-Tevatron ∼2 TeV, CERN LHC ∼4 TeV, LSGNA (a 60 TeV pp collider) ∼13 TeV while the e + e - discovery limits are 2--10x √s with the large variation reflecting the model dependence of the limits. While both types of colliders have comparable discovery limits the hadron colliders are generally less dependent on the specific Z' model and provide more robust limits since the signal has little background. In contrast, discovery limits for e + e - limits are more model dependent and, because they are based on indirect inferences of deviations from standard model predictions, they are more sensitive to systematic errors

Fragrance material review on 1-(2,5,5-trimethylcycloheptyl)ethan-1-one.

Science.gov (United States)

Scognamiglio, J; Letizia, C S; Api, A M

2013-12-01

A toxicologic and dermatologic review of 1-(2,5,5-trimethylcycloheptyl)ethan-1-one when used as a fragrance ingredient is presented. 1-(2,5,5-Trimethylcycloheptyl)ethan-1-one is a member of the fragrance structural group Alkyl Cyclic Ketones. These fragrances can be described as being composed of an alkyl, R1, and various substituted and bicyclic saturated or unsaturated cyclic hydrocarbons, R2, in which one of the rings may include up to 12 carbons. Alternatively, R2 may be a carbon bridge of C2-C4 carbon chain length between the ketone and cyclic hydrocarbon. This review contains a detailed summary of all available toxicology and dermatology papers that are related to this individual fragrance ingredient and is not intended as a stand-alone document. Available data for 1-(2,5,5-trimethylcycloheptyl)ethan-1-one were evaluated then summarized and includes physical properties, skin irritation, mucous membrane (eye) irritation, and skin sensitization data. A safety assessment of the entire Alkyl Cyclic Ketones will be published simultaneously with this document; please refer to Belsito et al. (Belsito, D., Bickers, D., Bruze, M., Calow, P., Dagli, M., Fryer, A.D., Greim, H., Miyachi, Y., Saurat, J.H., Sipes, I.G., 2013. A toxicologic and dermatologic assessment of alkyl cyclic ketones when used as fragrance ingredients. (submitted for publication)) for an overall assessment of the safe use of this material and all Alkyl Cyclic Ketones in fragrances. Copyright © 2013. Published by Elsevier Ltd.

New Methods of Low-Field Magnetic Resonance Imaging for Application to Traumatic Brain Injury

Science.gov (United States)

2013-02-01

8217+-8! $-𔄂&#+! 8#$’+)&4! )*! W! /*! 5)+6! ’! GX! OSB ! 1�)8+6! 9Y?D#)*+! *’/,(-8<@! 3-7&4*+$#7+)&4! )*! ,-$.&$/-8! #*)4%! +6-! ’(%-1$’)7! $-7&4...F! OSB ! *-,’$’+)&4@!N6-!*?//-+$)7!:;2!9(-.+<!$&+’+-*!&>-$! ^R]! 56)(-! +6-! &..*-+! :;2! $&+’+-*! &>-$! GXR]! 󈧴! ,$&>)8-*!*/’((-$!>&0-(!*)B-*!)4!+6

Ocular torsion before and after 1 hour centrifugation

NARCIS (Netherlands)

Groen, E.; Graaf, B. de; Bles, W.; Bos, J.E.

1996-01-01

To assess a possible otolith contribution to effects observed following prolonged expo-sure to hyper gravity, we used video-oculography to measure ocular torsion during static and dynamic conditions of lateral body tilt (roll) before and after one hour of centrifugation with a Gx-load of 3G. Static

On strongly J -clean rings associated with polynomial identity g ( x =0

Directory of Open Access Journals (Sweden)

Hamid Haj seyyed javadi

2014-05-01

Full Text Available In this paper‎, ‎we introduce the new notion of strongly $J $-clean rings associated with polynomial identity $g(x=0$‎, ‎as a generalization of strongly $ J $-clean rings‎. ‎We denote strongly $J $-clean rings associated with polynomial identity $g(x=0$ by strongly $ g(x $-$J $-clean rings‎. ‎Next‎, ‎we investigate some properties of strongly $ g(x $-$ J $-clean.

Anti-amyloid aggregation activity of novel carotenoids: implications for Alzheimer’s drug discovery

Directory of Open Access Journals (Sweden)

Lakey-Beitia J

2017-05-01

Full Text Available Johant Lakey-Beitia,1,2 Deborah Doens,2,3 D Jagadeesh Kumar,4 Enrique Murillo,5 Patricia L Fernandez,3 KS Rao,6 Armando A Durant-Archibold1,5 1Center for Biodiversity and Drug Discovery, Instituto de Investigaciones Científicas y Servicios de Alta Tecnología (INDICASAT AIP, Panama, Republic of Panama; 2Department of Biotechnology, Acharya Nagarjuna University, Guntur, India; 3Center for Molecular and Cellular Biology of Diseases, Instituto de Investigaciones Científicas y Servicios de Alta Tecnología (INDICASAT AIP, Panama, Republic of Panama; 4Department of Biotechnology, Sir M Visvesvaraya Institute of Technology, Bangalore, India; 5Department of Biochemistry, College of Natural, Exact Sciences and Technology, University of Panama, Panama, Republic of Panama; 6Center for Neuroscience, Instituto de Investigaciones Científicas y Servicios de Alta Tecnología (INDICASAT AIP, Panama, Republic of Panama Abstract: Alzheimer’s disease (AD is the leading cause of dementia, affecting approximately 33.5 million people worldwide. Aging is the main risk factor associated with AD. Drug discovery based on nutraceutical molecules for prevention and treatment of AD is a growing topic. In this sense, carotenoids are phytochemicals present mainly in fruits and vegetables with reported benefits for human health. In this research, the anti-amyloidogenic activity of three carotenoids, cryptocapsin, cryptocapsin-5,6-epoxide, and zeaxanthin, was assessed. Cryptocapsin showed the highest bioactivity, while cryptocapsin-5,6-epoxide and zeaxanthin exhibited similar activity on anti-aggregation assays. Molecular modeling analysis revealed that the evaluated carotenoids might follow two mechanisms for inhibiting Aβ aggregation: by preventing the formation of the fibril and through disruption of the Aβ aggregates. Our studies provided evidence that cryptocapsin, cryptocapsin-5,6-epoxide, and zeaxanthin have anti-amyloidogenic potential and could be used for

Intramolecular Parallel [4+3] Cycloadditions of Cyclopropane 1,1-Diesters with [3]Dendralenes: Efficient Construction of [5.3.0]Decane and Corresponding Polycyclic Skeletons.

Science.gov (United States)

Zhang, Chi; Tian, Jun; Ren, Jun; Wang, Zhongwen

2017-01-26

Aiming to develop efficient and general strategies for construction of complex and diverse polycyclic skeletons, we have successfully developed [4+3]IMPC (intramolecular parallel cycloaddition) of cyclopropane 1,1-diesters with [3]dendralenes. With a combination of the [4+3]IMPC and subsequent [4+n] cycloadditions, trans-[5.3.0]decane skeleton and its corresponding structurally complex and diverse polycyclic variants could be constructed efficiently. This novel [4+3] cycloaddition reaction mode of donor-acceptor cyclopropanes proceeds as a result of the ring-strain relief of a trans-[3.3.0]octane. We strongly believe that the developed methods will demonstrate potential applications in natural products synthesis and drug discovery. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Difficult scenarios for NMSSM Higgs discovery at the LHC

International Nuclear Information System (INIS)

Ellwanger, Ulrich; Gunion, John F.; Hugonie, Cyril

2005-01-01

We identify scenarios not ruled out by LEP data in which NMSSM Higgs detection at the LHC will be particularly challenging. We first review the 'no-lose' theorem for Higgs discovery at the LHC that applies if Higgs bosons do not decay to other Higgs bosons - namely, with L = 300 fb -1 , there is always one or more 'standard' Higgs detection channel with at least a 5σ signal. However, we provide examples of no-Higgs-to-Higgs cases for which all the standard signals are no larger than 7σ implying that if the available L is smaller or the simulations performed by ATLAS and CMS turn out to be overly optimistic, all standard Higgs signals could fall below 5σ even in the no-Higgs-to-Higgs part of NMSSM parameter space. In the vast bulk of NMSSM parameter space, there will be Higgs-to-Higgs decays. We show that when such decays are present it is possible for all the standard detection channels to have very small significance. In most such cases, the only strongly produced Higgs boson is one with fairly SM-like couplings that decays to two lighter Higgs bosons (either a pair of the lightest CP-even Higgs bosons, or, in the largest part of parameter space, a pair of the lightest CP-odd Higgs bosons). A number of representative bench-mark scenarios of this type are delineated in detail and implications for Higgs discovery at various colliders are discussed

Discovery of the Higgs Boson Decaying to Two Photons

CERN Document Server

AUTHOR|(CDS)2075371; Branson, James; Pieri, Marco

2014-09-10

The Standard Model (SM) of particle physics fundamentally relies on the existence of the Higgs boson. This massive particle is a relic of the underlying and hidden Higgs field, whose transformation into the Higgs boson provides mass to weak bosons and all massive fermions in the SM. This particle has been long-sought and finally using data from proton-proton collisions at the LHC, CMS and ATLAS experiments have discovered a particle which is compatible with the SM Higgs boson. Presented here is the development of one of the discovery channels, $\\mathrm{H}\\rightarrow\\gamma\\gamma$, and the final $\\mathrm{H}\\rightarrow\\gamma\\gamma$ analysis and results using the full luminosity of the LHC Run 1 dataset $\\sim$25 $\\mathrm{fb}^{-1}$ at 7 or 8 TeV center of mass energy. The observed (expected) significance of this di-photon excess in the final analysis is $5.7\\sigma$ ($5.2\\sigma$) with a measured signal strength of $\\sigma / \\sigma_{SM} = 1.14^{+0.26}_{-0.23}$. The mass of this Higgs boson is not predicted by t...

Discovery of massive neutral vector mesons

International Nuclear Information System (INIS)

Anon.

1976-01-01

Personal accounts of the discovery of massive neutral vector mesons (psi particles) are given by researchers S. Ting, G. Goldhaber, and B. Richter. The double-arm spectrometer and the Cherenkov effect are explained in a technical note, and the solenoidal magnetic detector is discussed in an explanatory note for nonspecialists. Reprints of three papers in Physical Review Letters which announced the discovery of the particles are given: Experimental observation of a heavy particle J, Discovery of a narrow resonance in e + e - annihilation, and Discovery of a second narrow resonance in e + e - annihilation. A discussion of subsequent developments and scientific biographies of the three authors are also presented. 25 figures

Risk score modeling of multiple gene to gene interactions using aggregated-multifactor dimensionality reduction

Directory of Open Access Journals (Sweden)

Dai Hongying

2013-01-01

Full Text Available Abstract Background Multifactor Dimensionality Reduction (MDR has been widely applied to detect gene-gene (GxG interactions associated with complex diseases. Existing MDR methods summarize disease risk by a dichotomous predisposing model (high-risk/low-risk from one optimal GxG interaction, which does not take the accumulated effects from multiple GxG interactions into account. Results We propose an Aggregated-Multifactor Dimensionality Reduction (A-MDR method that exhaustively searches for and detects significant GxG interactions to generate an epistasis enriched gene network. An aggregated epistasis enriched risk score, which takes into account multiple GxG interactions simultaneously, replaces the dichotomous predisposing risk variable and provides higher resolution in the quantification of disease susceptibility. We evaluate this new A-MDR approach in a broad range of simulations. Also, we present the results of an application of the A-MDR method to a data set derived from Juvenile Idiopathic Arthritis patients treated with methotrexate (MTX that revealed several GxG interactions in the folate pathway that were associated with treatment response. The epistasis enriched risk score that pooled information from 82 significant GxG interactions distinguished MTX responders from non-responders with 82% accuracy. Conclusions The proposed A-MDR is innovative in the MDR framework to investigate aggregated effects among GxG interactions. New measures (pOR, pRR and pChi are proposed to detect multiple GxG interactions.

Estudio de la viabilidad de fabricación de un sistema codo (fundición inoxidable ferrítica, GX 260 Cr27-tubo composite (Incolloy 800 HT+Stal 2465 solidario por fusión

Directory of Open Access Journals (Sweden)

Gutiérrez de Solabarría, S.

1995-10-01

Full Text Available Flying ashes captured by ciclones in the experimental plant for combustion in pressure fluid bed, in Escatrón Power Plant (Zaragoza, Spain, circulate through the gas cleaning system and are evacuated by means of pneumatic transport. The temperature of these ashes is aprox. 800 °C and the relative pressure is up to 8 negative bars relating the outdoor pressure of the transport pipe. The configuration of the pneumatic transport lines is Incolloy 800 HT quality composite tubes lined with Stal 2465 in straight stretches. Regarding direction changes, ferritic stainless casting, quality GX 260 Cr 27 elbows are used. The aim of this work is to study the possibility of manufacturing a solidary system by means of melting between the ferritic stainless casting elbow and the composite pipe.

Las cenizas volantes captadas por ciclones en la planta experimental de combustión en lecho fluido a presión, de la central térmica de Escatrón (Zaragoza, circulan por el sistema de depuración de gases y son evacuadas mediante transporte neumático. Estas cenizas se encuentran a una temperatura aproximada de 800 °C y a una presión relativa de hasta 8 bares negativos con respecto a la presión en el exterior de la tubería de transporte. Para configurar las líneas de transporte neumático, se utilizan en los tramos rectos tubos composite de calidad Incolloy 800 HT recubiertos interiormente de material Stal 2465. Para los cambios de dirección, se utilizan codos de fundición inoxidable ferrítica de calidad GX 260 Cr 27. El objetivo del presente trabajo es estudiar la viabilidad de fabricación de un sistema solidario por fusión entre el codo de fundición inoxidable ferrítica y la tubería composite.

Conceptual Design For Interplanetary Spaceship Discovery

Science.gov (United States)

Benton, Mark G.

2006-01-01

With the recently revived national interest in Lunar and Mars missions, this design study was undertaken by the author in an attempt to satisfy the long-term space exploration vision of human travel ``to the Moon, Mars, and beyond'' with a single design or family of vehicles. This paper describes a conceptual design for an interplanetary spaceship of the not-to-distant future. It is a design that is outwardly similar to the spaceship Discovery depicted in the novel ``2001 - A Space Odyssey'' and film of the same name. Like its namesake, this spaceship could one day transport a human expedition to explore the moons of Jupiter. This spaceship Discovery is a real engineering design that is capable of being implemented using technologies that are currently at or near the state-of-the-art. The ship's main propulsion and electrical power are provided by bi-modal nuclear thermal rocket engines. Configurations are presented to satisfy four basic Design Reference Missions: (1) a high-energy mission to Jupiter's moon Callisto, (2) a high-energy mission to Mars, (3) a low-energy mission to Mars, and (4) a high-energy mission to the Moon. The spaceship design includes dual, strap-on boosters to enable the high-energy Mars and Jupiter missions. Three conceptual lander designs are presented: (1) Two types of Mars landers that utilize atmospheric and propulsive braking, and (2) a lander for Callisto or Earth's Moon that utilizes only propulsive braking. Spaceship Discovery offers many advantages for human exploration of the Solar System: (1) Nuclear propulsion enables propulsive capture and escape maneuvers at Earth and target planets, eliminating risky aero-capture maneuvers. (2) Strap-on boosters provide robust propulsive energy, enabling flexibility in mission planning, shorter transit times, expanded launch windows, and free-return abort trajectories from Mars. (3) A backup abort propulsion system enables crew aborts at multiple points in the mission. (4) Clustered NTR

Functional principles of registry-based service discovery

NARCIS (Netherlands)

Sundramoorthy, V.; Tan, C.; Hartel, P.H.; Hartog, den J.I.; Scholten, J.

2005-01-01

As Service Discovery Protocols (SDP) are becoming increasingly important for ubiquitous computing, they must behave according to predefined principles. We present the functional Principles of Service Discovery for robust, registry-based service discovery. A methodology to guarantee adherence to

Historical aspects of the discovery of plutonium

International Nuclear Information System (INIS)

Clark, David L.

2016-01-01

The historical events that led up to the discovery of plutonium and subsequently, how that discovery helped shape the modern period table of the elements, and ushered in a new era of nuclear science and technology are discussed. When the first of the transuranium elements, neptunium was discovered, it was realized that the radioactive βdecay of "2"3"9Np should lead to the formation of element 94. The scale of the experiments at that time, however, precluded its identification. Plutonium was first produced late in 1940 by Seaborg, McMillan, Kennedy, and Wahl1,2 by bombarding uranium with deuterons to produce the isotope "2"3"8Pu

Materials Discovery | Materials Science | NREL

Science.gov (United States)

Discovery Materials Discovery Images of red and yellow particles NREL's research in materials characterization of sample by incoming beam and measuring outgoing particles, with data being stored and analyzed Staff Scientist Dr. Zakutayev specializes in design of novel semiconductor materials for energy

On the pulse of discovery

Science.gov (United States)

2017-12-01

What started 50 years ago as a `smudge' on paper has flourished into a fundamental field of astrophysics replete with unexpected applications and exciting discoveries. To celebrate the discovery of pulsars, we look at the past, present and future of pulsar astrophysics.

Discovery of rare protein-coding genes in model methylotroph Methylobacterium extorquens AM1.

Science.gov (United States)

Kumar, Dhirendra; Mondal, Anupam Kumar; Yadav, Amit Kumar; Dash, Debasis

2014-12-01

Proteogenomics involves the use of MS to refine annotation of protein-coding genes and discover genes in a genome. We carried out comprehensive proteogenomic analysis of Methylobacterium extorquens AM1 (ME-AM1) from publicly available proteomics data with a motive to improve annotation for methylotrophs; organisms capable of surviving in reduced carbon compounds such as methanol. Besides identifying 2482(50%) proteins, 29 new genes were discovered and 66 annotated gene models were revised in ME-AM1 genome. One such novel gene is identified with 75 peptides, lacks homolog in other methylobacteria but has glycosyl transferase and lipopolysaccharide biosynthesis protein domains, indicating its potential role in outer membrane synthesis. Many novel genes are present only in ME-AM1 among methylobacteria. Distant homologs of these genes in unrelated taxonomic classes and low GC-content of few genes suggest lateral gene transfer as a potential mode of their origin. Annotations of methylotrophy related genes were also improved by the discovery of a short gene in methylotrophy gene island and redefining a gene important for pyrroquinoline quinone synthesis, essential for methylotrophy. The combined use of proteogenomics and rigorous bioinformatics analysis greatly enhanced the annotation of protein-coding genes in model methylotroph ME-AM1 genome. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Discovery radiomics via evolutionary deep radiomic sequencer discovery for pathologically proven lung cancer detection.

Science.gov (United States)

Shafiee, Mohammad Javad; Chung, Audrey G; Khalvati, Farzad; Haider, Masoom A; Wong, Alexander

2017-10-01

While lung cancer is the second most diagnosed form of cancer in men and women, a sufficiently early diagnosis can be pivotal in patient survival rates. Imaging-based, or radiomics-driven, detection methods have been developed to aid diagnosticians, but largely rely on hand-crafted features that may not fully encapsulate the differences between cancerous and healthy tissue. Recently, the concept of discovery radiomics was introduced, where custom abstract features are discovered from readily available imaging data. We propose an evolutionary deep radiomic sequencer discovery approach based on evolutionary deep intelligence. Motivated by patient privacy concerns and the idea of operational artificial intelligence, the evolutionary deep radiomic sequencer discovery approach organically evolves increasingly more efficient deep radiomic sequencers that produce significantly more compact yet similarly descriptive radiomic sequences over multiple generations. As a result, this framework improves operational efficiency and enables diagnosis to be run locally at the radiologist's computer while maintaining detection accuracy. We evaluated the evolved deep radiomic sequencer (EDRS) discovered via the proposed evolutionary deep radiomic sequencer discovery framework against state-of-the-art radiomics-driven and discovery radiomics methods using clinical lung CT data with pathologically proven diagnostic data from the LIDC-IDRI dataset. The EDRS shows improved sensitivity (93.42%), specificity (82.39%), and diagnostic accuracy (88.78%) relative to previous radiomics approaches.

26 CFR 1.381(c)(5)-1 - Inventories.

Science.gov (United States)

2010-04-01

... 26 Internal Revenue 4 2010-04-01 2010-04-01 false Inventories. 1.381(c)(5)-1 Section 1.381(c)(5)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES Insolvency Reorganizations § 1.381(c)(5)-1 Inventories. (a) Carryover requirement—(1...

22 CFR 5.1 - Introduction.

Science.gov (United States)

2010-04-01

... 22 Foreign Relations 1 2010-04-01 2010-04-01 false Introduction. 5.1 Section 5.1 Foreign Relations DEPARTMENT OF STATE GENERAL ORGANIZATION § 5.1 Introduction. The sections in this part 5 are issued pursuant to section 3 of the Administrative Procedure Act, 5 U.S.C. 552, effective July 4, 1967. ...

The Wonders of Phosphodiesterase‑5 Inhibitors: A Majestic History

African Journals Online (AJOL)

A milestone in drug discovery was the selective inhibitors of. PDE‑5 that ... the pharmacotherapeutics of PDE‑5 inhibitors and the majestic history that led to their discovery. ..... including HIV protease inhibitors, ketoconazole, itraconazole,.

Discovery of inhibitors of bacterial histidine kinases

NARCIS (Netherlands)

Velikova, N.R.

2014-01-01

Discovery of Inhibitors of Bacterial Histidine Kinases Summary

The thesis is on novel antibacterial drug discovery (http://youtu.be/NRMWOGgeysM). Using structure-based and fragment-based drug discovery approach, we have identified small-molecule histidine-kinase

Queen's discovery lauded by top scientific journal

CERN Multimedia

McGrady, S

2002-01-01

A scientific breakthrough at Queen's University's Sudbury Neutrino Observatory has received major international recognition. The journal Science ranked the discovery that cracked the "neutrino problem" second, in the journal's top 10 scientific achievements of 2002 (1/2 page).

Hominin track assemblages from Okote Member deposits near Ileret, Kenya, and their implications for understanding fossil hominin paleobiology at 1.5 Ma.

Science.gov (United States)

Hatala, Kevin G; Roach, Neil T; Ostrofsky, Kelly R; Wunderlich, Roshna E; Dingwall, Heather L; Villmoare, Brian A; Green, David J; Braun, David R; Harris, John W K; Behrensmeyer, Anna K; Richmond, Brian G

2017-11-01

Tracks can provide unique, direct records of behaviors of fossil organisms moving across their landscapes millions of years ago. While track discoveries have been rare in the human fossil record, over the last decade our team has uncovered multiple sediment surfaces within the Okote Member of the Koobi Fora Formation near Ileret, Kenya that contain large assemblages of ∼1.5 Ma fossil hominin tracks. Here, we provide detailed information on the context and nature of each of these discoveries, and we outline the specific data that are preserved on the Ileret hominin track surfaces. We analyze previously unpublished data to refine and expand upon earlier hypotheses regarding implications for hominin anatomy and social behavior. While each of the track surfaces discovered at Ileret preserves a different amount of data that must be handled in particular ways, general patterns are evident. Overall, the analyses presented here support earlier interpretations of the ∼1.5 Ma Ileret track assemblages, providing further evidence of large, human-like body sizes and possibly evidence of a group composition that could support the emergence of certain human-like patterns of social behavior. These data, used in concert with other forms of paleontological and archaeological evidence that are deposited on different temporal scales, offer unique windows through which we can broaden our understanding of the paleobiology of hominins living in East Africa at ∼1.5 Ma. Copyright © 2017 Elsevier Ltd. All rights reserved.

The synthesis of 5'-[14C1] and 3a, 4-[13C2] labelled panadiplon (U-78875; 3-(5'-cyclopropyl-1,2,4-oxadiazol-3-yl)-5-(1-methylethyl)-imidazo-[1,5a]-quinoxalin-4(5H)-one)

International Nuclear Information System (INIS)

Ackland, M.J.; Howard, M.R.; Dring, L.G.

1993-01-01

5'-[ 14 C 1 ]Panadiplon was prepared in 3 steps starting from [ 14 C 1 ]cyclopropane carboxylic acid and 3-(5'-cyano-1,2,4-oxadiazol-3-yl)-5-(1-methylethyl)-imidazo-[1,5a] -quinoxalin-4(5H)-one. 3a, 4-[ 13 C 2 ]Panadiplon was prepared in two steps from 13 C 2 -oxalic acid and N-1-(1-methylethyl)-o-phenylenediamine. The position of labelling was confirmed by the appearance of two coupled resonances (J C-C =80.59 Hz) at 121.95 and 154.39 ppm in the assigned 13 C-NMR spectrum. (Author)

Synthesis 1, 3-bis (4-bromophenyl-5-isopropyl-1, 3, 5-triazacyclohexane

Directory of Open Access Journals (Sweden)

L. LEFRADA

2015-03-01

Full Text Available Condensation of an isopropylamine and an 4-bromoaniline with formaline in basic solution to give 1, 3-bis (4-bromophenyl-5- (isopropyl- 1, 3, 5- triazicyaclohexane. Through the interaction of rapid Schiff base, Structures of this compound have been elucidated by spectroscopic methods; IR, 1H NMR, 13C NMR. Their purities were confirmed by elemental analyses.

Service discovery using Bloom filters

NARCIS (Netherlands)

Goering, P.T.H.; Heijenk, Geert; Lelieveldt, B.P.F.; Haverkort, Boudewijn R.H.M.; de Laat, C.T.A.M.; Heijnsdijk, J.W.J.

A protocol to perform service discovery in adhoc networks is introduced in this paper. Attenuated Bloom filters are used to distribute services to nodes in the neighborhood and thus enable local service discovery. The protocol has been implemented in a discrete event simulator to investigate the

A statistical perspective on association studies of psychiatric disorders

DEFF Research Database (Denmark)

Foldager, Leslie

2014-01-01

Gene-gene (GxG) and gene-environment (GxE) interactions likely play an important role in the aetiology of complex diseases like psychiatric disorders. Thus, we aim at investigating methodological aspects of and apply methods from statistical genetics taking interactions into account. In addition we...... genes and maternal infection by virus. Paper 3 presents the initial steps (mainly data construction) of an ongoing simulation study aiming at guiding decisions by comparing methods for GxE interaction analysis including both traditional two-step logistic regression, exhaustive searches using efficient...... these markers. However, the validity of the identified haplotypes is also checked by inferring phased haplotypes from genotypes. Haplotype analysis is also used in paper 5 which is otherwise an example of a focused approach to narrow down a previously found signal to search for more precise positions of disease...

Using concepts in literature-based discovery : Simulating Swanson's Raynaud-fish oil and migraine-magnesium discoveries

NARCIS (Netherlands)

Weeber, M; Klein, Henny; de Jong-van den Berg, LTW; Vos, R

Literature-based discovery has resulted in new knowledge. In the biomedical context, Don R. Swanson has generated several literature-based hypotheses that have been corroborated experimentally and clinically. In this paper, we propose a two-step model of the discovery process in which hypotheses are

Many faces of compact objects: distance, optical extinction and multi-wavelength behaviour

International Nuclear Information System (INIS)

Corbel, Stephane

1999-01-01

This thesis is devoted to a multi-wavelength study of accretion-ejection phenomena around compact stars (black holes and neutron stars). The first part of this manuscript describes problems related to the determination of the distance and the optical extinction to compact objects - fundamental parameters for the evaluation of the energy budget of these systems. To this end, the structure and the dynamics of the Galaxy are studied by observations of the atomic and molecular gas along the line of sight to compact stars. This method leads to the first evaluation of the distance to two Soft Gamma Repeaters: SGR 1806-20 and SGR 1627-41. We then draw some conclusions on the nature of these sources of recurrent gamma-ray bursts. The above method is then applied to two X-ray binaries: Cir X-1 and GX 339-4. In the second part of this thesis, we present a multi-wavelength study of the Galactic black hole candidate GX 339-4. We first discuss the characteristics of the radio emission from GX 339-4. In 1998, GX 339-4 underwent a transition to a soft-high X-ray state and observations in three wavelength regimes (radio, soft and hard X-rays) revealed new patterns of behaviour. This allowed us to constrain the region of origin of the radio emission (a compact jet) in GX 339-4 and allowed a better understanding of the physical coupling between accretion and ejection in GX 339-4. An analogy with the black hole candidate Cyg X-1 is then presented. Finally, these results are discussed in the context of micro-quasars and active galactic nuclei in order to gain a deeper insight into the accretion-ejection coupling around compact objects. (author) [fr

Resource Discovery in Activity-Based Sensor Networks

DEFF Research Database (Denmark)

Bucur, Doina; Bardram, Jakob

This paper proposes a service discovery protocol for sensor networks that is specifically tailored for use in humancentered pervasive environments. It uses the high-level concept of computational activities (as logical bundles of data and resources) to give sensors in Activity-Based Sensor Networ....... ABSN enhances the generic Extended Zone Routing Protocol with logical sensor grouping and greatly lowers network overhead during the process of discovery, while keeping discovery latency close to optimal.......This paper proposes a service discovery protocol for sensor networks that is specifically tailored for use in humancentered pervasive environments. It uses the high-level concept of computational activities (as logical bundles of data and resources) to give sensors in Activity-Based Sensor Networks...... (ABSNs) knowledge about their usage even at the network layer. ABSN redesigns classical network-level service discovery protocols to include and use this logical structuring of the network for a more practically applicable service discovery scheme. Noting that in practical settings activity-based sensor...

Discovery and optimization of peptide-based anti-cobratoxins

DEFF Research Database (Denmark)

Sola, M.; Laustsen, Andreas Hougaard; Johannesen, J.

More than 5.5 million people per year are victims of snake envenomation, resulting in 125,000 deaths and 400,000amputations worldwide. Antivenoms are still produced by animal immunization procedures, and they areassociated with a high risk of severe adverse reactions. Alternatively, synthetic pep...... peptides may open the possibility for newtherapies with better efficacy and safety. Here, we report the discovery and optimization of a synthetic peptide directedagainst α-cobratoxin (α-CTX), the most toxic component of Monocled cobra (Naja kaouthia)....

Cyclooxygenase-2 inhibitors. Synthesis and pharmacological activities of 5-methanesulfonamido-1-indanone derivatives.

Science.gov (United States)

Li, C S; Black, W C; Chan, C C; Ford-Hutchinson, A W; Gauthier, J Y; Gordon, R; Guay, D; Kargman, S; Lau, C K; Mancini, J

1995-12-08

The recent discovery of an alternative form cyclooxygenase (cyclooxygenase-2, COX-2), which has been proposed to play a significant role in inflammatory conditions, may provide an opportunity to develop anti-inflammatory drugs with fewer side effects than existing non-steroidal anti-inflammatory drugs (NSAIDs). We have now identified 6-[(2,4-difluorophenyl)-thio]-5-methanesulfonamido-1-indanone++ + (20) (L-745,337) as a potent, selective, and orally active COX-2 inhibitor. The structure-activity relationships in this series have been extensively studied. Ortho- and para-substituted 6-phenyl substitutents are optimal for in vitro potency. Replacement of this phenyl ring by a variety of heterocycles gave compounds that were less active. The methanesulfonamido group seems to be the optimal group at the 5-position of the indanone system. Compound 20 has an efficacy profile that is superior or comparable to that of the nonselective COX inhibitor indomethacin in animal models of inflammation, pain, and fever and appears to be nonulcerogenic within the dosage ranges required for functional efficacy. Although 20 and its oxygen linkage analog 2 (flosulide) are equipotent in the in vitro assays, compound 20 is more potent in the rat paw edema assay, has a longer t1/2 in squirrel monkeys, and seems less ulcergenic than 2 in rats.

Price discovery in a continuous-time setting

DEFF Research Database (Denmark)

Dias, Gustavo Fruet; Fernandes, Marcelo; Scherrer, Cristina

We formulate a continuous-time price discovery model in which the price discovery measure varies (stochastically) at daily frequency. We estimate daily measures of price discovery using a kernel-based OLS estimator instead of running separate daily VECM regressions as standard in the literature. We...... show that our estimator is not only consistent, but also outperforms the standard daily VECM in finite samples. We illustrate our theoretical findings by studying the price discovery process of 10 actively traded stocks in the U.S. from 2007 to 2013....

Defining Creativity with Discovery

OpenAIRE

Wilson, Nicholas Charles; Martin, Lee

2017-01-01

The standard definition of creativity has enabled significant empirical and theoretical advances, yet contains philosophical conundrums concerning the nature of novelty and the role of recognition and values. In this work we offer an act of conceptual valeting that addresses these issues and in doing so, argue that creativity definitions can be extended through the use of discovery. Drawing on dispositional realist philosophy we outline why adding the discovery and bringing into being of new ...

On the antiproton discovery

International Nuclear Information System (INIS)

Piccioni, O.

1989-01-01

The author of this article describes his own role in the discovery of the antiproton. Although Segre and Chamberlain received the Nobel Prize in 1959 for its discovery, the author claims that their experimental method was his idea which he communicated to them informally in December 1954. He describes how his application for citizenship (he was Italian), and other scientists' manipulation, prevented him from being at Berkeley to work on the experiment himself. (UK)

Nuclear science in the 20th century. Its historical discoveries and impact on the world: Pt.1

International Nuclear Information System (INIS)

Liu Jun; Xu Furong; Zheng Chunkai; Shen Wenqing

2003-01-01

Nuclear science has been in existence for more than one hundred years, and has affected the world in many important aspects. In this paper, we give a brief overview of the history of nuclear science, including major discoveries such as the discovery of radioactivity, the electron, proton and neutron. The structures of atoms and atomic nuclei are explained, with some historic experiments and theories. The immense impact of nuclear science on the natural sciences and the world is reviewed

Discovery of a potent and selective free fatty acid receptor 1 agonist with low lipophilicity and high oral bioavailability

DEFF Research Database (Denmark)

Christiansen, Elisabeth; Due-Hansen, Maria E; Urban, Christian

2013-01-01

The free fatty acid receptor 1 (FFA1, also known as GPR40) mediates enhancement of glucose-stimulated insulin secretion and is emerging as a new target for the treatment of type 2 diabetes. Several FFA1 agonists are known, but the majority of these suffer from high lipophilicity. We have previously...... reported the FFA1 agonist 3 (TUG-424). We here describe the continued structure-activity exploration and optimization of this compound series, leading to the discovery of the more potent agonist 40, a compound with low lipophilicity, excellent in vitro metabolic stability and permeability, complete oral...

43 CFR 4.826 - Discovery.

Science.gov (United States)

2010-10-01