Science.gov

Sample records for 10-11 erg cm-2

  1. Cosmic Optical Background: The View from Pioneer 10/11

    NASA Astrophysics Data System (ADS)

    Matsuoka, Y.; Ienaka, N.; Kawara, K.; Oyabu, S.

    2011-08-01

    We present the new constraints on the cosmic optical background (COB) obtained from an analysis of the Pioneer 10/11 Imaging Photopolarimeter (IPP) data. After careful examination of data quality, the usable measurements free from the zodiacal light are integrated into sky maps at the blue (~0.44 μm) and red (~0.64 μm) band. Accurate starlight subtraction is achieved by referring to all-sky star catalogs and a Galactic stellar population synthesis model down to 32.0 mag. We find that the residual light is separated into two components: one component shows a clear correlation with thermal 100 μm brightness, while another betrays a constant level in the lowest 100 μm brightness region. The presence of the second component is significant after all the uncertainties and possible residual light in the Galaxy are taken into account, and thus it most likely has the extragalactic origin (i.e., the COB). The derived COB brightness is (1.8 ± 0.9) × 10-9 and (1.2 ± 0.9) × 10-9 erg s-1 cm-2 sr-1 Å-1 at the blue and red bands, respectively, or 7.9 ± 4.0 and 7.7 ± 5.8 nW m-2 sr-1. From comparison with the integrated brightness of galaxies, we conclude that bulk of the COB is comprised of normal galaxies which have already been resolved in the current deepest observations. There seems to be little room for contributions of other populations including "first stars" at these wavelengths. On the other hand, the first component of the IPP residual light represents the diffuse Galactic light (DGL)—scattered starlight by the interstellar dust. We derive mean DGL-to-100 μm brightness ratios of 2.1 × 10-3 and 4.6 × 10-3 at the two bands, which are roughly consistent with the previous observations toward the denser dust regions. Extended red emission in the diffuse interstellar medium is also confirmed.

  2. Cosmic Optical Background: the view from Pioneer 10/11

    NASA Astrophysics Data System (ADS)

    Matsuoka, Y.; Ienaka, N.; Kawara, K.; Oyabu, S.

    2012-08-01

    We present the new constraints on the cosmic optical background (COB) obtained from an analysis of the Pioneer 10/11 Imaging Photopolarimeter (IPP) data. After careful examination of data quality, the usable measurements free from the zodiacal light are integrated into sky maps at the blue (~0.44 μm) and red (~0.64 μm) bands. Accurate starlight subtraction is achieved by referring to all-sky star catalogs and a Galactic stellar population synthesis model down to 32.0 mag. We find that the residual light is separated into two components: one component shows a clear correlation with thermal 100 μm brightness, while another betrays a constant level in the lowest 100 μm brightness region. Presence of the second component is significant after all the uncertainties and possible residual light in the Galaxy are taken into account, thus it most likely has the extragalactic origin (i.e., the COB). The derived COB brightness is (1.8 +/- 0.9) × 10-9 and (1.2 +/- 0.9) × 10-9 erg s-1 cm-2 sr-1 Å-1 at the blue and red band, respectively, or 7.9 +/- 4.0 and 7.7 +/- 5.8 nW m-2 sr-1. Based on a comparison with the integrated brightness of galaxies, we conclude that the bulk of the COB is comprised of normal galaxies which have already been resolved by the current deepest observations. There seems to be little room for contributions of other populations including ``first stars'' at these wavelengths. On the other hand, the first component of the IPP residual light represents the diffuse Galactic light (DGL)--scattered starlight by the interstellar dust. We derive the mean DGL-to-100 μm brightness ratios of 2.1 × 10-3 and 4.6 × 10-3 at the two bands, which are roughly consistent with the previous observations toward denser dust regions. Extended red emission in the diffuse interstellar medium is also confirmed.

  3. Sedimentary record of erg migration

    SciTech Connect

    Porter, M.L.

    1986-06-01

    The sedimentary record of erg (eolian sand sea) migration consists of an idealized threefold division of sand-sea facies sequences. The basal division, here termed the fore-erg, is composed of a hierarchy of eolian sand bodies contained within sediments of the flanking depositional environment. The fore-erg represents the downwind, leading edge of the erg and records the onset of eolian sedimentation. Basin subsidence coupled with erg migration places the medial division, termed the central erg, over the fore-erg strata. Eolian influence on regional sedimentation patterns is greatest in the central erg, and most of the sand transported and deposited in the erg is contained within this region. Reduction in sand supply and continued erg migration will cover the central-erg deposits with a veneer of back-erg deposits. This upper division of the erg facies sequence resembles closely the fore-erg region. Back-erg deposits may be thin due to limited eolian influence on sedimentation or incomplete erg migration, or they may be completely absent because of great susceptibility to postdepositional erosion. Tectonic, climatic, and eustatic influences on sand-sea deposition will produce distinctive variations or modifications of the idealized erg facies sequence. The resulting variants in the sedimentary record of erg migration are illustrated with ancient examples from western North America, Europe, southern Africa, and South America. 38 references, 2 figures, 2 tables.

  4. 10 CFR 10.11 - Criteria.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 10 Energy 1 2010-01-01 2010-01-01 false Criteria. 10.11 Section 10.11 Energy NUCLEAR REGULATORY COMMISSION CRITERIA AND PROCEDURES FOR DETERMINING ELIGIBILITY FOR ACCESS TO RESTRICTED DATA OR NATIONAL... or administered by a physician licensed to dispense drugs in the practice of medicine,...

  5. 10 CFR 10.11 - Criteria.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 10 Energy 1 2013-01-01 2013-01-01 false Criteria. 10.11 Section 10.11 Energy NUCLEAR REGULATORY COMMISSION CRITERIA AND PROCEDURES FOR DETERMINING ELIGIBILITY FOR ACCESS TO RESTRICTED DATA OR NATIONAL... or administered by a physician licensed to dispense drugs in the practice of medicine,...

  6. 10 CFR 10.11 - Criteria.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 10 Energy 1 2011-01-01 2011-01-01 false Criteria. 10.11 Section 10.11 Energy NUCLEAR REGULATORY COMMISSION CRITERIA AND PROCEDURES FOR DETERMINING ELIGIBILITY FOR ACCESS TO RESTRICTED DATA OR NATIONAL... or administered by a physician licensed to dispense drugs in the practice of medicine,...

  7. 10 CFR 10.11 - Criteria.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 10 Energy 1 2014-01-01 2014-01-01 false Criteria. 10.11 Section 10.11 Energy NUCLEAR REGULATORY COMMISSION CRITERIA AND PROCEDURES FOR DETERMINING ELIGIBILITY FOR ACCESS TO RESTRICTED DATA OR NATIONAL... or administered by a physician licensed to dispense drugs in the practice of medicine,...

  8. Lessons Learned From CM-2 Modal Testing and Analysis

    NASA Technical Reports Server (NTRS)

    McNelis, Mark E.; Goodnight, Thomas W.; Carney, Kelly S.; Otten, Kim D.

    2002-01-01

    The Combustion Module-2 (CM-2) is a space experiment that launches on Shuttle mission STS-107 in the SPACEHAB Double Research Module. The CM-2 flight hardware is installed into SPACEHAB single and double racks. The CM-2 flight hardware was vibration tested in the launch configuration to characterize the structure's modal response. Cross-orthogonality between test and analysis mode shapes were used to assess model correlation. Lessons learned for pre-test planning and model verification are discussed.

  9. 44 CFR 10.11 - Environmental information.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 44 Emergency Management and Assistance 1 2014-10-01 2014-10-01 false Environmental information. 10... OF HOMELAND SECURITY GENERAL ENVIRONMENTAL CONSIDERATIONS Agency Implementing Procedures § 10.11 Environmental information. Interested persons may contact the Environmental Officer or the...

  10. 44 CFR 10.11 - Environmental information.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 44 Emergency Management and Assistance 1 2012-10-01 2011-10-01 true Environmental information. 10... OF HOMELAND SECURITY GENERAL ENVIRONMENTAL CONSIDERATIONS Agency Implementing Procedures § 10.11 Environmental information. Interested persons may contact the Environmental Officer or the...

  11. 46 CFR 90.10-11 - Coastwise.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) CARGO AND MISCELLANEOUS VESSELS GENERAL PROVISIONS Definition of Terms Used in This Subchapter § 90.10-11 Coastwise. Under this designation shall be included all vessels normally navigating the waters of any ocean or the Gulf of Mexico 20 nautical miles...

  12. 46 CFR 90.10-11 - Coastwise.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) CARGO AND MISCELLANEOUS VESSELS GENERAL PROVISIONS Definition of Terms Used in This Subchapter § 90.10-11 Coastwise. Under this designation shall be included all vessels normally navigating the waters of any ocean or the Gulf of Mexico 20 nautical miles...

  13. 46 CFR 90.10-11 - Coastwise.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) CARGO AND MISCELLANEOUS VESSELS GENERAL PROVISIONS Definition of Terms Used in This Subchapter § 90.10-11 Coastwise. Under this designation shall be included all vessels normally navigating the waters of any ocean or the Gulf of Mexico 20 nautical miles...

  14. 44 CFR 10.11 - Environmental information.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 44 Emergency Management and Assistance 1 2011-10-01 2011-10-01 false Environmental information. 10... OF HOMELAND SECURITY GENERAL ENVIRONMENTAL CONSIDERATIONS Agency Implementing Procedures § 10.11 Environmental information. Interested persons may contact the Environmental Officer or the...

  15. 44 CFR 10.11 - Environmental information.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 44 Emergency Management and Assistance 1 2010-10-01 2010-10-01 false Environmental information. 10... OF HOMELAND SECURITY GENERAL ENVIRONMENTAL CONSIDERATIONS Agency Implementing Procedures § 10.11 Environmental information. Interested persons may contact the Environmental Officer or the...

  16. CM-2 Environmental / Modal Testing of Spacehab Racks

    NASA Technical Reports Server (NTRS)

    McNelis, Mark E.; Goodnight, Thomas W.; Farkas, Michael A.

    2001-01-01

    Combined environmental/modal vibration testing has been implemented at the NASA Glenn Research Center's Structural Dynamics Laboratory. The benefits of combined vibration testing are that it facilitates test article modal characterization and vibration qualification testing. The Combustion Module-2 (CM-2) is a space experiment that launches on Shuttle mission STS 107 in the SPACEHAB Research Double Module. The CM-2 flight hardware is integrated into a SPACEHAB single and double rack. CM-2 rack level combined vibration testing was recently completed on a shaker table to characterize the structure's modal response and verify the random vibration response. Control accelerometers and limit force gauges, located between the fixture and rack interface, were used to verify the input excitation. Results of the testing were used to verify the loads and environments for flight on the Shuttle.

  17. Benchmarking and performance analysis of the CM-2. [SIMD computer

    NASA Technical Reports Server (NTRS)

    Myers, David W.; Adams, George B., II

    1988-01-01

    A suite of benchmarking routines testing communication, basic arithmetic operations, and selected kernel algorithms written in LISP and PARIS was developed for the CM-2. Experiment runs are automated via a software framework that sequences individual tests, allowing for unattended overnight operation. Multiple measurements are made and treated statistically to generate well-characterized results from the noisy values given by cm:time. The results obtained provide a comparison with similar, but less extensive, testing done on a CM-1. Tests were chosen to aid the algorithmist in constructing fast, efficient, and correct code on the CM-2, as well as gain insight into what performance criteria are needed when evaluating parallel processing machines.

  18. hERG me out.

    PubMed

    Czodrowski, Paul

    2013-09-23

    A detailed analysis of the hERG content inside the ChEMBL database is performed. The correlation between the outcome from binding assays and functional assays is probed. On the basis of descriptor distributions, design paradigms with respect to structural and physicochemical properties of hERG active and hERG inactive compounds are challenged. Finally, classification models with different data sets are trained. All source code is provided, which is based on the Python open source packages RDKit and scikit-learn to enable the community to rerun the experiments. The code is stored on github ( https://github.com/pzc/herg_chembl_jcim).

  19. hERG me out.

    PubMed

    Czodrowski, Paul

    2013-09-23

    A detailed analysis of the hERG content inside the ChEMBL database is performed. The correlation between the outcome from binding assays and functional assays is probed. On the basis of descriptor distributions, design paradigms with respect to structural and physicochemical properties of hERG active and hERG inactive compounds are challenged. Finally, classification models with different data sets are trained. All source code is provided, which is based on the Python open source packages RDKit and scikit-learn to enable the community to rerun the experiments. The code is stored on github ( https://github.com/pzc/herg_chembl_jcim). PMID:23944269

  20. Ganzfeld ERG in zebrafish larvae.

    PubMed

    Seeliger, Mathias W; Rilk, Albrecht; Neuhauss, Stephan C F

    2002-01-01

    In developmental biology, zebrafish are widely used to study the impact of mutations. The fast pace of development allows for a definitive morphological evaluation of the phenotype usually 5 days post fertilization (dpf). At that age, a functional analysis is already feasible using electroretinographic (ERG) methods. Corneal Ganzfeld ERGs were recorded with a glass microelectrode in anaesthetized, dark-adapted larvae aged 5 dpf, using a platinum wire beneath a moist paper towel as reference. ERG protocols included flash, flicker, and ON/OFF stimuli, both under scotopic and photopic conditions. Repetitive, isoluminant stimuli were used to assess the dynamic effect of pharmacological agents on the ERG. Single flash, flicker, and ON/OFF responses had adequately matured at this point to be informative. Typical signs of the cone dominance were the small scotopic a-wave and the large OFF responses. The analysis of consecutive single traces was possible because of the lack of EKG, breathing, and blink artefacts. After application of APB, which selectively blocks the ON channel via the mGluR6 receptor, the successive loss of the b-wave could be observed, which was quite different from the deterioration of the ERG after a circulatory arrest. The above techniques allowed to reliably obtain Ganzfeld ERGs in larvae aged 5 dpf. This underlines the important role of the zebrafish as a model for the functional analysis of mutations disrupting the visual system. PMID:11949809

  1. 47 CFR 10.11 - WEA implementation timeline.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 47 Telecommunication 1 2013-10-01 2013-10-01 false WEA implementation timeline. 10.11 Section 10.11 Telecommunication FEDERAL COMMUNICATIONS COMMISSION GENERAL WIRELESS EMERGENCY ALERTS General Information § 10.11 WEA implementation timeline. Notwithstanding anything in this part to the contrary,...

  2. 47 CFR 10.11 - WEA implementation timeline.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 47 Telecommunication 1 2014-10-01 2014-10-01 false WEA implementation timeline. 10.11 Section 10.11 Telecommunication FEDERAL COMMUNICATIONS COMMISSION GENERAL WIRELESS EMERGENCY ALERTS General Information § 10.11 WEA implementation timeline. Notwithstanding anything in this part to the contrary,...

  3. 46 CFR 188.10-11 - Chemistry laboratory.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 46 Shipping 7 2011-10-01 2011-10-01 false Chemistry laboratory. 188.10-11 Section 188.10-11 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) OCEANOGRAPHIC RESEARCH VESSELS GENERAL PROVISIONS Definition of Terms Used in This Subchapter § 188.10-11 Chemistry laboratory. This term...

  4. 46 CFR 188.10-11 - Chemistry laboratory.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 46 Shipping 7 2010-10-01 2010-10-01 false Chemistry laboratory. 188.10-11 Section 188.10-11 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) OCEANOGRAPHIC RESEARCH VESSELS GENERAL PROVISIONS Definition of Terms Used in This Subchapter § 188.10-11 Chemistry laboratory. This term...

  5. 46 CFR 30.10-11 - Coastwise-TB/C.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 46 Shipping 1 2013-10-01 2013-10-01 false Coastwise-TB/C. 30.10-11 Section 30.10-11 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY TANK VESSELS GENERAL PROVISIONS Definitions § 30.10-11 Coastwise—TB/C. Under this designation shall be included all tank vessels normally navigating the waters of...

  6. 46 CFR 30.10-11 - Coastwise-TB/C.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 46 Shipping 1 2014-10-01 2014-10-01 false Coastwise-TB/C. 30.10-11 Section 30.10-11 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY TANK VESSELS GENERAL PROVISIONS Definitions § 30.10-11 Coastwise—TB/C. Under this designation shall be included all tank vessels normally navigating the waters of...

  7. 46 CFR 30.10-11 - Coastwise-TB/C.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 46 Shipping 1 2011-10-01 2011-10-01 false Coastwise-TB/C. 30.10-11 Section 30.10-11 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY TANK VESSELS GENERAL PROVISIONS Definitions § 30.10-11 Coastwise—TB/C. Under this designation shall be included all tank vessels normally navigating the waters of...

  8. 1 CFR 10.11 - Scope and sources.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 1 General Provisions 1 2012-01-01 2012-01-01 false Scope and sources. 10.11 Section 10.11 General Provisions ADMINISTRATIVE COMMITTEE OF THE FEDERAL REGISTER SPECIAL EDITIONS OF THE FEDERAL REGISTER PRESIDENTIAL PAPERS Annual Publication § 10.11 Scope and sources. The basic text of the Public Papers...

  9. 1 CFR 10.11 - Scope and sources.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 1 General Provisions 1 2013-01-01 2012-01-01 true Scope and sources. 10.11 Section 10.11 General Provisions ADMINISTRATIVE COMMITTEE OF THE FEDERAL REGISTER SPECIAL EDITIONS OF THE FEDERAL REGISTER PRESIDENTIAL PAPERS Annual Publication § 10.11 Scope and sources. The basic text of the Public Papers...

  10. 1 CFR 10.11 - Scope and sources.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 1 General Provisions 1 2014-01-01 2012-01-01 true Scope and sources. 10.11 Section 10.11 General Provisions ADMINISTRATIVE COMMITTEE OF THE FEDERAL REGISTER SPECIAL EDITIONS OF THE FEDERAL REGISTER PRESIDENTIAL PAPERS Annual Publication § 10.11 Scope and sources. The basic text of the Public Papers...

  11. 46 CFR 188.10-11 - Chemistry laboratory.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 46 Shipping 7 2012-10-01 2012-10-01 false Chemistry laboratory. 188.10-11 Section 188.10-11 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) OCEANOGRAPHIC RESEARCH VESSELS GENERAL PROVISIONS Definition of Terms Used in This Subchapter § 188.10-11 Chemistry laboratory. This term...

  12. 46 CFR 188.10-11 - Chemistry laboratory.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 46 Shipping 7 2013-10-01 2013-10-01 false Chemistry laboratory. 188.10-11 Section 188.10-11 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) OCEANOGRAPHIC RESEARCH VESSELS GENERAL PROVISIONS Definition of Terms Used in This Subchapter § 188.10-11 Chemistry laboratory. This term...

  13. 46 CFR 188.10-11 - Chemistry laboratory.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 46 Shipping 7 2014-10-01 2014-10-01 false Chemistry laboratory. 188.10-11 Section 188.10-11 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) OCEANOGRAPHIC RESEARCH VESSELS GENERAL PROVISIONS Definition of Terms Used in This Subchapter § 188.10-11 Chemistry laboratory. This term...

  14. 46 CFR 30.10-11 - Coastwise-TB/C.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 46 Shipping 1 2010-10-01 2010-10-01 false Coastwise-TB/C. 30.10-11 Section 30.10-11 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY TANK VESSELS GENERAL PROVISIONS Definitions § 30.10-11 Coastwise—TB/C. Under this designation shall be included all tank vessels normally navigating the waters of...

  15. 1 CFR 10.11 - Scope and sources.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 1 General Provisions 1 2010-01-01 2010-01-01 false Scope and sources. 10.11 Section 10.11 General Provisions ADMINISTRATIVE COMMITTEE OF THE FEDERAL REGISTER SPECIAL EDITIONS OF THE FEDERAL REGISTER PRESIDENTIAL PAPERS Annual Publication § 10.11 Scope and sources. The basic text of the Public Papers...

  16. 1 CFR 10.11 - Scope and sources.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 1 General Provisions 1 2011-01-01 2011-01-01 false Scope and sources. 10.11 Section 10.11 General Provisions ADMINISTRATIVE COMMITTEE OF THE FEDERAL REGISTER SPECIAL EDITIONS OF THE FEDERAL REGISTER PRESIDENTIAL PAPERS Annual Publication § 10.11 Scope and sources. The basic text of the Public Papers...

  17. COSMIC OPTICAL BACKGROUND: THE VIEW FROM PIONEER 10/11

    SciTech Connect

    Matsuoka, Y.; Oyabu, S.; Ienaka, N.; Kawara, K.

    2011-08-01

    We present the new constraints on the cosmic optical background (COB) obtained from an analysis of the Pioneer 10/11 Imaging Photopolarimeter (IPP) data. After careful examination of data quality, the usable measurements free from the zodiacal light are integrated into sky maps at the blue ({approx}0.44 {mu}m) and red ({approx}0.64 {mu}m) band. Accurate starlight subtraction is achieved by referring to all-sky star catalogs and a Galactic stellar population synthesis model down to 32.0 mag. We find that the residual light is separated into two components: one component shows a clear correlation with thermal 100 {mu}m brightness, while another betrays a constant level in the lowest 100 {mu}m brightness region. The presence of the second component is significant after all the uncertainties and possible residual light in the Galaxy are taken into account, and thus it most likely has the extragalactic origin (i.e., the COB). The derived COB brightness is (1.8 {+-} 0.9) x 10{sup -9} and (1.2 {+-} 0.9) x 10{sup -9} erg s{sup -1} cm{sup -2} sr{sup -1} A{sup -1} at the blue and red bands, respectively, or 7.9 {+-} 4.0 and 7.7 {+-} 5.8 nW m{sup -2} sr{sup -1}. From comparison with the integrated brightness of galaxies, we conclude that bulk of the COB is comprised of normal galaxies which have already been resolved in the current deepest observations. There seems to be little room for contributions of other populations including 'first stars' at these wavelengths. On the other hand, the first component of the IPP residual light represents the diffuse Galactic light (DGL)-scattered starlight by the interstellar dust. We derive mean DGL-to-100 {mu}m brightness ratios of 2.1 x 10{sup -3} and 4.6 x 10{sup -3} at the two bands, which are roughly consistent with the previous observations toward the denser dust regions. Extended red emission in the diffuse interstellar medium is also confirmed.

  18. Heavy ion collision dynamics of 10,11B+10,11B reactions

    NASA Astrophysics Data System (ADS)

    Singh, BirBikram; Kaur, Manpreet; Kaur, Varinderjit; Gupta, Raj K.

    2015-01-01

    The dynamical cluster-decay model (DCM) of Gupta and collaborators has been applied successfully to the decay of very-light (A ˜ 30), light (A ˜ 40-80), medium, heavy and super-heavy mass compound nuclei for their decay to light particles (evaporation residues, ER), fusion-fission (ff), and quasi-fission (qf) depending on the reaction conditions. We intend to extend here the application of DCM to study the extreme case of decay of very-light nuclear systems 20,21,22Ne∗ formed in 10,11B+10,11B reactions, for which experimental data is available for their binary symmetric decay (BSD) cross sections, i.e., σBSD. For the systems under study, the calculations are presented for the σBSD in terms of their preformation and barrier penetration probabilities P0 and P. Interesting results are that in the decay of such lighter systems there is a competing reaction mechanism (specifically, the deep inelastic orbiting of non-compound nucleus (nCN) origin) together with ff. We have emipirically estimated the contribution of σnCN. Moreover, the important role of nuclear structure characteristics via P0 as well as angular momentum ℓ in the reaction dynamics are explored in the study.

  19. Microbiological study of the Murchison CM2 meteorite

    NASA Astrophysics Data System (ADS)

    Pikuta, Elena V.; Hoover, Richard B.

    2012-10-01

    In 1864, Louis Pasteur attempted to cultivate living microorganisms from pristine samples of the Orgueil CI1 carbonaceous meteorite. His results were negative and never published, but recorded it in his laboratory notebooks. At that time, only aerobic liquid or agar-based organic reach media were used, as his research on anaerobes had just started. In our laboratory the Murchison CM2 carbonaceous meteorite was selected to expand on these studies for microbiological study by cultivation on anaerobic mineral media. Since the surface could have been more easily contaminated, interior fragments of a sample of the Murchison meteorite were extracted and crushed under sterile conditions. The resulting powder was then mixed in anoxic medium and injected into Hungate tubes containing anaerobic media with various growth substrates at different pH and salinity and incubated at different temperatures. The goal of the experiments was to determine if living cells would grow from the material of freshly fractured interior fragments of the stone. If any growth occurred, work could then be carried out to assess the nature of the environmental contamination by observations of the culture growth (rates of speed and biodiversity); live/dead fluorescent staining to determine contamination level and DNA analysis to establish the microbial species present. In this paper we report the results of that study.

  20. Presolar grains in the CM2 chondrite Sutter's Mill

    NASA Astrophysics Data System (ADS)

    Zhao, Xuchao; Lin, Yangting; Yin, Qing-Zhu; Zhang, Jianchao; Hao, Jialong; Zolensky, Michael; Jenniskens, Peter

    2014-11-01

    The Sutter's Mill (SM) carbonaceous chondrite is a regolith breccia, composed predominantly of CM2 clasts with varying degrees of aqueous alteration and thermal metamorphism. An investigation of presolar grains in four Sutter's Mill sections, SM43, SM51, SM2-4, and SM18, was carried out using NanoSIMS ion mapping technique. A total of 37 C-anomalous grains and one O-anomalous grain have been identified, indicating an abundance of 63 ppm for presolar C-anomalous grains and 2 ppm for presolar oxides. Thirty-one silicon carbide (SiC), five carbonaceous grains, and one Al-oxide (Al2O3) were confirmed based on their elemental compositions determined by C-N-Si and O-Si-Mg-Al isotopic measurements. The overall abundance of SiC grains in Sutter's Mill (55 ppm) is consistent with those in other CM chondrites. The absence of presolar silicates in Sutter's Mill suggests that they were destroyed by aqueous alteration on the parent asteroid. Furthermore, SM2-4 shows heterogeneous distributions of presolar SiC grains (12-54 ppm) in different matrix areas, indicating that the fine-grained matrix clasts come from different sources, with various thermal histories, in the solar nebula.

  1. 40 CFR 10.11 - Relationship to other agency regulations.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 1 2013-07-01 2013-07-01 false Relationship to other agency regulations. 10.11 Section 10.11 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY GENERAL... regulations in this part apply to the consideration by the Environmental Protection Agency of...

  2. 40 CFR 10.11 - Relationship to other agency regulations.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 1 2011-07-01 2011-07-01 false Relationship to other agency regulations. 10.11 Section 10.11 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY GENERAL... regulations in this part apply to the consideration by the Environmental Protection Agency of...

  3. 40 CFR 10.11 - Relationship to other agency regulations.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 1 2014-07-01 2014-07-01 false Relationship to other agency regulations. 10.11 Section 10.11 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY GENERAL... regulations in this part apply to the consideration by the Environmental Protection Agency of...

  4. 40 CFR 10.11 - Relationship to other agency regulations.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 1 2012-07-01 2012-07-01 false Relationship to other agency regulations. 10.11 Section 10.11 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY GENERAL... regulations in this part apply to the consideration by the Environmental Protection Agency of...

  5. 40 CFR 10.11 - Relationship to other agency regulations.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 1 2010-07-01 2010-07-01 false Relationship to other agency regulations. 10.11 Section 10.11 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY GENERAL... regulations in this part apply to the consideration by the Environmental Protection Agency of...

  6. 47 CFR 10.11 - CMAS implementation timeline.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 47 Telecommunication 1 2011-10-01 2011-10-01 false CMAS implementation timeline. 10.11 Section 10... Information § 10.11 CMAS implementation timeline. Notwithstanding anything in this part to the contrary, a participating CMS provider shall begin an 18 month period of development, testing and deployment of the CMAS...

  7. 47 CFR 10.11 - CMAS implementation timeline.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 47 Telecommunication 1 2012-10-01 2012-10-01 false CMAS implementation timeline. 10.11 Section 10... Information § 10.11 CMAS implementation timeline. Notwithstanding anything in this part to the contrary, a participating CMS provider shall begin an 18 month period of development, testing and deployment of the CMAS...

  8. 47 CFR 10.11 - CMAS implementation timeline.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 47 Telecommunication 1 2010-10-01 2010-10-01 false CMAS implementation timeline. 10.11 Section 10... Information § 10.11 CMAS implementation timeline. Notwithstanding anything in this part to the contrary, a participating CMS provider shall begin an 18 month period of development, testing and deployment of the CMAS...

  9. 27 CFR 10.11 - Meaning of terms.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 27 Alcohol, Tobacco Products and Firearms 1 2014-04-01 2014-04-01 false Meaning of terms. 10.11... OF THE TREASURY ALCOHOL COMMERCIAL BRIBERY Definitions § 10.11 Meaning of terms. As used in this part, unless the context otherwise requires, terms have the meanings given in this section. Any other...

  10. 27 CFR 10.11 - Meaning of terms.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 27 Alcohol, Tobacco Products and Firearms 1 2012-04-01 2012-04-01 false Meaning of terms. 10.11... OF THE TREASURY LIQUORS COMMERCIAL BRIBERY Definitions § 10.11 Meaning of terms. As used in this part, unless the context otherwise requires, terms have the meanings given in this section. Any other...

  11. 27 CFR 10.11 - Meaning of terms.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 27 Alcohol, Tobacco Products and Firearms 1 2013-04-01 2013-04-01 false Meaning of terms. 10.11... OF THE TREASURY ALCOHOL COMMERCIAL BRIBERY Definitions § 10.11 Meaning of terms. As used in this part, unless the context otherwise requires, terms have the meanings given in this section. Any other...

  12. Intragenic ERG Deletions Do Not Explain the Biology of ERG-Related Acute Lymphoblastic Leukemia

    PubMed Central

    Potuckova, Eliska; Zuna, Jan; Hovorkova, Lenka; Starkova, Julia; Stary, Jan; Trka, Jan; Zaliova, Marketa

    2016-01-01

    Intragenic ERG deletions occur in 3–5% of B-cell precursor acute lymphoblastic leukemia, specifically in B-other subtype lacking the classifying genetic lesions. They represent the only genetic lesion described so far present in the majority of cases clustering into a subgroup of B-other subtype characterized by a unique gene expression profile, probably sharing a common, however, not yet fully described, biological background. We aimed to elucidate whether ERG deletions could drive the specific biology of this ERG-related leukemia subgroup through expression of aberrant or decreased expression of wild type ERG isoforms. We showed that leukemic cells with endogenous ERG deletion express an aberrant transcript translated into two proteins in transfected cell lines and that one of these proteins colocalizes with wild type ERG. However, we did not confirm expression of the proteins in acute lymphoblastic leukemia cases with endogenous ERG deletion. ERG deletions resulted in significantly lower expression of wild type ERG transcripts compared to B-other cases without ERG deletion. However, cases with subclonal ERG deletion, clustering to the same ERG deletion associated subgroup, presented similar levels of wild type ERG as cases without ERG deletion. In conclusion, our data suggest that neither the expression of aberrant proteins from internally deleted allele nor the reduced expression of wild type ERG seem to provide a plausible explanation of the specific biology of ERG -related leukemia subgroup. PMID:27494621

  13. Truncated ERG Oncoproteins from TMPRSS2-ERG Fusions Are Resistant to SPOP-Mediated Proteasome Degradation.

    PubMed

    An, Jian; Ren, Shancheng; Murphy, Stephen J; Dalangood, Sumiya; Chang, Cunjie; Pang, Xiaodong; Cui, Yangyan; Wang, Liguo; Pan, Yunqian; Zhang, Xiaowei; Zhu, Yasheng; Wang, Chenji; Halling, Geoffrey C; Cheng, Liang; Sukov, William R; Karnes, R Jeffrey; Vasmatzis, George; Zhang, Qing; Zhang, Jun; Cheville, John C; Yan, Jun; Sun, Yinghao; Huang, Haojie

    2015-09-17

    SPOP mutations and TMPRSS2-ERG rearrangements occur collectively in up to 65% of human prostate cancers. Although the two events are mutually exclusive, it is unclear whether they are functionally interrelated. Here, we demonstrate that SPOP, functioning as an E3 ubiquitin ligase substrate-binding protein, promotes ubiquitination and proteasome degradation of wild-type ERG by recognizing a degron motif at the N terminus of ERG. Prostate cancer-associated SPOP mutations abrogate the SPOP-mediated degradation function on the ERG oncoprotein. Conversely, the majority of TMPRSS2-ERG fusions encode N-terminal-truncated ERG proteins that are resistant to the SPOP-mediated degradation because of degron impairment. Our findings reveal degradation resistance as a previously uncharacterized mechanism that contributes to elevation of truncated ERG proteins in prostate cancer. They also suggest that overcoming ERG resistance to SPOP-mediated degradation represents a viable strategy for treatment of prostate cancers expressing either mutated SPOP or truncated ERG.

  14. 6. Historic view, Pier 9, 10, 11. Aerial Views to ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    6. Historic view, Pier 9, 10, 11. Aerial Views to east, 1943. Photographic copy of photo. Boston National Historical Park Archives, Charlestown Navy Yard. - Charlestown Navy Yard, Pier 9, Between Piers 8 & 10, along Mystic River on Charlestown Waterfront at eastern edge of Navy Yard, Boston, Suffolk County, MA

  15. 46 CFR 30.10-11 - Coastwise-TB/C.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... GUARD, DEPARTMENT OF HOMELAND SECURITY TANK VESSELS GENERAL PROVISIONS Definitions § 30.10-11 Coastwise—TB/C. Under this designation shall be included all tank vessels normally navigating the waters of any ocean or the Gulf of Mexico 20 nautical miles or less offshore....

  16. 17 CFR 10.11 - Appearance in adjudicatory proceedings.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 17 Commodity and Securities Exchanges 1 2010-04-01 2010-04-01 false Appearance in adjudicatory... OF PRACTICE General Provisions § 10.11 Appearance in adjudicatory proceedings. (a) Appearance—(1) By... suspended or disbarred from appearance and practice before the Commission in accordance with the...

  17. Considerations for applying VARSKIN mod 2 to skin dose calculations averaged over 10 cm2.

    PubMed

    Durham, James S

    2004-02-01

    VARSKIN Mod 2 is a DOS-based computer program that calculates the dose to skin from beta and gamma contamination either directly on skin or on material in contact with skin. The default area for calculating the dose is 1 cm2. Recently, the U.S. Nuclear Regulatory Commission issued new guidelines for calculating shallow dose equivalent from skin contamination that requires the dose be averaged over 10 cm2. VARSKIN Mod 2 was not filly designed to calculate beta or gamma dose estimates averaged over 10 cm2, even though the program allows the user to calculate doses averaged over 10 cm2. This article explains why VARSKIN Mod 2 overestimates the beta dose when applied to 10 cm2 areas, describes a manual method for correcting the overestimate, and explains how to perform reasonable gamma dose calculations averaged over 10 cm2. The article also describes upgrades underway in Varskin 3. PMID:14744063

  18. An improved synthesis of 10,11-didehydro Cinchona alkaloids.

    PubMed

    Kacprzak, Karol M; Lindner, Wolfgang; Maier, Norbert M

    2008-03-01

    A revised procedure for the conversion of the four major Cinchona alkaloids (quinine, quinidine, cinchonidine, and cinchonine) into their respective 10,11-didehydro derivatives is described. The reported protocol offers several advantages over a recently published synthetic route. These include (i) enhanced robustness (ii) ready scalability (iii) reduced operational complexity and number of steps (iv) chromatography-free work-up. In addition, toxic solvents were replaced by environmentally less problematic alternatives.

  19. Role of the CM2 Protein in the Influenza C Virus Replication Cycle ▿

    PubMed Central

    Furukawa, Takatoshi; Muraki, Yasushi; Noda, Takeshi; Takashita, Emi; Sho, Ri; Sugawara, Kanetsu; Matsuzaki, Yoko; Shimotai, Yoshitaka; Hongo, Seiji

    2011-01-01

    CM2 is the second membrane protein of influenza C virus. Although its biochemical characteristics, coding strategy, and properties as an ion channel have been extensively studied, the role(s) of CM2 in the virus replication cycle remains to be clarified. In order to elucidate this role, in the present study we generated CM2-deficient influenza C virus-like particles (VLPs) and examined the VLP-producing 293T cells, VLPs, and VLP-infected HMV-II cells. Quantification of viral RNA (vRNA) in the VLPs by real-time PCR revealed that the CM2-deficient VLPs contain approximately one-third of the vRNA found in wild-type VLPs although no significant differences were detected in the expression levels of viral components in VLP-producing cells or in the number and morphology of the generated VLPs. This finding suggests that CM2 is involved in the genome packaging process into VLPs. Furthermore, HMV-II cells infected with CM2-deficient VLPs exhibited significantly reduced reporter gene expression. Although CM2-deficient VLPs could be internalized into HMV-II cells as efficiently as wild-type VLPs, a smaller amount of vRNA was detected in the nuclear fraction of CM2-deficient VLP-infected cells than in that of wild-type VLP-infected cells, suggesting that the uncoating process of the CM2-deficient VLPs in the infected cells did not proceed in an appropriate manner. Taken together, the data obtained in the present study indicate that CM2 has a potential role in the genome packaging and uncoating processes of the virus replication cycle. PMID:21106743

  20. Multielectron ultrastrong laser field ionization of Arn+, Krm+ and Xel+ (n <= 9, m <= 9, l <= 12) at intensities from 1015 W cm-2 to 1018 W cm-2

    NASA Astrophysics Data System (ADS)

    Palaniyappan, S.; Di Chiara, A.; Ghebregziabher, I.; Huskins, E. L.; Falkowski, A.; Pajerowski, D.; Walker, B. C.

    2006-07-01

    Ionization yields are reported for Ar, Kr and Xe in ultrastrong fields from 1015 W cm-2 to 1018 W cm-2. Non-sequential ionization (NSI) is shown to be a robust and general feature in ultrahigh field ionization. NSI yields measured are consistent with the trends predicted by a rescattering model, but as one proceeds to higher Z atoms more NSI is observed than predicted theoretically. Additional recollision mechanisms that may need to be considered in future theories of ultrastrong field-atom interactions include 'chain' NSI, NSI from excited states of the atom (e.g. Rydberg states or inner-shell holes) and the possibility of ultrastrong field enhanced recollision/impact processes.

  1. Development and characterization of a 280 cm2 vanadium/oxygen fuel cell

    NASA Astrophysics Data System (ADS)

    Noack, Jens; Cremers, Carsten; Bayer, Domnik; Tübke, Jens; Pinkwart, Karsten

    2014-05-01

    A vanadium/oxygen fuel cell with an active area of 280 cm2 has been developed. The cell consisted of two membranes with two half-cells and an intermediate chamber. The maximum achieved power density was 23 mW cm-2 at 0.56 V with lambda air = 3 and a 1.6 M V2+ solution at room temperature. The average discharge power density was 19.6 mW cm-2 at a constant current density of 40 mA cm-2 with an average voltage efficiency of 33%. The fuel based energy density was 18.2% of the theoretical value with 11.8 Wh L-1. In comparison with a similarly constructed 50 cm2 cell, both achieved similar performance levels. An analysis using the half-cell potential profiles and by means of impedance spectroscopy revealed that, as for the 50 cm2 cell, the low rate of oxygen reduction reaction significantly affected the performance of the cell. Thus gives potential for the optimization of the cathode reaction and a reduction in the ohmic resistances potential for higher power densities.

  2. GFDL's CM2 global coupled climate models. Part I: Formulation and simulation characteristics

    USGS Publications Warehouse

    Delworth, T.L.; Broccoli, A.J.; Rosati, A.; Stouffer, R.J.; Balaji, V.; Beesley, J.A.; Cooke, W.F.; Dixon, K.W.; Dunne, J.; Dunne, K.A.; Durachta, J.W.; Findell, K.L.; Ginoux, P.; Gnanadesikan, A.; Gordon, C.T.; Griffies, S.M.; Gudgel, R.; Harrison, M.J.; Held, I.M.; Hemler, R.S.; Horowitz, L.W.; Klein, S.A.; Knutson, T.R.; Kushner, P.J.; Langenhorst, A.R.; Lee, H.-C.; Lin, S.-J.; Lu, J.; Malyshev, S.L.; Milly, P.C.D.; Ramaswamy, V.; Russell, J.; Schwarzkopf, M.D.; Shevliakova, E.; Sirutis, J.J.; Spelman, M.J.; Stern, W.F.; Winton, M.; Wittenberg, A.T.; Wyman, B.; Zeng, F.; Zhang, R.

    2006-01-01

    The formulation and simulation characteristics of two new global coupled climate models developed at NOAA's Geophysical Fluid Dynamics Laboratory (GFDL) are described. The models were designed to simulate atmospheric and oceanic climate and variability from the diurnal time scale through multicentury climate change, given our computational constraints. In particular, an important goal was to use the same model for both experimental seasonal to interannual forecasting and the study of multicentury global climate change, and this goal has been achieved. Tw o versions of the coupled model are described, called CM2.0 and CM2.1. The versions differ primarily in the dynamical core used in the atmospheric component, along with the cloud tuning and some details of the land and ocean components. For both coupled models, the resolution of the land and atmospheric components is 2?? latitude ?? 2.5?? longitude; the atmospheric model has 24 vertical levels. The ocean resolution is 1?? in latitude and longitude, with meridional resolution equatorward of 30?? becoming progressively finer, such that the meridional resolution is 1/3?? at the equator. There are 50 vertical levels in the ocean, with 22 evenly spaced levels within the top 220 m. The ocean component has poles over North America and Eurasia to avoid polar filtering. Neither coupled model employs flux adjustments. The co ntrol simulations have stable, realistic climates when integrated over multiple centuries. Both models have simulations of ENSO that are substantially improved relative to previous GFDL coupled models. The CM2.0 model has been further evaluated as an ENSO forecast model and has good skill (CM2.1 has not been evaluated as an ENSO forecast model). Generally reduced temperature and salinity biases exist in CM2.1 relative to CM2.0. These reductions are associated with 1) improved simulations of surface wind stress in CM2.1 and associated changes in oceanic gyre circulations; 2) changes in cloud tuning and

  3. [The ERG contribution in early diagnosis of chloroquine and hydroxychloroquine maculopathy].

    PubMed

    Karkanová, Michala; Matusková, V; Vlková, E; Dosková, H; Uhmannová, R

    2010-04-01

    Derivates of chloroquine (Plaquenil, Delagil), used for long-term treatment of rheumatic diseases, may cause clinically proven irreversible maculopathy, which may progress even after the discontinuation of their application. The optimal early diagnosis of ocular toxicity of chloroquine or hydroxychloroquine drug remains controversial up to now. The aim of this review paper was to evaluate how appropriate is the indication of the electroretinographic (ERG) examination due to the early diagnosis of cumulative drug-related maculopathy. Photopic, pattern, and multifocal ERG (Retiscan, according to the ISCEV methodology) were examined in 10 patients (20 eyes) treated by means of antimalarics, 9 due to the rheumatoid arthritis (RA) and 1 due to the systemic lupus erythremathodes (SLE). The average age of the patients was 60 +/- 15 years, the treatment period was 10 +/- 11 years; the median of the treatment period was 5 years. The control group consisted of 12 healthy, age matched patients (20 eyes) without any obvious ocular pathology. In all of them, the complete ophthalmologic examination was performed: the best corrected visual acuity (BCVA) for far using the Snellen charts, intraocular pressure (IOP) measured by means of the non contact tonometer NIDEK NT-2000, the Amsler grid test, examination of the anterior segment and the posterior segment with the slit lamp. The entry criteria in both groups were BCVA 5/7,5 (0.67) and better, the IOP in the normal range, negative Amsler grid test, anterior segment without significant decrease of the transparency, and physiological posterior segment or with subtle granular pigment dysgrupancies in the macula only. The significant difference between the group treated with chloroquine or hydrochloroquine and the control group at the 1% level of significance was found in following parameters: in the photopic ERG the value of the b wave latency [ms], in pattern ERG, the values of the waves N35 - P50 [microV] and P50 - N95 [micro

  4. CM2 antigen, a potential novel molecule participating in glucuronide transport on rat hepatocyte canalicular membrane.

    PubMed

    Wang, L; Wang, J; Zhou, X; Li, J; Shi, Y; Han, Z; Wang, X; Li, S; Yang, Z; Wang, R; Fan, D; Han, Y

    2012-06-29

    The polarized molecules predominately distributing at hepatocyte canalicular surface play a vital role in disclosing the process of bile formation and etiopathogenisis of cholestatic live diseases. Therefore, it is important to find novel polarized molecules on hepatocyte canalicular membrane. In the present study, canalicular membrane vesicles (CMVs) isolated from rat hepatocyte by density gradient centrifugation were used as immunogens to produce hybridoma and 46 strains of monoclonal antibodies (mAb) against CMVs were obtained. With a series of morphological assay methods, including immunohistochemistry, immunofluorescence and immuno-electron microscope, the antigens recognized by canalicular mAb1 (CM1) and canalicular mAb2 (CM2) were confirmed to predominately distribute at hepatocyte canalicular membrane. Transport activity assay revealed that CM2 could inhibit ATP-dependent E217βG uptake of rat hepatocyte CMVs. Meanwhile, Western blotting analysis showed that the molecular mass of CM2 antigen was approximately 110kDa, which was much less than Mr 180kDa of multidrug resistance-associated protein 2 (MRP2) involved in glucuronide transport. These data indicated that CM2 antigen might be a potential novel molecule participating in glucuronide transport on the hepatocyte canalicular membrane.

  5. Aliphatic amines in Antarctic CR2, CM2, and CM1/2 carbonaceous chondrites

    NASA Astrophysics Data System (ADS)

    Aponte, José C.; McLain, Hannah L.; Dworkin, Jason P.; Elsila, Jamie E.

    2016-09-01

    Meteoritic water-soluble organic compounds provide a unique record of the processes that occurred during the formation of the solar system and the chemistry preceding the origins of life on Earth. We have investigated the molecular distribution, compound-specific δ13C isotopic ratios and enantiomeric compositions of aliphatic monoamines present in the hot acid-water extracts of the carbonaceous chondrites LAP 02342 (CR2), GRA 95229 (CR2), LON 94101 (CM2), LEW 90500 (CM2), and ALH 83100 (CM1/2). Analyses of the concentration of monoamines in these meteorites revealed: (a) the CR2 chondrites studied here contain higher concentrations of monoamines relative to the analyzed CM2 chondrites; (b) the concentration of monoamines decreases with increasing carbon number; and (c) isopropylamine is the most abundant monoamine in these CR2 chondrites, while methylamine is the most abundant amine species in these CM2 and CM1/2 chondrites. The δ13C values of monoamines in CR2 chondrite do not correlate with the number of carbon atoms; however, in CM2 and CM1/2 chondrites, the 13C enrichment decreases with increasing monoamine carbon number. The δ13C values of methylamine in CR2 chondrites ranged from -1 to +10‰, while in CM2 and CM1/2 chondrites the δ13C values of methylamine ranged from +41 to +59‰. We also observed racemic compositions of sec-butylamine, 3-methyl-2-butylamine, and sec-pentylamine in the studied carbonaceous chondrites. Additionally, we compared the abundance and δ13C isotopic composition of monoamines to those of their structurally related amino acids. We found that monoamines are less abundant than amino acids in CR2 chondrites, with the opposite being true in CM2 and CM1/2 chondrites. We used these collective data to evaluate different primordial synthetic pathways for monoamines in carbonaceous chondrites and to understand the potential common origins these molecules may share with meteoritic amino acids.

  6. The EET87513 clast N: A CM2 fragment in an HED polymict breccia

    NASA Technical Reports Server (NTRS)

    Buchanan, P. C.; Zolensky, M. E.; Reid, A. M.; Barrett, R. A.

    1993-01-01

    Xenoliths of material resembling carbonaceous chondrites have been found in several HED polymict breccias. Most workers concluded that these clasts are related to CM2 meteorites on the basis of texture, bulk composition, and mineralogy. Data on clast N, a carbonaceous chondrite fragment from the howardite EET87513 large enough (approximately 4x5mm on the surface of the slab from which it was separated) to extract bulk samples for INAA and oxygen isotope analysis and to provide a thin section for electron microprobe, SEM, and TEM analysis is reported. Preliminary data for this clast were previously reported. INAA was performed at Oregon State University and bulk oxygen isotopic composition was determined at the University of Chicago. These data confirm that EET87513 clast N is a fragment of CM2 material.

  7. Investigation of pyridine carboxylic acids in CM2 carbonaceous chondrites: Potential precursor molecules for ancient coenzymes

    NASA Astrophysics Data System (ADS)

    Smith, Karen E.; Callahan, Michael P.; Gerakines, Perry A.; Dworkin, Jason P.; House, Christopher H.

    2014-07-01

    The distribution and abundances of pyridine carboxylic acids (including nicotinic acid) in eight CM2 carbonaceous chondrites (ALH 85013, DOM 03183, DOM 08003, EET 96016, LAP 02333, LAP 02336, LEW 85311, and WIS 91600) were investigated by liquid chromatography coupled to UV detection and high resolution Orbitrap mass spectrometry. We find that pyridine monocarboxylic acids are prevalent in CM2-type chondrites and their abundance negatively correlates with the degree of pre-terrestrial aqueous alteration that the meteorite parent body experienced. We also report the first detection of pyridine dicarboxylic acids in carbonaceous chondrites. Additionally, we carried out laboratory studies of proton-irradiated pyridine in carbon dioxide-rich ices (a 1:1 mixture) to serve as a model of the interstellar ice chemistry that may have led to the synthesis of pyridine carboxylic acids. Analysis of the irradiated ice residue shows that a comparable suite of pyridine mono- and dicarboxylic acids was produced, although aqueous alteration may still play a role in the synthesis (and ultimate yield) of these compounds in carbonaceous meteorites. Nicotinic acid is a precursor to nicotinamide adenine dinucleotide, a likely ancient molecule used in cellular metabolism in all of life, and its common occurrence in CM2 chondrites may indicate that meteorites may have been a source of molecules for the emergence of more complex coenzymes on the early Earth.

  8. Investigation of Pyridine Carboxylic Acids in CM2 Carbonaceous Chondrites: Potential Precursor Molecules for Ancient Coenzymes

    NASA Technical Reports Server (NTRS)

    Smith, Karen E.; Callahan, Michael P.; Gerakines, Perry A.; Dworkin, Jason P.; House, Christopher H.

    2014-01-01

    The distribution and abundances of pyridine carboxylic acids (including nicotinic acid) in eight CM2 carbonaceous chondrites (ALH 85013, DOM 03183, DOM 08003, EET 96016, LAP 02333, LAP 02336, LEW 85311, and WIS 91600) were investigated by liquid chromatography coupled to UV detection and high resolution Orbitrap mass spectrometry. We find that pyridine monocarboxylic acids are prevalent in CM2-type chondrites and their abundance negatively correlates with the degree of pre-terrestrial aqueous alteration that the meteorite parent body experienced. We lso report the first detection of pyridine dicarboxylic acids in carbonaceous chondrites. Additionally, we carried out laboratory studies of proton-irradiated pyridine in carbon dioxide-rich ices (a 1:1 mixture) to serve as a model of the interstellar ice chemistry that may have led to the synthesis of pyridine carboxylic acids. Analysis of the irradiated ice residue shows that a comparable suite of pyridine mono- and dicarboxylic acids was produced, although aqueous alteration may still play a role in the synthesis (and ultimate yield) of these compounds in carbonaceous meteorites. Nicotinic acid is a precursor to nicotinamide adenine dinucleotide, a likely ancient molecule used in cellular metabolism in all of life, and its common occurrence in CM2 chondrites may indicate that meteorites may have been a source of molecules for the emergence of more complex coenzymes on the early Earth.

  9. Investigation of Pyridine Carboxylic Acids in CM2 Carbonaceous Chondrites: Potential Precursor Molecules for Ancient Coenzymes

    NASA Technical Reports Server (NTRS)

    Smith, Karen E.; Callahan, Michael P.; Gerakines, Perry A.; Dworkin, Jason P.; House, Christopher H.

    2014-01-01

    The distribution and abundances of pyridine carboxylic acids (including nicotinic acid) in eight CM2 carbonaceous chondrites (ALH 85013, DOM 03183, DOM 08003, EET 96016, LAP 02333, LAP 02336, LEW 85311, and WIS 91600) were investigated by liquid chromatography coupled to UV detection and high resolution Orbitrap mass spectrometry. We find that pyridine monocarboxylic acids are prevalent in CM2-type chondrites and their abundance negatively correlates with the degree of pre-terrestrial aqueous alteration that the meteorite parent body experienced. We also report the first detection of pyridine dicarboxylic acids in carbonaceous chondrites. Additionally, we carried out laboratory studies of proton-irradiated pyridine in carbon dioxide-rich ices (a 1:1 mixture) to serve as a model of the interstellar ice chemistry that may have led to the synthesis of pyridine carboxylic acids. Analysis of the irradiated ice residue shows that a comparable suite of pyridine mono- and dicarboxylic acids was produced, although aqueous alteration may still play a role in the synthesis (and ultimate yield) of these compounds in carbonaceous meteorites. Nicotinic acid is a precursor to nicotinamide adenine dinucleotide, a likely ancient molecule used in cellular metabolism in all of life, and its common occurrence in CM2 chondrites may indicate that meteorites may have been a source of molecules for the emergence of more complex coenzymes on the early Earth.

  10. 46 CFR 39.10-11 - Personnel training-TB/ALL.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 46 Shipping 1 2012-10-01 2012-10-01 false Personnel training-TB/ALL. 39.10-11 Section 39.10-11 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY TANK VESSELS VAPOR CONTROL SYSTEMS General § 39.10-11 Personnel training—TB/ALL. (a) A person in charge of a transfer operation utilizing a vapor...

  11. 46 CFR 39.10-11 - Personnel training-TB/ALL.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 46 Shipping 1 2010-10-01 2010-10-01 false Personnel training-TB/ALL. 39.10-11 Section 39.10-11 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY TANK VESSELS VAPOR CONTROL SYSTEMS General § 39.10-11 Personnel training—TB/ALL. (a) A person in charge of a transfer operation utilizing a vapor...

  12. ERG oncogene modulates prostaglandin signaling in prostate cancer cells.

    PubMed

    Mohamed, Ahmed A; Tan, Shyh-Han; Sun, Chen; Shaheduzzaman, Syed; Hu, Ying; Petrovics, Gyorgy; Chen, Yongmei; Sesterhenn, Isabell A; Li, Hua; Sreenath, Taduru; McLeod, David G; Dobi, Albert; Srivastava, Shiv

    2011-02-15

    Androgen dependent induction of the ETS related gene (ERG) expression in more than half of all prostate cancers results from gene fusions involving regulatory sequence of androgen regulated genes (i.e. TMPRSS2, SLC45A3 and NDRG1) and protein coding sequence of the ERG. Emerging studies in experimental models underscore the functions of ERG in prostate tumorigenesis. However, biological and biochemical functions of ERG in prostate cancer (CaP) remain to be elucidated. This study suggests that ERG activation plays a role in prostaglandin signaling because knockdown of ERG expression in TMPRSS2-ERG fusion containing CaP cells leads to altered levels of the 15-hydroxy-prostaglandin dehydrogenase (HPGD), a tumor suppressor and prostaglandin catabolizing enzyme, and prostaglandin E2 (PGE2) . We demonstrate that HPGD expression is regulated by the binding of the ERG protein to the core promoter of this gene. Moreover, prostaglandin E2 dependent cell growth and urokinase-type plasminogen activator (uPA) expression are also affected by ERG knockdown. Together, these data imply that the ERG oncoprotein in CaP cells positively influence prostaglandin mediated signaling, which may contribute to tumor progression. PMID:21178489

  13. ERG oncoprotein expression in prostate carcinoma patients of different ethnicities

    PubMed Central

    KELLY, GREGORY M.; KONG, YINK HEAY; DOBI, ALBERT; SRIVASTAVA, SHIV; SESTERHENN, ISABELL A.; PATHMANATHAN, RAJADURAI; TAN, HUI MENG; TAN, SHYH-HAN; CHEONG, SOK CHING

    2015-01-01

    Overexpression of the erythroblast transformation-specific-related gene (ERG) oncoprotein due to transmembrane protease, serine 2 (TMPRSS2)-ERG fusion, the most prevalent genomic alteration in prostate cancer (CaP), is more frequently observed among Caucasian patients compared to patients of African or Asian descent. To the best of our knowledge, this is the first study to investigate the prevalence of ERG alterations in a multiethnic cohort of CaP patients. A total of 191 formalin-fixed paraffin-embedded sections of transrectal ultrasound-guided prostate biopsy specimens, collected from 120 patients treated at the Sime Darby Medical Centre, Subang Jaya, Malaysia, were analyzed for ERG protein expression by immunohistochemistry using the anti-ERG monoclonal antibody 9FY as a surrogate for the detection of ERG fusion events. The overall frequency of ERG protein expression in the population evaluated in this study was 39.2%. Although seemingly similar to rates reported in other Asian communities, the expression of ERG was distinct amongst different ethnic groups (P=0.004). Malaysian Indian (MI) patients exhibited exceedingly high expression of ERG in their tumors, almost doubling that of Malaysian Chinese (MC) patients, whereas ERG expression was very low amongst Malay patients (12.5%). When collectively analyzing data, we observed a significant correlation between younger patients and higher ERG expression (P=0.04). The prevalence of ERG expression was significantly different amongst CaP patients of different ethnicities. The higher number of ERG-expressing tumors among MI patients suggested that the TMPRSS2-ERG fusion may be particularly important in the pathogenesis of CaP amongst this group of patients. Furthermore, the more frequent expression of ERG among the younger patients analyzed suggested an involvement of ERG in the early onset of CaP. The results of this study underline the value of using ERG status to better understand the differences in the etiology

  14. ERG oncoprotein expression in prostate carcinoma patients of different ethnicities.

    PubMed

    Kelly, Gregory M; Kong, Yink Heay; Dobi, Albert; Srivastava, Shiv; Sesterhenn, Isabell A; Pathmanathan, Rajadurai; Tan, Hui Meng; Tan, Shyh-Han; Cheong, Sok Ching

    2015-01-01

    Overexpression of the erythroblast transformation-specific-related gene (ERG) oncoprotein due to transmembrane protease, serine 2 (TMPRSS2)-ERG fusion, the most prevalent genomic alteration in prostate cancer (CaP), is more frequently observed among Caucasian patients compared to patients of African or Asian descent. To the best of our knowledge, this is the first study to investigate the prevalence of ERG alterations in a multiethnic cohort of CaP patients. A total of 191 formalin-fixed paraffin-embedded sections of transrectal ultrasound-guided prostate biopsy specimens, collected from 120 patients treated at the Sime Darby Medical Centre, Subang Jaya, Malaysia, were analyzed for ERG protein expression by immunohistochemistry using the anti-ERG monoclonal antibody 9FY as a surrogate for the detection of ERG fusion events. The overall frequency of ERG protein expression in the population evaluated in this study was 39.2%. Although seemingly similar to rates reported in other Asian communities, the expression of ERG was distinct amongst different ethnic groups (P=0.004). Malaysian Indian (MI) patients exhibited exceedingly high expression of ERG in their tumors, almost doubling that of Malaysian Chinese (MC) patients, whereas ERG expression was very low amongst Malay patients (12.5%). When collectively analyzing data, we observed a significant correlation between younger patients and higher ERG expression (P=0.04). The prevalence of ERG expression was significantly different amongst CaP patients of different ethnicities. The higher number of ERG-expressing tumors among MI patients suggested that the TMPRSS2-ERG fusion may be particularly important in the pathogenesis of CaP amongst this group of patients. Furthermore, the more frequent expression of ERG among the younger patients analyzed suggested an involvement of ERG in the early onset of CaP. The results of this study underline the value of using ERG status to better understand the differences in the etiology

  15. ERG induces taxane resistance in castration-resistant prostate cancer

    PubMed Central

    Galletti, Giuseppe; Matov, Alexandre; Beltran, Himisha; Fontugne, Jacqueline; Miguel Mosquera, Juan; Cheung, Cynthia; MacDonald, Theresa Y.; Sung, Matthew; O’Toole, Sandra; Kench, James G.; Suk Chae, Sung; Kimovski, Dragi; Tagawa, Scott T.; Nanus, David M.; Rubin, Mark A.; Horvath, Lisa G.; Giannakakou, Paraskevi; Rickman, David S.

    2014-01-01

    Taxanes are the only chemotherapies used to treat patients with metastatic castration-resistant prostate cancer (CRPC). Despite the initial efficacy of taxanes in treating CRPC, all patients ultimately fail due to the development of drug resistance. In this study, we show that ERG overexpression in in vitro and in vivo models of CRPC is associated with decreased sensitivity to taxanes. ERG affects several parameters of microtubule dynamics and inhibits effective drug-target engagement of docetaxel or cabazitaxel with tubulin. Finally, analysis of a cohort of 34 men with metastatic CRPC treated with docetaxel chemotherapy reveals that ERG-overexpressing prostate cancers have twice the chance of docetaxel resistance than ERG-negative cancers. Our data suggest that ERG plays a role beyond regulating gene expression and functions outside the nucleus to cooperate with tubulin towards taxane insensitivity. Determining ERG rearrangement status may aid in patient selection for docetaxel or cabazitaxel therapy and/or influence co-targeting approaches. PMID:25420520

  16. The role of the ETS Factor erg in Zebrafish Vasculogenesis

    PubMed Central

    Ellett, Felix; Kile, Benjamin T.; Lieschke, Graham J.

    2009-01-01

    Erg, a member of the ETS family of transcription factors, has been implicated by previous studies in endothelial and haematopoietic development. Deregulation of the human ERG locus is associated with acute myeloid leukaemia, prostate cancer and Ewing's sarcoma. To better understand the role of Erg during early development, we utilised the zebrafish as a model amenable to descriptive and functional studies in vivo. Zebrafish have a single erg gene that is expressed in mesoderm and its vascular derivatives during angioblast migration, vasculogenesis and early angiogenesis. Mutant and morphant expression analyses placed erg in a genetic pathway downstream of cloche, tal1/scl and etsrp during early angioblast migration. Furthermore, a combination of gain-of-function and loss-of-function studies suggested a redundant yet specific role for erg in both angioblast specification/proliferation and early angiogenesis, and a synergistic interaction with the critical ETS factor etsrp. PMID:19027849

  17. Experimental investigation of a 1 kA/cm2 sheet beam plasma cathode electron gun

    NASA Astrophysics Data System (ADS)

    Kumar, Niraj; Narayan Pal, Udit; Kumar Pal, Dharmendra; Prajesh, Rahul; Prakash, Ram

    2015-01-01

    In this paper, a cold cathode based sheet-beam plasma cathode electron gun is reported with achieved sheet-beam current density ˜1 kA/cm2 from pseudospark based argon plasma for pulse length of ˜200 ns in a single shot experiment. For the qualitative assessment of the sheet-beam, an arrangement of three isolated metallic-sheets is proposed. The actual shape and size of the sheet-electron-beam are obtained through a non-conventional method by proposing a dielectric charging technique and scanning electron microscope based imaging. As distinct from the earlier developed sheet beam sources, the generated sheet-beam has been propagated more than 190 mm distance in a drift space region maintaining sheet structure without assistance of any external magnetic field.

  18. Actinic defect counting statistics over 1 cm2 area of EUVL mask blank

    SciTech Connect

    Jeong, Seongtae; Lai, Chih-Wei; Rekawa, Seno; Walton, Chris W.; Bokor, Jeffrey

    2000-02-18

    As a continuation of comparison experiments between EUV inspection and visible inspection of defects on EUVL mask blanks, we report on the result of an experiment where the EUV defect inspection tool is used to perform at-wavelength defect counting over 1 cm{sup 2} of EUVL mask blank. Initial EUV inspection found five defects over the scanned area and the subsequent optical scattering inspection was able to detect all of the five defects. Therefore, if there are any defects that are only detectable by EUV inspection, the density is lower than the order of unity per cm2. An upgrade path to substantially increase the overall throughput of the EUV inspection system is also identified in the manuscript.

  19. Vibration Energy Harvesting Characterization of 1 cm2 Poly(vinylidene fluoride) Generators in Vacuum

    NASA Astrophysics Data System (ADS)

    Cao, Ziping; Zhang, Jinya; Kuwano, Hiroki

    2011-09-01

    In this study, poly(vinylidene fluoride) (PVDF) was used as a piezoelectric element to fabricate small size (two-dimensional area <1 cm2) generators with low resonant frequency (about 100 Hz) for matching the frequency of vibration sources. To clarify the effect of the air damping on the vibration energy harvesting, PVDF generators were investigated in three measurement conditions: “unpackaged in air”, “packaged in air”, and “unpackaged in vacuum”. It was found that the output power of generators “unpackaged in vacuum” was almost twice that of generators “packaged in air” at 0.5g acceleration. With the increase in vibration acceleration, the output power of generators “unpackaged in vacuum” rapidly increased in a quadratic relationship with the acceleration at low acceleration level, and then the increasing ratio decreased at high acceleration. At 4.31g acceleration, the output power reached 100.833 µW.

  20. Compositions of Partly Altered Olivine and Replacement Serpentine in the CM2 Chondrite QUE93005

    NASA Technical Reports Server (NTRS)

    Velbel, M. A.; Tonui, E. K.; Zolensky, M. E.

    2005-01-01

    Some phyllosilicates in CM carbonaceous chondrites formed by aqueous alteration of anhydrous precursor phases. Although broad trends in the compositions of hydrous phyllosilicates are recognized and believed to be related to trends in degree of aqueous alteration, details of the reactions that formed specific secondary minerals remain obscure. This paper reports compositional relationships between remnants of partially pseudomorphically (or alteromorphically) replaced silicates and their alteration products (serpentine) in the CM2 chondrite QUE93005 and compares it with previously published results for ALH81002. Reactants and products were characterized by optical petrography, backscattered scanning electron microscopy (BSEM), and electron microprobe. By focusing on serpentine formed from known reactants (olivines), and on only those instances in which some of the reactant silicate remains, direct compositional relationships between reactants and products, and the elemental mobility required by the reactions, can be established. Additional information is included in the original extended abstract.

  1. Organic blend semiconductors and transistors with hole mobility exceeding 10 cm2/Vs (Presentation Recording)

    NASA Astrophysics Data System (ADS)

    Paterson, Alexandra F.; Anthopoulos, Thomas D.

    2015-10-01

    Plastic electronics that can be manufactured using solution-based methods are the subject of great research interest due to their potential for low-cost, large-area electronic applications. The interest in this field has led to considerable research and subsequent advances in device performance. To this end solution-processed organic thin-film transistors (OTFTs) have shown impressive improvements in recent years through the increasing values of charge carrier mobility. Here we report the development of next generation organic blend materials for OTFTs with hole mobilities of 10 cm2/Vs. These high performance devices have been achieved using a novel semiconducting blend system comprising of an amorphous-like conjugated polymer and a high mobility small molecule. The combination of a highly crystalline small molecule with the polymer binder aids the formation of uniform films as well as enables an element of control over the nucleation and growth of the small molecule. The polymer binders investigated belongs to the family of indacenodithiophene-based copolymers which are renowned for their high carrier mobilities regardless of their apparent structural disorder. The addition of the polymer with carefully chosen small molecules is found to further increase the hole mobility of the resulting blend OTFT to over 10 cm2/Vs. These organic devices provide an interesting insight into this rather complex blend system, highlighting the correlation between the morphology developed following solution processing and device performance, as well as exploring the role of each of the two components in the blend in terms of their contribution to charge transport.

  2. Spectral content of buried Ag foils at 1016 W/cm2 laser illuminationa)

    NASA Astrophysics Data System (ADS)

    Huntington, C. M.; Maddox, B. R.; Park, H.-S.; Prisbrey, S.; Remington, B. A.

    2014-11-01

    Sources of 5-12 keV thermal Heα x-rays are readily generated by laser irradiation of mid-Z foils at intensities >1014 W/cm2, and are widely used as probes for inertial confinement fusion and high-energy-density experiments. Higher energy 17-50 keV x-ray sources are efficiently produced from "cold" Kα emission using short pulse, petawatt lasers at intensities >1018 W/cm2 [H.-S. Park, B. R. Maddox et al., "High-resolution 17-75 keV backlighters for high energy density experiments," Phys. Plasmas 15(7), 072705 (2008); B. R. Maddox, H. S. Park, B. A. Remington et al., "Absolute measurements of x-ray backlighter sources at energies above 10 keV," Phys. Plasmas 18(5), 056709 (2011)]. However, when long pulse (>1 ns) lasers are used with Z > 30 elements, the spectrum contains contributions from both K shell transitions and from ionized atomic states. Here we show that by sandwiching a silver foil between layers of high-density carbon, the ratio of Kα:Heα in the x-ray spectrum is significant increased over directly illuminated Ag foils, with narrower lines from K-shell transitions. Additionally, the emission volume is more localized for the sandwiched target, producing a more planar x-ray sheet. This technique may be useful for generating probes requiring spectral purity and a limited spatial extent, for example, in incoherent x-ray Thomson scattering experiments.

  3. The amino acid composition of the Sutter's Mill CM2 carbonaceous chondrite

    NASA Astrophysics Data System (ADS)

    Burton, Aaron S.; Glavin, Daniel P.; Elsila, Jamie E.; Dworkin, Jason P.; Jenniskens, Peter; Yin, Qing-Zhu

    2014-11-01

    We determined the abundances and enantiomeric compositions of amino acids in Sutter's Mill fragment #2 (designated SM2) recovered prior to heavy rains that fell April 25-26, 2012, and two other meteorite fragments, SM12 and SM51, that were recovered postrain. We also determined the abundance, enantiomeric, and isotopic compositions of amino acids in soil from the recovery site of fragment SM51. The three meteorite stones experienced terrestrial amino acid contamination, as evidenced by the low D/L ratios of several proteinogenic amino acids. The D/L ratios were higher in SM2 than in SM12 and SM51, consistent with rain introducing additional L-amino acid contaminants to SM12 and SM51. Higher percentages of glycine, β-alanine, and γ-amino-n-butyric acid were observed in free form in SM2 and SM51 compared with the soil, suggesting that these free amino acids may be indigenous. Trace levels of D+L-β-aminoisobutyric acid (β-AIB) observed in all three meteorites are not easily explained as terrestrial contamination, as β-AIB is rare on Earth and was not detected in the soil. Bulk carbon and nitrogen and isotopic ratios of the SM samples and the soil also indicate terrestrial contamination, as does compound-specific isotopic analysis of the amino acids in the soil. The amino acid abundances in SM2, the most pristine SM meteorite analyzed here, are approximately 20-fold lower than in the Murchison CM2 carbonaceous chondrite. This may be due to thermal metamorphism in the Sutter's Mill parent body at temperatures greater than observed for other aqueously altered CM2 meteorites.

  4. 43 CFR 10.11 - Disposition of culturally unidentifiable human remains.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... human remains. 10.11 Section 10.11 Public Lands: Interior Office of the Secretary of the Interior NATIVE AMERICAN GRAVES PROTECTION AND REPATRIATION REGULATIONS Human Remains, Funerary Objects, Sacred Objects, or... unidentifiable human remains. (a) General. This section implements section 8(c)(5) of the Act and applies...

  5. 43 CFR 10.11 - Disposition of culturally unidentifiable human remains.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... human remains. 10.11 Section 10.11 Public Lands: Interior Office of the Secretary of the Interior NATIVE AMERICAN GRAVES PROTECTION AND REPATRIATION REGULATIONS Human Remains, Funerary Objects, Sacred Objects, or... unidentifiable human remains. (a) General. This section implements section 8(c)(5) of the Act and applies...

  6. 43 CFR 10.11 - Disposition of culturally unidentifiable human remains.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... human remains. 10.11 Section 10.11 Public Lands: Interior Office of the Secretary of the Interior NATIVE AMERICAN GRAVES PROTECTION AND REPATRIATION REGULATIONS Human Remains, Funerary Objects, Sacred Objects, or... unidentifiable human remains. (a) General. This section implements section 8(c)(5) of the Act and applies...

  7. 43 CFR 10.11 - Disposition of culturally unidentifiable human remains.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... human remains. 10.11 Section 10.11 Public Lands: Interior Office of the Secretary of the Interior NATIVE AMERICAN GRAVES PROTECTION AND REPATRIATION REGULATIONS Human Remains, Funerary Objects, Sacred Objects, or... unidentifiable human remains. (a) General. This section implements section 8(c)(5) of the Act and applies...

  8. Course Information for the Graduation Program: Grade 10, 11 and 12 Courses, 2009-2010

    ERIC Educational Resources Information Center

    British Columbia Ministry of Education, 2009

    2009-01-01

    This manual, "Course Information for the Graduation Program, Grade 10, 11, and 12 Courses: 2009-2010," was approved by the Minister of Education on July 30, 2009 for setting out graduation requirements. The manual provides information for schools about courses that students take in Grades 10, 11, and 12. It is updated annually with relevant…

  9. A minimum column density of 1 g cm(-2) for massive star formation.

    PubMed

    Krumholz, Mark R; McKee, Christopher F

    2008-02-28

    Massive stars are very rare, but their extreme luminosities make them both the only type of young star we can observe in distant galaxies and the dominant energy sources in the Universe today. They form rarely because efficient radiative cooling keeps most star--forming gas clouds close to isothermal as they collapse, and this favours fragmentation into stars of one solar mass or lower. Heating of a cloud by accreting low-mass stars within it can prevent fragmentation and allow formation of massive stars, but the necessary properties for a cloud to form massive stars-and therefore where massive stars form in a galaxy--have not yet been determined. Here we show that only clouds with column densities of at least 1 g cm(-2) can avoid fragmentation and form massive stars. This threshold, and the environmental variation of the stellar initial mass function that it implies, naturally explain the characteristic column densities associated with massive star clusters and the difference between the radial profiles of Halpha and ultraviolet emission in galactic disks. The existence of a threshold also implies that the initial mass function should show detectable variation with environment within the Galaxy, that the characteristic column densities of clusters containing massive stars should vary between galaxies, and that star formation rates in some galactic environments may have been systematically underestimated.

  10. On the Behavior of Phosphorus During the Aqueous Alteration of CM2 Carbonaceous Chondrites

    NASA Technical Reports Server (NTRS)

    Brearley, Adrian J.; Chizmadia, Lysa J.

    2005-01-01

    During the earliest period of solar system formation, water played an important role in the evolution of primitive dust, both after accretion of planetesimals and possible before accretion within the protoplanetary disk. Many chondrites show evidence of variable degrees of aqueous alteration, the CM2 chondrites being among the most studied [1]. This group of chondrites is characterized by mineral assemblages of both primary and secondary alteration phases. Hence, these meteorites retain a particularly important record of the reactions that occurred between primary high temperature nebular phases and water. Studies of these chondrites can provide information on the conditions and environments of aqueous alteration and the mobility of elements during alteration. This latter question is at the core of a debate concerning the location of aqueous alteration, i.e. whether alteration occurred predominantly within a closed system after accretion (parent body alteration) or whether some degree of alteration occurred within the solar nebula or on ephemeral protoplanetary bodies prior to accretion. At the core of the parent body alteration model is the hypothesis that elemental exchange between different components, principally chondrules and matrix, must have occurred. chondrules and matrix, must have occurred. In this study, we focus on the behavior of the minor element, phosphorus. This study was stimulated by observations of the behavior of P during the earliest stages of alteration in glassy mesostasis in type II chondrules in CR chondrites and extends the preliminary observations of on Y791198 to other CM chondrites.

  11. N-15-Rich Organic Globules in a Cluster IDP and the Bells CM2 Chondrite

    NASA Technical Reports Server (NTRS)

    Messenger, S.; Nakamura-Messenger, K.; Keller, Lindsay P.

    2008-01-01

    Organic matter in primitive meteorites and chondritic porous interplanetary dust particles (CP IDPs) is commonly enriched in D/H and 15N/14N relative to terrestrial values [1-3]. These anomalies are ascribed to the partial preservation of presolar cold molecular cloud material [1]. Some meteorites and IDPs contain m-size inclusions with extreme H and N isotopic anomalies [2-4], possibly due to preserved pristine primordial organic grains. We recently showed that the in the Tagish Lake meteorite, the principle carriers of these anomalies are sub- m, hollow organic globules [5]. The globules likely formed by photochemical processing of organic ices in a cold molecular cloud or the outermost regions of the protosolar disk [5]. We proposed that similar materials should be common among primitive meteorites, IDPs, and comets. Similar objects have been observed in organic extracts of carbonaceous chondrites [6-8], however their N and H isotopic compositions are generally unknown. Bulk H and N isotopic compositions may indicate which meteorites best preserve interstellar organic compounds. Thus, we selected the Bells CM2 carbonaceous chondrites for study based on its large bulk 15N (+335 %) and D (+990 %) [9].

  12. Urinary TMPRSS2:ERG and PCA3 in an active surveillance cohort: results from a baseline analysis in the Canary Prostate Active Surveillance Study

    PubMed Central

    Lin, Daniel W.; Newcomb, Lisa F.; Brown, Elissa C.; Brooks, James D.; Carroll, Peter R.; Feng, Ziding; Gleave, Martin E.; Lance, Raymond S.; Sanda, Martin G.; Thompson, Ian M.; Wei, John T.; Nelson, Peter S.

    2013-01-01

    Purpose Active surveillance is used to manage low risk prostate cancer. Both PCA3 and TMRPSS2-ERG are promising biomarkers that may be associated with aggressive disease. This study examines the correlation of these biomarkers with higher cancer volume and grade determined at the time of biopsy in an active surveillance cohort. Experimental Design Post-DRE urine was collected prospectively as part of the multi-institutional Canary Prostate Active Surveillance Study (PASS). PCA3 and TMPRSS2-ERG levels were analyzed in urine collected at study entry. Biomarker scores were correlated to clinical and pathologic variables. Results In 387 men, both PCA3 and TMPRSS2-ERG scores were significantly associated with higher volume disease. For a negative repeat biopsy, and 1–10%, 11–33%, ≥34% positive cores, median PCA3 and TMPRSS2-ERG scores increased incrementally (P < 0.005). Both PCA3 and TMPRSS2-ERG scores were also significantly associated with presence of high grade disease. For a negative repeat biopsy, Gleason 6 and Gleason ≥7 cancers, the median PCA3 and TMPRSS2-ERG scores also increased incrementally (P = 0.02 and P = 0.001, respectively). Using the marker scores as a continuous variables, the odds ratio for a biopsy in which cancer was detected versus a negative repeat biopsy (ref) on modeling was 1.41 (95% CI 1.07–1.85), P = 0.01 for PCA3 and 1.28 (95% CI 1.10–1.49), P = 0.001 for TMPRSS2-ERG. Conclusions For men on active surveillance both PCA3 and TMPRSS2-ERG appear to stratify risk of having aggressive cancer as defined by tumor volume or Gleason score. PMID:23515404

  13. In silico prediction of hERG inhibition.

    PubMed

    Jing, Yankang; Easter, Alison; Peters, David; Kim, Norman; Enyedy, Istvan J

    2015-01-01

    The voltage-gated potassium channel encoded by hERG carries a delayed rectifying potassium current (IKr) underlying repolarization of the cardiac action potential. Pharmacological blockade of the hERG channel results in slowed repolarization and therefore prolongation of action potential duration and an increase in the QT interval as measured on an electrocardiogram. Those are possible to cause sudden death, leading to the withdrawals of many drugs, which is the reason for hERG screening. Computational in silico prediction models provide a rapid, economic way to screen compounds during early drug discovery. In this review, hERG prediction models are classified as 2D and 3D quantitative structure-activity relationship models, pharmacophore models, classification models, and structure based models (using homology models of hERG).

  14. Effects of donepezil on hERG potassium channels.

    PubMed

    Chae, Yun Ju; Lee, Hong Joon; Jeon, Ji Hyun; Kim, In-Beom; Choi, Jin-Sung; Sung, Ki-Wug; Hahn, Sang June

    2015-02-01

    Donepezil is a potent, selective inhibitor of acetylcholinesterase, which is used for the treatment of Alzheimer's disease. Whole-cell patch-clamp technique and Western blot analyses were used to study the effects of donepezil on the human ether-a-go-go-related gene (hERG) channel. Donepezil inhibited the tail current of the hERG in a concentration-dependent manner with an IC50 of 1.3 μM. The metabolites of donepezil, 6-ODD and 5-ODD, inhibited the hERG currents in a similar concentration-dependent manner; the IC50 values were 1.0 and 1.5 μM, respectively. A fast drug perfusion system demonstrated that donepezil interacted with both the open and inactivated states of the hERG. A fast application of donepezil during the tail currents inhibited the open state of the hERG in a concentration-dependent manner with an IC50 of 2.7 μM. Kinetic analysis of donepezil in an open state of the hERG yielded blocking and unblocking rate constants of 0.54 µM(-1)s(-1) and 1.82 s(-1), respectively. The block of the hERG by donepezil was voltage-dependent with a steep increase across the voltage range of channel activation. Donepezil caused a reduction in the hERG channel protein trafficking to the plasma membrane at low concentration, but decreased the channel protein expression at higher concentrations. These results suggest that donepezil inhibited the hERG at a supratherapeutic concentration, and that it did so by preferentially binding to the activated (open and/or inactivated) states of the channels and by inhibiting the trafficking and expression of the hERG channel protein in the plasma membrane.

  15. Fe and O EELS Studies of Ion Irradiated Murchison CM2 Carbonaceous Chondrite Matrix

    NASA Technical Reports Server (NTRS)

    Keller, L. P.; Christofferson, R.; Dukes, C. A.; Baragiola, R. A.; Rahman, Z.

    2015-01-01

    Introduction: The physical and chemical response of hydrated carbonaceous chondrite materials to space weathering processes is poorly understood. Improving this understanding is a key part of establishing how regoliths on primitive carbonaceous asteroids respond to space weathering processes, knowledge that supports future sample return missions (Hayabusa 2 and OSIRISREx) that are targeting objects of this type. We previously reported on He+ irradiation of Murchison matrix and showed that the irradiation resulted in amorphization of the matrix phyllosilicates, loss of OH, and surface vesiculation. Here, we report electron energy-loss spectroscopy (EELS) measurements of the irradiated material with emphasis on the Fe and O speciation. Sample and Methods: A polished thin section of the Murchison CM2 carbonaceous chondrite was irradiated with 4 kilovolts He(+) (normal incidence) to a total dose of 1 x 10(exp 18) He(+) per square centimeter. We extracted thin sections from both irradiated and unirradiated regions in matrix using focused ion beam (FIB) techniques with electron beam deposition for the protective carbon strap to minimize surface damage artifacts from the FIB milling. The FIB sections were analyzed using a JEOL 2500SE scanning and transmission electron microscope (STEM) equipped with a Gatan Tridiem imaging filter. EELS spectra were collected from 50 nanometer diameter regions with an energy resolution of 0.7 electronvolts FWHM at the zero loss. EELS spectra were collected at low electron doses to minimize possible artifacts from electron-beam irradiation damage. Results and Discussion: Fe L (sub 2,3) EELS spectra from matrix phyllosilicates in CM chondrites show mixed Fe(2+)/Fe(3+) oxidation states with Fe(3+)/Sigma Fe approximately 0.5. Fe L(sub 2,3) spectra from the irradiated/ amorphized matrix phyllosilicates show higher Fe(2+)/Fe(3+) ratios compared to spectra obtained from pristine material at depths beyond the implantation/amorphization layer. We

  16. Formation of spinel-, hibonite-rich inclusions found in CM2 carbonaceous chrondrites

    SciTech Connect

    Simon, S B; Grossman, L; Hutcheon, I D; Phinney, D L; Weber, P K; Fallon, S J

    2005-11-03

    We report petrography, mineral chemistry, bulk chemistry, and bulk isotopic compositions of a suite of 40 spinel-rich inclusions from the Murchison (CM2) carbonaceous chondrite. Seven types of inclusions are identified based on mineralogy: spinel-hibonite-perovskite; spinel-perovskite-pyroxene; spinel-perovskite-melilite; spinel-hibonite-perovskite-melilite; spinel-hibonite; spinel-pyroxene; and spinel-melilite-anorthite. Hibonite-bearing inclusions have Ti-poor spinel compared to the hibonite-free ones, and spinel-hibonite-perovskite inclusions have the highest average bulk TiO{sub 2} contents (7.8 wt%). The bulk CaO/Al{sub 2}O{sub 3} ratios of the inclusions range from 0.005-0.21, well below the solar value of 0.79. Hibonite-, spinel-rich inclusions consist of phases that are not predicted by condensation calculations to coexist; in the equilibrium sequence, hibonite is followed by melilite, which is followed by spinel. Therefore, hibonite-melilite or melilite-spinel inclusions should be dominant instead. One explanation for the 'missing melilite' is that it condensed as expected but was lost due to evaporation of Mg and Ca during heating and melting of spherule precursors. If this theory were correct, melilite-poor spherules would have isotopically heavy Mg and Ca. Except for one inclusion with F{sub Mg} = 4.3 {+-} 2.6{per_thousand}/amu and another with isotopically light Ca (F{sub Ca} = 3.4 {+-} 2.0{per_thousand}/amu), however, all the inclusions we analyzed have normal isotopic compositions within their 2{sigma} uncertainties. Thus, we found no evidence for significant mass-dependent fractionation. Our preferred explanation for the general lack of melilite among hibonite-, spinel-bearing inclusions is kinetic inhibition of melilite condensation relative to spinel. Because of similarities between the crystal structures of hibonite and spinel, it should be easier for spinel to form from hibonite than for melilite to do so.

  17. Impact-Induced Chondrule Deformation and Aqueous Alteration of CM2 Murchison

    NASA Technical Reports Server (NTRS)

    Hanna, R. D.; Zolensky, M.; Ketcham, R. A.; Behr, W. M.; Martinez, J. E.

    2014-01-01

    Deformed chondrules in CM2 Murchison have been found to define a prominent foliation [1,2] and lineation [3] in 3D using X-ray computed tomography (XCT). It has been hypothesized that chondrules in foliated chondrites deform by "squeezing" into surrounding pore space [4,5], a process that also likely removes primary porosity [6]. However, shock stage classification based on olivine extinction in Murchison is consistently low (S1-S2) [4-5,7] implying that significant intracrystalline plastic deformation of olivine has not occurred. One objective of our study is therefore to determine the microstructural mechanisms and phases that are accommodating the impact stress and resulting in relative displacements within the chondrules. Another question regarding impact deformation in Murchison is whether it facilitated aqueous alteration as has been proposed for the CMs which generally show a positive correlation between degree of alteration and petrofabric strength [7,2]. As pointed out by [2], CM Murchison represents a unique counterpoint to this correlation: it has a strong petrofabric but a relatively low degree of aqueous alteration. However, Murchison may not represent an inconsistency to the proposed causal relationship between impact and alteration, if it can be established that the incipient aqueous alteration post-dated chondrule deformation. Methods: Two thin sections from Murchison sample USNM 5487 were cut approximately perpendicular to the foliation and parallel to lineation determined by XCT [1,3] and one section was additionally polished for EBSD. Using a combination of optical petrography, SEM, EDS, and EBSD several chondrules were characterized in detail to: determine phases, find microstructures indicative of strain, document the geometric relationships between grain-scale microstructures and the foliation and lineation direction, and look for textural relationships of alteration minerals (tochilinite and Mg-Fe serpentine) that indicate timing of their

  18. Indexing molecules for their hERG liability.

    PubMed

    Rayan, Anwar; Falah, Mizied; Raiyn, Jamal; Da'adoosh, Beny; Kadan, Sleman; Zaid, Hilal; Goldblum, Amiram

    2013-07-01

    The human Ether-a-go-go-Related-Gene (hERG) potassium (K(+)) channel is liable to drug-inducing blockage that prolongs the QT interval of the cardiac action potential, triggers arrhythmia and possibly causes sudden cardiac death. Early prediction of drug liability to hERG K(+) channel is therefore highly important and preferably obligatory at earlier stages of any drug discovery process. In vitro assessment of drug binding affinity to hERG K(+) channel involves substantial expenses, time, and labor; and therefore computational models for predicting liabilities of drug candidates for hERG toxicity is of much importance. In the present study, we apply the Iterative Stochastic Elimination (ISE) algorithm to construct a large number of rule-based models (filters) and exploit their combination for developing the concept of hERG Toxicity Index (ETI). ETI estimates the molecular risk to be a blocker of hERG potassium channel. The area under the curve (AUC) of the attained model is 0.94. The averaged ETI of hERG binders, drugs from CMC, clinical-MDDR, endogenous molecules, ACD and ZINC, were found to be 9.17, 2.53, 3.3, -1.98, -2.49 and -3.86 respectively. Applying the proposed hERG Toxicity Index Model on external test set composed of more than 1300 hERG blockers picked from chEMBL shows excellent performance (Matthews Correlation Coefficient of 0.89). The proposed strategy could be implemented for the evaluation of chemicals in the hit/lead optimization stages of the drug discovery process, improve the selection of drug candidates as well as the development of safe pharmaceutical products. PMID:23727540

  19. Marginal erg facies: A trial approach toward a descriptive classification

    SciTech Connect

    Caputo, M.V. ); Langford, R.P. )

    1991-03-01

    During the late 1970s and early 1980s, sedimentologists began recognizing the margins of eolian sand seas as separate, components which differed from interior sand seas in geometry, extent, and facies. Stratigraphers have now observed these differences in eolian rocks. Erg margins may be grouped in five ways: (1) by associations with extradunal environments-coastal plain, lacustrine, periglacial, marine (tidal flat, coastal sabkha, beach, and lagoon), and arid alluvial (alluvial fan, fluvial, playa, inland sabkha); (2) by allocyclic controls-eustasy, plate tectonism, and climate; (3) by autocyclic controls-local tectonism, topography, vegetation, hydrology, structure, sediment source and supply, and wind regime; (4) by geographic position-upwind, downwind, and along-wind margins; and (5) by sedimentary facies-texture and architecture. In contrast with erg interiors, erg margins are characterized by smaller, less complex dune-forms related to thinner sand accumulation; elementary dune architecture; more vegetation and bioturbation; high occurrence of sand sheet, zibar, and serir facies; expansive, low-relief interdunes with widely distributed dunes; and a greater proportion of interbedded extradunal deposits. Some of the published studies on ancient eolian systems have identified erg margin facies that have been influences by marine and arid alluvial processes. Few reports have described lacustrine-eolian and periglacial-eolian interactions. This study is an attempt to organize known features of modern and ancient erg margins into a scheme based on erg margin controls.

  20. Nanoimprinted polymer lasers with threshold below 100 W/cm2 using mixed-order distributed feedback resonators.

    PubMed

    Wang, Yue; Tsiminis, Georgios; Kanibolotsky, Alexander L; Skabara, Peter J; Samuel, Ifor D W; Turnbull, Graham A

    2013-06-17

    Organic semiconductor lasers were fabricated by UV-nanoimprint lithography with thresholds as low as 57 W/cm(2) under 4 ns pulsed operation. The nanoimprinted lasers employed mixed-order distributed feedback resonators, with second-order gratings surrounded by first-order gratings, combined with a light-emitting conjugated polymer. They were pumped by InGaN LEDs to produce green-emitting lasers, with thresholds of 208 W/cm(2) (102 nJ/pulse). These hybrid lasers incorporate a scalable UV-nanoimprint lithography process, compatible with high-performance LEDs, therefore we have demonstrated a coherent, compact, low-cost light source.

  1. hERG quality control and the long QT syndrome.

    PubMed

    Foo, Brian; Williamson, Brittany; Young, Jason C; Lukacs, Gergely; Shrier, Alvin

    2016-05-01

    Long-QT syndrome type-2 (LQT2) is characterized by reduced functional expression of the human ether-à-go-go related (hERG) gene product, resulting in impaired cardiac repolarization and predisposition to fatal arrhythmia. Previous studies have implicated abnormal trafficking of misfolded hERG as the primary mechanism of LQT2, with misfolding being caused by mutations in the hERG gene (inherited) or drug treatment (acquired). More generally, environmental and metabolic stresses present a constant challenge to the folding of proteins, including hERG, and must be countered by robust protein quality control (QC) systems. Disposal of partially unfolded yet functional plasma membrane (PM) proteins by protein QC contributes to the loss-of-function phenotype in various conformational diseases including cystic fibrosis (CF) and long-QT syndrome type-2 (LQT2). The prevalent view has been that the loss of PM expression of hERG is attributed to biosynthetic block by endoplasmic reticulum (ER) QC pathways. However, there is a growing appreciation for protein QC pathways acting at post-ER cellular compartments, which may contribute to conformational disease pathogenesis. This article will provide a background on the structure and cellular trafficking of hERG as well as inherited and acquired LQT2. We will review previous work on hERG ER QC and introduce the more novel view that there is a significant peripheral QC at the PM and peripheral cellular compartments. Particular attention is drawn to the unique role of the peripheral QC system in acquired LQT2. Understanding the QC process and players may provide targets for therapeutic intervention in dealing with LQT2. PMID:26718903

  2. Comparison of visible and near-infrared reflectance spectra of CM2 carbonaceous chondrites and primitive asteroids

    NASA Technical Reports Server (NTRS)

    Vilas, F.; Hiroi, T.; Zolensky, M. E.

    1993-01-01

    Spectra of primitive asteroids (defined as C, P, and D classes and associated subclasses) were compared to the limited number of spectra of CM2 carbonaceous chondrites. An absorption feature located at 0.7 microns attributed to an Fe(+2) - Fe(+3) charge transfer absorption in iron oxides in phyllosilicates is apparent in some of the CM2 carbonaceous chondrite spectra and many of the asteroid spectra. Sawyer found a correlation between the area of the 0.7 micron feature and the mean semimajor axis of the asteroids. Spectra of a larger sample of carbonaceous chondrites, including 7 CM2 chondrites, covering a spectral interval of 0.30-2.5 microns were recently obtained using the Relab instrument at Brown University. These spectra were compared with spectrophotometric asteroid observations in a separate abstract. Those spectra of CM2 chondrites were isolated into the UV, visible and near-infrared spectral regions in order to compare them with high-quality narrowband reflectance spectra.

  3. Successful Capture, Extraction and Identification of Hypervelocity CM2 Meteorite Fragments Shot by Light-Gas Gun

    NASA Technical Reports Server (NTRS)

    Snead, C.; Westphal, A. J.; Dominguez, G.; Zolensky, M. E.

    2003-01-01

    Here we report the successful capture, extraction and identification of two fragments of a CM2 meteorite (ALH83100) into lowdensity aerogel. The shot was carried out at the AVGR at NASAARC. A mixture of powdered ALH83100 and borosilicate glass microspheres was shot at 4.55.0 km/sec into 50 mg cm silicate aerogel.

  4. Functional antagonism of TMPRSS2-ERG splice variants in prostate cancer.

    PubMed

    Rastogi, Anshu; Tan, Shyh-Han; Mohamed, Ahmed A; Chen, Yongmei; Hu, Ying; Petrovics, Gyorgy; Sreenath, Taduru; Kagan, Jacob; Srivastava, Sudhir; McLeod, David G; Sesterhenn, Isabell A; Srivastava, Shiv; Dobi, Albert; Srinivasan, Alagarsamy

    2014-07-01

    The fusion between ERG coding sequences and the TMPRSS2 promoter is the most prevalent in prostate cancer (CaP). The presence of two main types of TMPRSS2-ERG fusion transcripts in CaP specimens, Type I and Type II, prompted us to hypothesize that the cumulative actions of different ERG variants may impact CaP development/progression. Using TMPRSS2-ERG3 (Type I) and TMPRSS2-ERG8 (Type II) expression vectors, we determined that the TMPRSS2- ERG8 encoded protein is deficient in transcriptional regulation compared to TMPRSS2-ERG3. Co-transfection of vectors resulted in decreased transcriptional regulation compared to TMPRSS2-ERG3 alone, suggesting transdominance of ERG8. Expression of exogenous ERG8 protein resulted in a decrease in endogenous ERG3 protein levels in TMPRSS2-ERG positive VCaP cells, with a concomitant decrease in C-MYC. Further, we showed a physical association between ERG3 and ERG8 in live cells by the bimolecular fluorescence complementation assay, providing a basis for the observed effects. Inhibitory effects of TMPRSS2-ERG8 on TMPRSS2- ERG3 were also corroborated by gene expression data from human prostate cancers, which showed a positive correlation between C-MYC expression and TMPRSS2-ERG3/TMPRSS2- ERG8 ratio. We propose that an elevated TMPRSS2-ERG3/TMPRSS2-ERG8 ratio results in elevated C-MYC in CaP, providing a strong rationale for the biomarker and therapeutic utility of ERG splice variants, along with C-MYC.

  5. Autoinhibitory mechanisms of ERG studied by molecular dynamics simulations

    NASA Astrophysics Data System (ADS)

    Lu, Yan; Salsbury, Freddie R.

    2015-01-01

    ERG, an ETS-family transcription factor, acts as a regulator of differentiation of early hematopoietic cells. It contains an autoinhibitory domain, which negatively regulates DNA-binding. The mechanism of autoinhibitory is still illusive. To understand the mechanism, we study the dynamical properties of ERG protein by molecular dynamics simulations. These simulations suggest that DNA binding autoinhibition associates with the internal dynamics of ERG. Specifically, we find that (1), The N-C terminal correlation in the inhibited ERG is larger than that in uninhibited ERG that contributes to the autoinhibition of DNA-binding. (2), DNA-binding changes the property of the N-C terminal correlation from being anti-correlated to correlated, that is, changing the relative direction of the correlated motions and (3), For the Ets-domain specifically, the inhibited and uninhibited forms exhibit essentially the same dynamics, but the binding of the DNA decreases the fluctuation of the Ets-domain. We also find from PCA analysis that the three systems, even with quite different dynamics, do have highly similar free energy surfaces, indicating that they share similar conformations.

  6. 43 CFR 10.11 - Disposition of culturally unidentifiable human remains.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... AMERICAN GRAVES PROTECTION AND REPATRIATION REGULATIONS Human Remains, Funerary Objects, Sacred Objects, or Objects of Cultural Patrimony in Museums and Federal Collections § 10.11 Disposition of culturally... culturally unidentifiable human remains and associated funerary objects: (i) Within 90 days of receiving...

  7. 15 CFR 10.11 - Revision or amendment of a standard.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... DEVELOPMENT OF VOLUNTARY PRODUCT STANDARDS § 10.11 Revision or amendment of a standard. (a) A published... or the design characteristics of the product being standardized, or which cannot reasonably be... revision does not change the level of performance or safety or the design characteristics of the...

  8. Easy Growth Experiment on Peas Stimulates Interest in Biology for 10-11 Year Old Pupils

    ERIC Educational Resources Information Center

    McEwen, Birgitta

    2007-01-01

    How do we support the enthusiasm children show for biology in school? Unfortunately, lack of exciting practical work and boring biology lessons seem to make science less popular. As a senior lecturer in plant physiology at Karlstad University I have simplified experiments intended for students at university and then tested them on 10-11 year old…

  9. 46 CFR 39.10-11 - Personnel training-TB/ALL.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY TANK VESSELS VAPOR CONTROL SYSTEMS General § 39.10-11 Personnel training—TB/ALL. (a) A person in charge of a transfer operation utilizing a vapor collection.... Training must include drills or demonstrations using the installed vapor control system covering...

  10. Astemizole Derivatives as Fluorescent Probes for hERG Potassium Channel Imaging.

    PubMed

    Wang, Beilei; Liu, Zhenzhen; Ma, Zhao; Li, Minyong; Du, Lupei

    2016-03-10

    The detection and imaging of hERG potassium channels in living cells can provide useful information for hERG-correlation studies. Herein, three small-molecule fluorescent probes, based on the potent hERG channel inhibitor astemizole, for the imaging of hERG channels in hERG-transfected HEK293 cells (hERG-HEK293) and human colorectal cancer cells (HT-29), are described. These probes are expected to be applied in the physiological and pathological studies of hERG channels. PMID:26985309

  11. Tropical Atlantic climate simulated in the GFDL CM2.5 high-resolution coupled climate model

    NASA Astrophysics Data System (ADS)

    Doi, T.; Vecchi, G. A.; Rosati, A. J.; Delworth, T. L.

    2012-12-01

    Using two fully coupled ocean-atmosphere models of CM2.1 (the Climate Model version 2.1 developed at the Geophysical Fluid Dynamics Laboratory) and CM2.5 (a new high-resolution climate model based on CM2.1), the characteristics and sources of SST and precipitation biases associated with the Atlantic ITCZ have been investigated. CM2.5 has an improved simulation of the annual mean and the annual cycle of the rainfall over the Sahel and the northern South America, while CM2.1 shows excessive Sahel rainfall and lack of northern South America rainfall in boreal summer. This marked improvement in CM2.5 is due to not only high-resolved orography, but also a significant reduction of biases in the seasonal meridional migration of the ITCZ. In particular, the seasonal northward migration of the ITCZ in boreal summer is coupled to the seasonal variation of the SST and a subsurface doming of the thermocline in the northeastern tropical Atlantic, known as the Guinea Dome. Improvements in the ITCZ allow for better representation of the coupled processes that are important for an abrupt seasonally phase-locked decay of the interannual SST anomaly in the northern tropical Atlantic. Nevertheless, the differences between CM2.5 and CM2.1 were not sufficient to reduce the warm SST biases in the eastern equatorial region and Angola-Benguela Area. The weak bias of southerly winds along the southwestern African coast associated with the excessive southward migration bias of the ITCZ may be a key to improve the warm SST biases there. Also, response of climate conditions in the Atlantic Hurricane Main Development Region (MDR) to doubling of atmospheric CO2 with CM2.5 has been explored. In the annual mean, the SST in the MDR warms by about 2°C in the CO2 doubling run relative to the Control run, the trade winds become weaker in the northern tropical Atlantic, and the rainfall increases over the ITCZ and its northern region. The amplitude of the annual cycle of the SST over the MDR is not

  12. Voltage-Dependent Gating of hERG Potassium Channels

    PubMed Central

    Cheng, Yen May; Claydon, Tom W.

    2012-01-01

    The mechanisms by which voltage-gated channels sense changes in membrane voltage and energetically couple this with opening of the ion conducting pore has been the source of significant interest. In voltage-gated potassium (Kv) channels, much of our knowledge in this area comes from Shaker-type channels, for which voltage-dependent gating is quite rapid. In these channels, activation and deactivation are associated with rapid reconfiguration of the voltage-sensing domain unit that is electromechanically coupled, via the S4–S5 linker helix, to the rate-limiting opening of an intracellular pore gate. However, fast voltage-dependent gating kinetics are not typical of all Kv channels, such as Kv11.1 (human ether-à-go-go related gene, hERG), which activates and deactivates very slowly. Compared to Shaker channels, our understanding of the mechanisms underlying slow hERG gating is much poorer. Here, we present a comparative review of the structure–function relationships underlying activation and deactivation gating in Shaker and hERG channels, with a focus on the roles of the voltage-sensing domain and the S4–S5 linker that couples voltage sensor movements to the pore. Measurements of gating current kinetics and fluorimetric analysis of voltage sensor movement are consistent with models suggesting that the hERG activation pathway contains a voltage independent step, which limits voltage sensor transitions. Constraints upon hERG voltage sensor movement may result from loose packing of the S4 helices and additional intra-voltage sensor counter-charge interactions. More recent data suggest that key amino acid differences in the hERG voltage-sensing unit and S4–S5 linker, relative to fast activating Shaker-type Kv channels, may also contribute to the increased stability of the resting state of the voltage sensor. PMID:22586397

  13. hERG drug response measured in droplet bilayers.

    PubMed

    Portonovo, Shiva A; Salazar, Carl S; Schmidt, Jacob J

    2013-04-01

    We show measurements of the human cardiac potassium ion channel Kv11.1 (hERG) in droplet bilayers incorporated directly from commercial membrane preparations of HEK293 cells. Although we do not obtain ensemble conductance kinetics and rectification observed in patch clamp measurements of hERG, ensemble currents measured in our system showed inhibition dependent on astemizole and E-4031 concentration, with IC50 values similar to those found with patch clamp. The availability of engineered HEK cells expressing a variety of ion channels, combined with the simplicity of the inhibition measurement, suggest that droplet bilayers may have considerable technological potential for determination of ion channel drug potency. PMID:23160842

  14. Markedly Elevated Carbamazepine-10,11-epoxide/Carbamazepine Ratio in a Fatal Carbamazepine Ingestion

    PubMed Central

    Russell, Jason L.; Spiller, Henry A.; Baker, Daniel D.

    2015-01-01

    Carbamazepine is a widely used anticonvulsant. Its metabolite, carbamazepine-10,11-epoxide, has been found to display similar anticonvulsant and neurotoxic properties. While the ratio of parent to metabolite concentration varies significantly, at therapeutic doses the epoxide concentration is generally about 20% of the parent. We report a case of fatal carbamazepine overdose in which the epoxide metabolite concentration was found to be 450% higher than the parent compound, suggesting a potential role for metabolite quantification in severe toxicity. PMID:26550016

  15. A comparison of two patient-friendly ERG electrodes.

    PubMed

    Hidajat, R R; McLay, J L; Elder, M J; Goode, D H; Morton, J P; Burley, C D

    2003-03-01

    The ideal electroretinography (ERG) electrode does not exist. In deciding which electrode should be used in clinical practice the capacity to provide reproducible waveforms, maximal amplitudes and minimal irritation to the patient's eyes are the most important characteristics. This study tested two patient friendly electrodes, the gold foil (CH Electrodes, UK) and the H-K loop (Avanta, Slovenia). Seventeen normal volunteers were subjected to three standard measurements namely flash ERGs under photopic and scotopic conditions and the transient pattern ERG (PERG). Each test followed the guidelines set by the International Society for Clinical Electrophysiology of Vision (ISCEV). It was found that the mean values of the flash ERG a and b wave amplitudes and the PERG P50 and N95 amplitudes from the gold foil electrodes were approximately a factor of two larger than those from the H-K loop. In addition most of the subjects (13/17) felt less discomfort with the gold foil electrodes. We reached the conclusion that gold foil electrodes are the electrode of choice because they provide good patient comfort, reasonably high amplitudes and relatively reproducible results. PMID:12854623

  16. Comparing the photopic ERG i-wave in different species.

    PubMed

    Rosolen, Serge G; Rigaudière, Florence; LeGargasson, Jean-François; Chalier, Catherine; Rufiange, Marianne; Racine, Julie; Joly, Sandrine; Lachapelle, Pierre

    2004-01-01

    The i-wave, a post b-wave component of the human photopic electroretinogram (ERG), is claimed to originate at the level of the retinal ganglion cells (RGC) or more distally. We investigated whether this wave is a feature common to all species. Photopic ERGs were obtained from the following species: Beagle dog, European cat, New Zealand white rabbit, Göttingen minipig, Cynomolgus monkey, Sprague-Dawley and brown Norway rats, Hartley guinea pig, and CD1 and C57BL6 mice. Results were compared with those obtained from normal human subjects. Except for rats and mice, all species yielded a well-demarcated i-wave, easily identifiable and separated from the a-b-wave complex by approximately 20 ms. Our sample suggests that the i-wave is a feature common to the photopic ERG of most species including humans. In view of its suggested origin, the i-wave would offer a unique opportunity to test, with the flash ERG, the functional integrity of the retinal ganglion cells in animals where use of a pattern stimulus is not always easily obtained. PMID:15091327

  17. The ERG Model: Expansion and Application to Navy Personnel.

    ERIC Educational Resources Information Center

    Wilcove, Gerry L.

    1978-01-01

    The existence, relatedness, and growth (ERG) model represents a major effort to understand need satisfaction. Questionnaire items on existing and proposed need concepts were administered to 630 Navy male enlisted personnel in 11 types of organizations. Factor analysis confirmed the empirical validity of the organizational respect concept. (Author)

  18. Rosuvastatin blocks hERG current and prolongs cardiac repolarization.

    PubMed

    Plante, Isabelle; Vigneault, Patrick; Drolet, Benoît; Turgeon, Jacques

    2012-02-01

    Blocking of the potassium current I(Kr) [human ether-a-go-go related gene (hERG)] is generally associated with an increased risk of long QT syndrome (LQTS). The 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitor, rosuvastatin, is a methanesulfonamide derivative, which shows structural similarities with several I(Kr) blockers. Hence, we assessed the effects of rosuvastatin on cardiac repolarization by using in vitro, ex vivo, and in vivo models. Patch clamp experiments on hERG-transfected human embryonic kidney (HEK) 293 cells established the potency of rosuvastatin to block hERG [half maximal inhibitory concentration (IC(50) ) = 195 nM]. We showed in isolated guinea pig hearts that 195 nM rosuvastatin prolonged (basic cycle length of 250 ms; p < 0.05) the monophasic action potential duration at 90% repolarization (MAPD(90) ) by 11 ± 1 ms. Finally, rosuvastatin (10 mg/kg, intraperitoneal) prolonged corrected QT interval (QTc) in conscious and unrestrained guinea pigs from 201 ± 1 to 210 ± 2 ms (p < 0.05). Thus, rosuvastatin blocks I(Kr) and prolongs cardiac repolarization. In additional experiments, we also show that hERG blockade in HEK 293 cells was modulated by coexpression of efflux [breast cancer resistance protein (BCRP), multidrug resistance gene (MDR1)] and influx [organic anion transporting polypeptide (OATP) 2B1] transporters involved in the disposition and cardiac distribution of the drug. Genetic polymorphisms observed for BCRP, MDR1, and OATP2B1, and IC(50) determined for hERG blocking lead us to propose that some patients may be at risk of rosuvastatin-induced LQTS.

  19. A 50 EW/cm;2 Ti:sapphire laser system for studying relativistic light-matter interactions.

    PubMed

    Walker, B; Toth, C; Fittinghoff, D; Guo, T; Kim, D E; Rose-Petruck, C; Squier, J; Yamakawa, K; Wilson, K; Barty, C

    1999-11-01

    A 10-Hz repetition rate, 60-TW peak power, Ti:sapphire laser system was developed for use in experiments where relativistic effects dominate the physics. The temporal, spectral, energy and spatial characteristics of the laser pulses were measured in single shot format. The pulse duration ranged from 22 fs to 25 fs and the pulse energy averaged 1.3 J. Atomic photoionization measurements quantified the peak intensity of the laser pulse in situ. The measurements indicated an intensity of at least 510 19 W/cm 2 was produced.

  20. Functional evolution of Erg potassium channel gating reveals an ancient origin for IKr

    PubMed Central

    Martinson, Alexandra S.; van Rossum, Damian B.; Diatta, Fortunay H.; Layden, Michael J.; Rhodes, Sarah A.; Martindale, Mark Q.; Jegla, Timothy

    2014-01-01

    Mammalian Ether-a-go-go related gene (Erg) family voltage-gated K+ channels possess an unusual gating phenotype that specializes them for a role in delayed repolarization. Mammalian Erg currents rectify during depolarization due to rapid, voltage-dependent inactivation, but rebound during repolarization due to a combination of rapid recovery from inactivation and slow deactivation. This is exemplified by the mammalian Erg1 channel, which is responsible for IKr, a current that repolarizes cardiac action potential plateaus. The Drosophila Erg channel does not inactivate and closes rapidly upon repolarization. The dramatically different properties observed in mammalian and Drosophila Erg homologs bring into question the evolutionary origins of distinct Erg K+ channel functions. Erg channels are highly conserved in eumetazoans and first evolved in a common ancestor of the placozoans, cnidarians, and bilaterians. To address the ancestral function of Erg channels, we identified and characterized Erg channel paralogs in the sea anemone Nematostella vectensis. N. vectensis Erg1 (NvErg1) is highly conserved with respect to bilaterian homologs and shares the IKr-like gating phenotype with mammalian Erg channels. Thus, the IKr phenotype predates the divergence of cnidarians and bilaterians. NvErg4 and Caenorhabditis elegans Erg (unc-103) share the divergent Drosophila Erg gating phenotype. Phylogenetic and sequence analysis surprisingly indicates that this alternate gating phenotype arose independently in protosomes and cnidarians. Conversion from an ancestral IKr-like gating phenotype to a Drosophila Erg-like phenotype correlates with loss of the cytoplasmic Ether-a-go-go domain. This domain is required for slow deactivation in mammalian Erg1 channels, and thus its loss may partially explain the change in gating phenotype. PMID:24706772

  1. Study of 11Li and 10,11Be nuclei through elastic scattering and breakup reactions

    NASA Astrophysics Data System (ADS)

    Gaidarov, M. K.; Lukyanov, V. K.; Kadrev, D. N.; Zemlyanaya, E. V.; Antonov, A. N.; Lukyanov, K. V.; Spasova, K.

    2016-01-01

    The hybrid model of the microscopic optical potential (OP) is applied to calculate the 11Li+p, 10,11Be+p, and 10,11Be+12C elastic scattering cross sections at energies E < 100 MeV/nucleon. The OP's contain the folding-model real part (ReOP) with the direct and exchange terms included, while its imaginary part (ImOP) is derived within the high-energy approximation (HEA) theory. For the 11Li+p elastic scattering, the microscopic large-scale shell model (LSSM) density of 11Li is used, while the density distributions of 10,11Be nuclei obtained within the quantum Monte Carlo (QMC) model and the generator coordinate method (GCM) are utilized to calculate the microscopic OPs and cross sections of elastic scattering of these nuclei on protons and 12C. The depths of the real and imaginary parts of OP are fitted to the elastic scattering data, being simultaneously adjusted to reproduce the true energy dependence of the corresponding volume integrals. Also, the cluster models, in which 11Li consists of 2n-halo and the 9Li core having its own LSSM form of density and 11Be consists of a n-halo and the 10Be core, are adopted. Within the latter, we give predictions for the longitudinal momentum distributions of 9Li fragments produced in the breakup of 11Li at 62 MeV/nucleon on a proton target. It is shown that our results for the diffraction and stripping reaction cross sections in 11Be scattering on 9Be, 93Nb, 181Ta, and 238U targets at 63 MeV/nucleon are in a good agreement with the available experimental data.

  2. Design of a Two-Stage Light Gas Gun for Muzzle Velocities of 10 - 11 kms

    NASA Technical Reports Server (NTRS)

    Bogdanoff, David W.

    2016-01-01

    Space debris poses a major risk to spacecraft. In low earth orbit, impact velocities can be 10 11 kms and as high as 15 kms. For debris shield design, it would be desirable to be able to launch controlled shape projectiles to these velocities. The design of the proposed 10 11 kmsec gun uses, as a starting point, the Ames 1.280.22 two stage gun, which has achieved muzzle velocities of 10 11.3 kmsec. That gun is scaled up to a 0.3125 launch tube diameter. The gun is then optimized with respect to maximum pressures by varying the pump tube length to diameter ratio (LD), the piston mass and the hydrogen pressure. A pump tube LD of 36.4 is selected giving the best overall performance. Piezometric ratios for the optimized guns are found to be 2.3, much more favorable than for more traditional two stage light gas guns, which range from 4 to 6. The maximum powder chamber pressures are 20 to 30 ksi. To reduce maximum pressures, the desirable range of the included angle of the cone of the high pressure coupling is found to be 7.3 to 14.6 degrees. Lowering the break valve rupture pressure is found to lower the maximum projectile base pressure, but to raise the maximum gun pressure. For the optimized gun with a pump tube LD of 36.4, increasing the muzzle velocity by decreasing the projectile mass and increasing the powder loads is studied. It appears that saboted spheres could be launched to 10.25 and possibly as high as 10.7 10.8 kmsec, and that disc-like plastic models could be launched to 11.05 kms. The use of a tantalum liner to greatly reduce bore erosion and increase muzzle velocity is discussed. With a tantalum liner, CFD code calculations predict muzzle velocities as high as 12 to 13 kms.

  3. Neutron dosimetry and damage calculation for the JP-10, 11, 13, and 16 experiments in HFIR

    SciTech Connect

    Greenwood, L.R.; Ratner, R.T.

    1996-04-01

    Neutron fluence measurements and radiation damage calculations are reported for the joint U.S./Japanese experiments JP-10, 11, 13, and 16 in the target of the High Flux Isotope Reactor (HFIR) at Oak Ridge National Lab (ORNL). These experiments were irradiated at 85 MW for 238.5 EFPD. The maximum fast neutron fluence >0.1 MeV was about 2.1E + 22 n/cm{sup 2} for all of the experiments resulting in about 17.3 dpa in 316 stainless steel.

  4. Coulomb-Boltzmann-Shifted distribution in laser-generated plasmas from 1010 up to 1019 W/cm2 intensities

    NASA Astrophysics Data System (ADS)

    Torrisi, L.

    2016-02-01

    The charge production from laser-generated plasmas generates not isotropically ion acceleration in vacuum and with mean kinetic energy proportional to the ion charge state. The ion velocity depends on many factors of which the most important are the plasma temperature, the adiabatic gas expansion in vacuum and the Coulomb acceleration. The ion energy distributions of the emitted ions from the plasma can be well explained by the Coulomb-Boltzmann-Shifted function, with a cut-off limitation at high energy for a wide range of laser intensities. It can be applied for intensities of 1010 W/cm2, when plasma is produced only in the backward direction from thick targets (backward plasma acceleration regime), as well as at intensities of the order of 1019 W/cm2, when plasma is produced in the forward direction from thin targets in target-normal sheath acceleration regime. It loses of validity in radiation pressure acceleration regime, at which ions are emitted near mono-energetically.

  5. Focal cone ERGs of rhodopsin Pro347Leu transgenic rabbits.

    PubMed

    Ueno, Shinji; Koyasu, Toshiyuki; Kominami, Taro; Sakai, Takao; Kondo, Mineo; Yasuda, Shunsuke; Terasaki, Hiroko

    2013-10-18

    A rhodopsin P347L transgenic (Tg) rabbit, a model of retinitis pigmentosa, has been generated in our laboratory. The purpose of this study was to determine the properties of focal areas of the retina in this rabbit model during the course of retinal degeneration. To accomplish this, we recorded focal ERGs from wild-type (WT) and Tg rabbits at ages 3, 6, and 12 months. A 15° stimulus spot was used to elicit the focal ERGs from the center of the visual streak and from four surrounding areas. We found that the amplitudes of the focal cone ERG b-waves and oscillatory potentials (OPs) of the Tg rabbits in the five areas decreased progressively with increasing age and became almost non-recordable at 12 months. There were no significant regional differences in the b-waves of Tg rabbits recorded from the 5 areas. The amplitudes of the OPs were better preserved than the b-waves and the OPs/b-wave ratio was higher than that in WT rabbits at every recording area. The summed OPs amplitudes, which most likely originate from the amacrine and/or ganglion cells, recorded from the area superior to the optic disc was significantly larger than that from other areas at 3- and 6-months-old. This indicated that the inner retinal neurons were not altered equally after photoreceptor degeneration in this rabbit model.

  6. New potential binding determinant for hERG channel inhibitors

    PubMed Central

    Saxena, P.; Zangerl-Plessl, E.-M.; Linder, T.; Windisch, A.; Hohaus, A.; Timin, E.; Hering, S.; Stary-Weinzinger, A.

    2016-01-01

    Human ether-à-go-go related gene (hERG) 1 channels conduct the rapid delayed rectifier K+ current (IKr) and are essential for the repolarization of the cardiac action potential. hERG1 inhibition by structurally diverse drugs may lead to life threatening arrhythmia. Putative binding determinants of hERG1 channel blockers include T623, S624 and V625 on the pore helix, and residues G648, Y652 and F656, located on segment S6. We and others have previously hypothesized that additional binding determinants may be located on helix S5, which is in close contact with the S6 segments. In order to test this hypothesis, we performed a detailed investigation combining ionic current measurements with two-microelectrode voltage clamp and molecular modeling techniques. We identified a novel aromatic high affinity binding determinant for blockers located in helix S5, F557, which is equally potent as Y652. Modeling supports a direct interaction with the outer pore helix. PMID:27067805

  7. Backward-going MeV electrons and gamma rays from 1018 W/cm2 laser interactions with water

    NASA Astrophysics Data System (ADS)

    Feister, Scott; Morrison, John T.; Frische, Kyle D.; Orban, Chris; Ovchinnikov, Vladimir M.; Nees, John A.; Austin, Drake R.; Chowdhury, Enam A.; Freeman, Richard R.; Roquemore, W. Melvyn

    2015-05-01

    Gamma rays with ~1 MeV energy are measured following the relativistic interaction of a 3 mJ, 1018 W/cm2 short pulse laser with a 30 μm diameter flowing water column. Contrary to expectations, radiation emission is peaked in the direction opposite to the normally-incident laser propagation (specular direction). Experimental measurements and particle-in-cell (PIC) simulations of laser-plasma interaction show a pre-formed-plasma-dependent, backward-going, beam-like primary electron source. The MeV component of the electron and gamma ray spectrum, which is more than five times the ponderomotive energy scale of the laser, is highly sensitive to the presence of a nanosecond-timescale laser pre-pulse. This research was sponsored by the Quantum and Non-Equilibrium Processes Division of the Air Force Office of Scientific Research, under the management of Dr. Enrique Parra, Program Manager.

  8. Spin-Hall-Effect-Assisted Electroresistance in Antiferromagnets via 105 A/cm2 dc Current

    NASA Astrophysics Data System (ADS)

    Han, Jiahao; Wang, Yuyan; Pan, Feng; Song, Cheng

    2016-08-01

    Antiferromagnet (AFM) spintronics with reduced electrical current is greatly expected to process information with high integration and low power consumption. In Pt/FeMn and Ta/FeMn hybrids, we observe significant resistance variation (up to 7% of the total resistance) manipulated by 105 A/cm2 dc current. We have excluded the contribution of isotropic structural effects, and confirmed the critical role of the spin Hall injection from Pt (or Ta) to FeMn. This electrical current-manipulated resistance (i.e. electroresistance) is proposed to be attributed to the spin-Hall-effect-induced spin-orbit torque in FeMn. Similar results have also been detected in plain IrMn films, where the charge current generates spin current via the spin Hall effect with the existence of Ir atoms. All the measurements are free from external magnetic fields and ferromagnets. Our findings present an interesting step towards high-efficiency spintronic devices.

  9. Xenoliths in the CM2 Carbonaceous Chondrite LON 94101: Implications for Complex Mixing on the Asteroidal Parent Body

    NASA Technical Reports Server (NTRS)

    Lindgren, P.; Lee, M. R.; Sofe, M.; Zolensky, M. E.

    2011-01-01

    Xenoliths are foreign clasts that oc-cur in various classes of meteorites, e.g. [1,2,3]. A re-cent study reveals the presence of several distinct classes of xenoliths in regolith-bearing meteorites, in-cluding in over 20 different carbonaceous chondrites [4]. The most common types of xenoliths are fine-grained hydrous clasts, often referred to as C1 or CI clasts in the literature, although their mineralogy is actually more similar to hydrous micrometeorites [5,6]. Xenoliths in meteorites present an opportunity to study material not yet classified or available as separate meteorites, and can provide additional information on processes in the dynamic early history of the Solar Sys-tem. Here we have performed chemical and mineralogi-cal analyses of xenoliths in the CM2 carbonaceous chondrite LON 94101, using scanning electron micro-scopy (SEM) and transmission electron microscopy (TEM).

  10. High e+/e- Ratio Dense Pair Creation with 1021W.cm-2 Laser Irradiating Solid Targets

    NASA Astrophysics Data System (ADS)

    Liang, E.; Clarke, T.; Henderson, A.; Fu, W.; Lo, W.; Taylor, D.; Chaguine, P.; Zhou, S.; Hua, Y.; Cen, X.; Wang, X.; Kao, J.; Hasson, H.; Dyer, G.; Serratto, K.; Riley, N.; Donovan, M.; Ditmire, T.

    2015-09-01

    We report results of new pair creation experiments using ~100 Joule pulses of the Texas Petawatt Laser to irradiate solid gold and platinum targets, with intensities up to ~1.9 × 1021 W.cm-2 and pulse durations as short as ~130 fs. Positron to electron (e+/e-) ratios >15% were observed for many thick disk and rod targets, with the highest e+/e- ratio reaching ~50% for a Pt rod. The inferred pair yield was ~ few ×1010 with emerging pair density reaching ~1015/cm3 so that the pair skin depth becomes < pair jet transverse size. These results represent major milestones towards the goal of creating a significant quantity of dense pair-dominated plasmas with e+/e- approaching 100% and pair skin depth ≪ pair plasma size, which will have wide-ranging applications to astrophysics and fundamental physics.

  11. Stereoselective Blockage of Quinidine and Quinine in the hERG Channel and the Effect of Their Rescue Potency on Drug-Induced hERG Trafficking Defect

    PubMed Central

    Yan, Meng; Fan, Pan; Shi, Yanhui; Feng, Lifang; Wang, Junnan; Zhan, Ge; Li, Baoxin

    2016-01-01

    Diastereoisomers of quinidine and quinine are used to treat arrhythmia and malaria, respectively. It has been reported that both drugs block the hERG (human ether-a-go-go-related gene) potassium channel which is essential for myocardium repolarization. Abnormality of repolarization increases risk of arrhythmia. The aim of our research is to study and compare the impacts of quinidine and quinine on hERG. Results show that both drugs block the hERG channel, with quinine 14-fold less potent than quinidine. In addition, they presented distinct impacts on channel dynamics. The results imply their stereospecific block effect on the hERG channel. However, F656C-hERG reversed this stereoselectivity. The mutation decreases affinity of the two drugs with hERG, and quinine was more potent than quinidine in F656C-hERG blockage. These data suggest that F656 residue contributes to the stereoselective pocket for quinidine and quinine. Further study demonstrates that both drugs do not change hERG protein levels. In rescue experiments, we found that they exert no reverse effect on pentamidine- or desipramine-induced hERG trafficking defect, although quinidine has been reported to rescue trafficking-deficient pore mutation hERG G601S based on the interaction with F656. Our research demonstrated stereoselective effects of quinidine and quinine on the hERG channel, and this is the first study to explore their reversal potency on drug-induced hERG deficiency. PMID:27690007

  12. Analysis of the biases in the downward shortwave surface flux in the GFDL CM2.1 general circulation model

    NASA Astrophysics Data System (ADS)

    Freidenreich, Stuart M.; Ramaswamy, V.

    2011-04-01

    Simulations of downward shortwave surface fluxes by the coupled Geophysical Fluid Dynamics Laboratory (GFDL) CM2.1 general circulation model are compared against climatology derived from the Baseline Surface Radiation Network (BSRN), Global Energy Balance Archive, and International Satellite Cloud Climatology Project ISCCP-FD data sets. The spatial pattern of the model's biases is evaluated. An investigation is made of how these relate to accompanying biases in total cloud amount and aerosol optical depth and how they affect the surface temperature simulation. Comparing CM2.1's clear-sky fluxes against BSRN site values, for European, Asian, and North American locations, there are underestimates in the direct and overestimates in the diffuse, resulting in underestimates in the total flux. These are related to overestimates of sulfate aerosol optical depth, arising owing to the behavior of the parameterization function for hygroscopic growth of these aerosols at very high relative humidity. Contrastingly, flux overestimate biases at lower latitude locations are associated with underestimates in sea-salt and carbonaceous aerosol amounts. All-sky flux biases consist of underestimates for North America, Eurasia, southern Africa, and northern oceanic regions and overestimates for the Amazon region, equatorial Africa, off the west coast of the Americas, and southern oceanic regions. These biases show strong correlations with cloud amount biases. There are modest correlations of the flux biases with cool surface temperature biases over North America and Eurasia, warm biases over the Amazon region, and cool (warm) biases over the northern (southern) oceanic regions. Analyses assuming nonhygroscopicity illustrate that there is a reduction of surface temperature biases accompanying a reduction of sulfate aerosol optical depth biases, whereas a more significant improvement in the temperature simulation requires refining the model's simulation of cloudiness.

  13. Pioneer 10/11 data analysis of the magnetic field experiment

    NASA Technical Reports Server (NTRS)

    Jones, D. E.

    1982-01-01

    Work conducted in support of the Pioneer missions to Jupiter (10,11), and Saturn (11) as well as the reduction, analysis and interpretation of magnetic field data obtained by the vector helium magnetometer on the Pioneer 10 and 11 spacecraft is summarized. Initial efforts concentrated primarily on the interplanetary data, and those aspcts of the data of relevance to obtaining a better understanding of the interaction of the magnetized solar wind with the terrestrial magnetic field. After encounters of Jupiter and Saturn, the emphasis of research was directed primarily to an analysis of the planetary data. In particular, it soon became clear that there was a need for modelling of the various candidate magnetospheric currents suggested by the data. Results not published as yet, are also summarized.

  14. Antibody-independent Targeted Quantification of TMPRSS2-ERG Fusion Protein Products in Prostate Cancer

    SciTech Connect

    He, Jintang; Sun, Xuefei; Shi, Tujin; Schepmoes, Athena A.; Fillmore, Thomas L.; Petyuk, Vladislav A.; Xie, Fang; Zhao, Rui; Gritsenko, Marina A.; Yang, Feng; Kitabayashi, Naoki; Chae, Sung Suk; Rubin, Mark; Siddiqui, Javed; Wei, John; Chinnaiyan, Arul M.; Qian, Weijun; Smith, Richard D.; Kagan, Jacob; Srivastava, Sudhir; Rodland, Karin D.; Liu, Tao; Camp, David G.

    2014-10-01

    Fusions between the transmembrane protease serine 2 (TMPRSS2) and ETS related gene (ERG) represent one of the most specific biomarkers that define a distinct molecular subtype of prostate cancer. The studies on TMPRSS2-ERG gene fusions have seldom been performed at the protein level, primarily due to the lack of high-quality antibodies or an antibody-independent method that is sufficiently sensitive for detecting the truncated ERG protein products resulting from TMPRSS2-ERG gene fusions and alternative splicing. Herein, we applied a recently developed PRISM (high-pressure high-resolution separations with intelligent selection and multiplexing)-SRM (selected reaction monitoring) strategy for quantifying ERG protein in prostate cancer cell lines and tumors. The highly sensitive PRISM-SRM assays led to confident detection of 6 unique ERG peptides in either the TMPRSS2-ERG positive cell lines or tissues but not in the negative controls, indicating that ERG protein expression is highly correlated with TMPRSS2-ERG gene rearrangements. Significantly, our results demonstrated for the first time that at least two groups of ERG protein isoforms were simultaneously expressed at variable levels in TMPRSS2-ERG positive samples as evidenced by concomitant detection of two mutually exclusive peptides. Three peptides shared across almost all fusion protein products were determined to be the most abundant peptides, and hence can be used as “signature” peptides for detecting ERG overexpression resulting from TMPRSS2-ERG gene fusion. These PRISM-SRM assays provide valuable tools for studying TMPRSS2-ERG gene fusion protein products, thus improving our understanding of the role of TMPRSS2-ERG gene fusion in the biology of prostate cancer.

  15. Sperm FISH and chromatin integrity in spermatozoa from a t(6;10;11) carrier.

    PubMed

    Olszewska, Marta; Huleyuk, Nataliya; Fraczek, Monika; Zastavna, Danuta; Wiland, Ewa; Kurpisz, Maciej

    2014-05-01

    Complex chromosome rearrangements (CCRs) are structurally balanced or unbalanced aberrations involving more than two breakpoints on two or more chromosomes. CCRs can be a potential reason for genomic imbalance in gametes, which leads to a drastic reduction in fertility. In this study, the meiotic segregation pattern, aneuploidy of seven chromosomes uninvolved in the CCR and chromatin integrity were analysed in the ejaculated spermatozoa of a 46,XY,t(6;10;11)(q25.1;q24.3;q23.1)mat carrier with asthenozoospermia and a lack of conception. The frequency of genetically unbalanced spermatozoa was 78.8% with a prevalence of 4:2 segregants of 38.2%, while the prevalence of the adjacent 3:3 mode was 35.3%. Analysis of the aneuploidy of chromosomes 13, 15, 18, 21, 22, X and Y revealed an approximately fivefold increased level in comparison with that of the control group, indicating the presence of an interchromosomal effect. Sperm chromatin integrity status was evaluated using chromomycin A3 and aniline blue staining (deprotamination), acridine orange test and TUNEL assay (sperm DNA fragmentation). No differences were found when comparisons were made with a control group. We suggest that the accumulation of genetically unbalanced spermatozoa, significantly increased sperm aneuploidy level and decreased sperm motility (20%, progressive) were not responsible for the observed lack of reproductive success in the analysed infertile t(6;10;11) carrier. Interestingly, in the case described herein, a high level of sperm chromosomal imbalance appears not to be linked to sperm chromatin integrity status.

  16. ERG2 and ERG24 Are Required for Normal Vacuolar Physiology as Well as Candida albicans Pathogenicity in a Murine Model of Disseminated but Not Vaginal Candidiasis.

    PubMed

    Luna-Tapia, Arturo; Peters, Brian M; Eberle, Karen E; Kerns, Morgan E; Foster, Timothy P; Marrero, Luis; Noverr, Mairi C; Fidel, Paul L; Palmer, Glen E

    2015-10-01

    Several important classes of antifungal agents, including the azoles, act by blocking ergosterol biosynthesis. It was recently reported that the azoles cause massive disruption of the fungal vacuole in the prevalent human pathogen Candida albicans. This is significant because normal vacuolar function is required to support C. albicans pathogenicity. This study examined the impact of the morpholine antifungals, which inhibit later steps of ergosterol biosynthesis, on C. albicans vacuolar integrity. It was found that overexpression of either the ERG2 or ERG24 gene, encoding C-8 sterol isomerase or C-14 sterol reductase, respectively, suppressed C. albicans sensitivity to the morpholines. In addition, both erg2Δ/Δ and erg24Δ/Δ mutants were hypersensitive to the morpholines. These data are consistent with the antifungal activity of the morpholines depending upon the simultaneous inhibition of both Erg2p and Erg24p. The vacuoles within both erg2Δ/Δ and erg24Δ/Δ C. albicans strains exhibited an aberrant morphology and accumulated large quantities of the weak base quinacrine, indicating enhanced vacuolar acidification compared with that of control strains. Both erg mutants exhibited significant defects in polarized hyphal growth and were avirulent in a mouse model of disseminated candidiasis. Surprisingly, in a mouse model of vaginal candidiasis, both mutants colonized mice at high levels and induced a pathogenic response similar to that with the controls. Thus, while targeting Erg2p or Erg24p alone could provide a potentially efficacious therapy for disseminated candidiasis, it may not be an effective strategy to treat vaginal infections. The potential value of drugs targeting these enzymes as adjunctive therapies is discussed.

  17. Chimeric hERG channels containing a tetramerization domain are functional and stable.

    PubMed

    Hausammann, Georg J; Grütter, Markus G

    2013-12-23

    Biochemical and detailed structural information of human ether-a-go-go-related gene (hERG) potassium channels are scarce but are a prerequisite to understand the unwanted interactions of hERG with drugs and the effect of mutations that lead to long QT syndrome. Despite the huge interest in hERG, to our knowledge, procedures that provide a purified, functional, and tetrameric hERG channel are not available. Here, we describe hybrid hERG molecules, termed chimeric hERG channels, in which the N-terminal Per-Arnt-Sim (PAS) domain is deleted and the C-terminal C-linker as well as the cyclic nucleotide binding domain (CNBD) portion is replaced by an artificial tetramerization domain. These chimeric hERG channels can be overexpressed in HEK cells, solubilized in detergent, and purified as tetramers. When expressed in Xenopus laevis oocytes, the chimeric channels exhibit efficient trafficking to the cell surface, whereas a hERG construct lacking the PAS and C-linker/CNBD domains is retained in the cytoplasm. The chimeric hERG channels retain essential hERG functions such as voltage-dependent gating and inhibition by astemizole and the scorpion toxin BeKm-1. The chimeric channels are thus powerful tools for helping to understand the contribution of the cytoplasmic hERG domains to the gating process and are suitable for in vitro biochemical and structural studies. PMID:24325597

  18. Antineoplastic Effects of siRNA against TMPRSS2-ERG Junction Oncogene in Prostate Cancer

    PubMed Central

    Urbinati, Giorgia; Ali, Hafiz Muhammad; Rousseau, Quentin; Chapuis, Hubert; Desmaële, Didier; Couvreur, Patrick; Massaad-Massade, Liliane

    2015-01-01

    TMPRSS2-ERG junction oncogene is present in more than 50% of patients with prostate cancer and its expression is frequently associated with poor prognosis. Our aim is to achieve gene knockdown by siRNA TMPRSS2-ERG and then to assess the biological consequences of this inhibition. First, we designed siRNAs against the two TMPRSS2-ERG fusion variants (III and IV), most frequently identified in patients’ biopsies. Two of the five siRNAs tested were found to efficiently inhibit mRNA of both TMPRSS2-ERG variants and to decrease ERG protein expression. Microarray analysis further confirmed ERG inhibition by both siRNAs TMPRSS2-ERG and revealed one common down-regulated gene, ADRA2A, involved in cell proliferation and migration. The siRNA against TMPRSS2-ERG fusion variant IV showed the highest anti-proliferative effects: Significantly decreased cell viability, increased cleaved caspase-3 and inhibited a cluster of anti-apoptotic proteins. To propose a concrete therapeutic approach, siRNA TMPRSS2-ERG IV was conjugated to squalene, which can self-organize as nanoparticles in water. The nanoparticles of siRNA TMPRSS2-ERG-squalene injected intravenously in SCID mice reduced growth of VCaP xenografted tumours, inhibited oncoprotein expression and partially restored differentiation (decrease in Ki67). In conclusion, this study offers a new prospect of treatment for prostate cancer based on siRNA-squalene nanoparticles targeting TMPRSS2-ERG junction oncogene. PMID:25933120

  19. Gas-Phase Oxidation of Cm+ and Cm2+ -- Thermodynamics of neutral and ionized CmO

    SciTech Connect

    Gibson, John K; Haire, Richard G.; Santos, Marta; Pires de Matos, Antonio; Marcalo, Joaquim

    2008-12-08

    Fourier transform ion cyclotron resonance mass spectrometry was employed to study the products and kinetics of gas-phase reactions of Cm+ and Cm2+; parallel studies were carried out with La+/2+, Gd+/2+ and Lu+/2+. Reactions with oxygen-donor molecules provided estimates for the bond dissociation energies, D[M+-O](M = Cm, Gd, Lu). The first ionization energy, IE[CmO], was obtained from the reactivity of CmO+ with dienes, and the second ionization energies, IE[MO+](M = Cm, La, Gd, Lu), from the rates of electron-transfer reactions from neutrals to the MO2+ ions. The following thermodynamic quantities for curium oxide molecules were obtained: IE[CmO]= 6.4+-0.2 eV; IE[CmO+]= 15.8+-0.4 eV; D[Cm-O]= 710+-45 kJ mol-1; D[Cm+-O]= 670+-40 kJ mol-1; and D[Cm2+-O]= 342+-55 kJ mol-1. Estimates for the M2+-O bond energies for M = Cm, La, Gd and Lu are all intermediate between D[N2-O]and D[OC-O]--i.e., 167 kJ mol-1< D[M2+-O]< 532 kJ mol-1 -- such that the four MO2+ ions fulfill the thermodynamic requirement for catalytic O-atom transport from N2O to CO. It was demonstrated that the kinetics are also favorable and that the CmO2+, LaO2+, GdO2+ and LuO2+ dipositive ions each catalyze the gas-phase oxidation of CO to CO2 by N2O. The CmO2+ ion appeared during the reaction of Cm+ with O2 when the intermediate, CmO+, was not collisionally cooled -- although its formation is kinetically and/or thermodynamically unfavorable, CmO2+ is a stable species.

  20. Structural and dynamic studies of the transcription factor ERG reveal DNA binding is allosterically autoinhibited

    PubMed Central

    Regan, Michael C.; Horanyi, Peter S.; Pryor, Edward E.; Sarver, Jessica L.; Cafiso, David S.; Bushweller, John H.

    2013-01-01

    The Ets-Related Gene (ERG) belongs to the Ets family of transcription factors and is critically important for maintenance of the hematopoietic stem cell population. A chromosomal translocation observed in the majority of human prostate cancers leads to the aberrant overexpression of ERG. We have identified regions flanking the ERG Ets domain responsible for autoinhibition of DNA binding and solved crystal structures of uninhibited, autoinhibited, and DNA-bound ERG. NMR-based measurements of backbone dynamics show that uninhibited ERG undergoes substantial dynamics on the millisecond-to-microsecond timescale but autoinhibited and DNA-bound ERG do not. We propose a mechanism whereby the allosteric basis of ERG autoinhibition is mediated predominantly by the regulation of Ets-domain dynamics with only modest structural changes. PMID:23898196

  1. Diversity of TMPRSS2-ERG fusion transcripts in the human prostate.

    PubMed

    Clark, J; Merson, S; Jhavar, S; Flohr, P; Edwards, S; Foster, C S; Eeles, R; Martin, F L; Phillips, D H; Crundwell, M; Christmas, T; Thompson, A; Fisher, C; Kovacs, G; Cooper, C S

    2007-04-19

    TMPRSS2-ERG gene fusions have recently been reported to be present in a high proportion of human prostate cancers. In the current study, we show that great diversity exists in the precise structure of TMPRSS2-ERG hybrid transcripts found in human prostates. Fourteen distinct hybrid transcripts are characterized, each containing different combinations of sequences from the TMPRSS2 and ERG genes. The transcripts include two that are predicted to encode a normal full-length ERG protein, six that encode N-terminal truncated ERG proteins and one that encodes a TMPRSS2-ERG fusion protein. Interestingly, distinct patterns of hybrid transcripts were found in samples taken from separate regions of individual cancer-containing prostates, suggesting that TMPRSS2-ERG gene fusions may be arising independently in different regions of a single prostate.

  2. Spin-Hall-Effect-Assisted Electroresistance in Antiferromagnets via 10(5) A/cm(2) dc Current.

    PubMed

    Han, Jiahao; Wang, Yuyan; Pan, Feng; Song, Cheng

    2016-01-01

    Antiferromagnet (AFM) spintronics with reduced electrical current is greatly expected to process information with high integration and low power consumption. In Pt/FeMn and Ta/FeMn hybrids, we observe significant resistance variation (up to 7% of the total resistance) manipulated by 10(5) A/cm(2) dc current. We have excluded the contribution of isotropic structural effects, and confirmed the critical role of the spin Hall injection from Pt (or Ta) to FeMn. This electrical current-manipulated resistance (i.e. electroresistance) is proposed to be attributed to the spin-Hall-effect-induced spin-orbit torque in FeMn. Similar results have also been detected in plain IrMn films, where the charge current generates spin current via the spin Hall effect with the existence of Ir atoms. All the measurements are free from external magnetic fields and ferromagnets. Our findings present an interesting step towards high-efficiency spintronic devices. PMID:27546199

  3. Clasts in the CM2 carbonaceous chondrite Lonewolf Nunataks 94101: Evidence for aqueous alteration prior to complex mixing

    NASA Astrophysics Data System (ADS)

    Lindgren, Paula; Lee, Martin R.; Sofe, Mahmood R.; Zolensky, Michael E.

    2013-06-01

    Clasts in the CM2 carbonaceous chondrite Lonewolf Nunataks (LON) 94101 have been characterized using scanning and transmission electron microscopy and electron microprobe analysis to determine their degrees of aqueous alteration, and the timing of alteration relative to incorporation of clasts into the host. The provenance of the clasts, and the mechanism by which they were incorporated and mixed with their host material are also considered. Results show that at least five distinct types of clasts occur in LON 94101, of which four have been aqueously altered to various degrees and one is largely anhydrous. The fact that they have had different alteration histories implies that the main part of aqueous activity occurred prior to the mixing and assimilation of the clasts with their host. Further, the presence of such a variety of clasts suggests complex mixing in a dynamic environment involving material from various sources. Two of the clasts, one containing approximately 46 vol% carbonate and the other featuring crystals of pyrrhotite up to approximately 1 mm in size, are examples of unusual lithologies and indicate concentration of chemical elements in discrete areas of the parent body(ies), possibly by flow of aqueous solutions.

  4. Spin-Hall-Effect-Assisted Electroresistance in Antiferromagnets via 105 A/cm2 dc Current

    PubMed Central

    Han, Jiahao; Wang, Yuyan; Pan, Feng; Song, Cheng

    2016-01-01

    Antiferromagnet (AFM) spintronics with reduced electrical current is greatly expected to process information with high integration and low power consumption. In Pt/FeMn and Ta/FeMn hybrids, we observe significant resistance variation (up to 7% of the total resistance) manipulated by 105 A/cm2 dc current. We have excluded the contribution of isotropic structural effects, and confirmed the critical role of the spin Hall injection from Pt (or Ta) to FeMn. This electrical current-manipulated resistance (i.e. electroresistance) is proposed to be attributed to the spin-Hall-effect-induced spin-orbit torque in FeMn. Similar results have also been detected in plain IrMn films, where the charge current generates spin current via the spin Hall effect with the existence of Ir atoms. All the measurements are free from external magnetic fields and ferromagnets. Our findings present an interesting step towards high-efficiency spintronic devices. PMID:27546199

  5. Frequent TMPRSS2-ERG rearrangement in prostatic small cell carcinoma detected by fluorescence in situ hybridization: the superiority of fluorescence in situ hybridization over ERG immunohistochemistry.

    PubMed

    Schelling, Lindsay A; Williamson, Sean R; Zhang, Shaobo; Yao, Jorge L; Wang, Mingsheng; Huang, Jiaoti; Montironi, Rodolfo; Lopez-Beltran, Antonio; Emerson, Robert E; Idrees, Muhammad T; Osunkoya, Adeboye O; Man, Yan-Gao; Maclennan, Gregory T; Baldridge, Lee Ann; Compérat, Eva; Cheng, Liang

    2013-10-01

    Small cell carcinoma of the prostate is both morphologically and immunohistochemically similar to small cell carcinoma of other organs such as the urinary bladder or lung. TMPRSS2-ERG gene fusion appears to be a highly specific alteration in prostatic carcinoma that is frequently shared by small cell carcinoma. In adenocarcinoma, immunohistochemistry for the ERG protein product has been reported to correlate well with the presence of the gene fusion, although in prostatic small cell carcinoma, this relationship is not completely understood. We evaluated 54 cases of small cell carcinoma of the prostate and compared TMPRSS2-ERG gene fusion status by fluorescence in situ hybridization (FISH) to immunohistochemical staining with antibody to ERG. Of 54 cases of prostatic small cell carcinoma, 26 (48%) were positive for TMPRSS2-ERG gene fusion by FISH and 12 (22%) showed overexpression of ERG protein by immunohistochemistry. Of the 26 cases positive by FISH, 11 were also positive for ERG protein by immunohistochemistry. One tumor was positive by immunohistochemistry but negative by FISH. Urinary bladder small cell carcinoma (n = 25) showed negative results by both methods; however, 2 of 14 small cell carcinomas of other organs (lung, head, and neck) showed positive immunohistochemistry but negative FISH. Positive staining for ERG by immunohistochemistry is present in a subset of prostatic small cell carcinomas and correlates with the presence of TMPRSS2-ERG gene fusion. Therefore, it may be useful in confirming prostatic origin when molecular testing is not accessible. However, sensitivity and specificity of ERG immunohistochemistry in small cell carcinoma are decreased compared to FISH.

  6. Formation of a rotating jet during the filament eruption on 2013 April 10-11

    NASA Astrophysics Data System (ADS)

    Filippov, B.; Srivastava, A. K.; Dwivedi, B. N.; Masson, S.; Aulanier, G.; Joshi, N. C.; Uddin, W.

    2015-07-01

    We analyse multiwavelength and multiviewpoint observations of a helically twisted plasma jet formed during a confined filament eruption on 2013 April 10-11. Given a rather large-scale event with its high spatial and temporal resolution observations, it allows us to clearly understand some new physical details about the formation and triggering mechanism of twisting jet. We identify a pre-existing flux rope associated with a sinistral filament, which was observed several days before the event. The confined eruption of the filament within a null-point topology, also known as an Eiffel tower (or inverted-Y) magnetic field configuration results in the formation of a twisted jet after the magnetic reconnection near a null point. The sign of helicity in the jet is found to be the same as that of the sign of helicity in the filament. Untwisting motion of the reconnected magnetic field lines gives rise to the accelerating plasma along the jet axis. The event clearly shows the twist injection from the pre-eruptive magnetic field to the jet.

  7. Geomagnetic activity during 10 - 11 solar cycles that has been observed by old Russian observatories.

    NASA Astrophysics Data System (ADS)

    Seredyn, Tomasz; Wysokinski, Arkadiusz; Kobylinski, Zbigniew; Bialy, Jerzy

    2016-07-01

    A good knowledge of solar-terrestrial relations during past solar activity cycles could give the appropriate tools for a correct space weather forecast. The paper focuses on the analysis of the historical collections of the ground based magnetic observations and their operational indices from the period of two sunspot solar cycles 10 - 11, period 1856 - 1878 (Bartels rotations 324 - 635). We use hourly observations of H and D geomagnetic field components registered at Russian stations: St. Petersburg - Pavlovsk, Barnaul, Ekaterinburg, Nertshinsk, Sitka, and compare them to the data obtained from the Helsinki observatory. We compare directly these records and also calculated from the data of the every above mentioned station IHV indices introduced by Svalgaard (2003), which have been used for further comparisons in epochs of assumed different polarity of the heliospheric magnetic field. We used also local index C9 derived by Zosimovich (1981) from St. Petersburg - Pavlovsk data. Solar activity is represented by sunspot numbers. The correlative and continuous wavelet analyses are applied for estimation of the correctness of records from different magnetic stations. We have specially regard to magnetic storms in the investigated period and the special Carrington event of 1-2 Sep 1859. Generally studied magnetic time series correctly show variability of the geomagnetic activity. Geomagnetic activity presents some delay in relation to solar one as it is seen especially during descending and minimum phase of the even 11-year cycle. This pattern looks similarly in the case of 16 - 17 solar cycles.

  8. Rare Mechanisms of Stopped Pion Absorption by 10,11B Nuclei

    NASA Astrophysics Data System (ADS)

    Chernyshev, B. A.; Gurov, Yu. B.; Korotkova, L. Yu.; Lapushkin, S. V.; Pritula, R. V.

    2015-06-01

    Correlation measurements of the stopped π--meson absorption reactions 10B(π-, dt)X and 11B(π-, tt)X were carried out at low energy pion channel of LAMPF with the two-arm multilayer semiconductor spectrometer of charged particles. The analysis of twodimensional distributions (Dalitz' diagram) and the momentum distribution of the residual nucleus allowed to identify the process of pion absorption on the intranuclear lithium clusters 5,6Li and to get the evidence on the existence of the configurations 5Li + 5Heg.s and 6Li + 5Heg.s in the boron nuclei 10,11B. The levels of 8Li* isotope with the resonance parameters (Ex, C): (8.7 ± 0.2, 1.9 ± 0.4) MeV and (10.1 ± 0.3, 4.0 ± 1.3) MeV were observed for the first time. These states break up with the triton emission: 8Li* → t + 5He..

  9. Microwave remote sensing of Saharan ergs and Amazon vegetation

    NASA Astrophysics Data System (ADS)

    Stephen, Haroon

    This dissertation focuses on relating spaceborne microwave data to the geophysical characteristics of the Sahara desert and the Amazon vegetation. Radar and radiometric responses of the Saharan ergs are related to geophysical properties of sand formations and near surface winds. The spatial and temporal variability of the Amazon vegetation is studied using multi-frequency and multi-polarization data. The Sahara desert includes large expanses of sand dunes called ergs that are constantly reshaped by prevailing winds. Radar backscatter (sigma°) measurements observed at various incidence (theta) and azimuth (φ) angles from the NASA Scatterometer (NSCAT), the ERS scatterometer (ESCAT), the SeaWinds scatterometer aboard QuikScat (QSCAT), and the Precipitation Radar (TRMM-PR) aboard the Tropical Rain Monitoring Mission (TRMM) are used to model the sigma° response from sand dunes. Backscatter theta and φ variation depends upon the slopes and orientations of the dune slopes. Sand dunes are modeled as a composite of tilted rough facets, which are characterized by a probability distribution of tilt. The small ripples are modeled as cosinusoidal surface waves that contribute to the return signal at Bragg angles. The sigma° response is high at look angles equal to the mean tilts of the rough facets and is lower elsewhere. The modeled sigma° response is similar to NSCAT and ESCAT observations. sigma° also varies spatially and reflects the spatial inhomogeneity of the sand surface. A model incorporating the sigma° φ-modulation and spatial inhomogeneity is proposed. The maxima of the φ-modulation at theta = 33° reflect the orientation of the slip-sides on the sand surface. These slip-side orientations are consistent with the European Centre for Medium-Range Weather Forecasts wind directions spatially and temporally. Radiometric emissions from the ergs have strong dependence on the surface geometry. The radiometric temperature (Tb) of ergs is modeled as the weighted sum

  10. The endothelial transcription factor ERG promotes vascular stability and growth through Wnt/β-catenin signaling.

    PubMed

    Birdsey, Graeme M; Shah, Aarti V; Dufton, Neil; Reynolds, Louise E; Osuna Almagro, Lourdes; Yang, Youwen; Aspalter, Irene M; Khan, Samia T; Mason, Justin C; Dejana, Elisabetta; Göttgens, Berthold; Hodivala-Dilke, Kairbaan; Gerhardt, Holger; Adams, Ralf H; Randi, Anna M

    2015-01-12

    Blood vessel stability is essential for embryonic development; in the adult, many diseases are associated with loss of vascular integrity. The ETS transcription factor ERG drives expression of VE-cadherin and controls junctional integrity. We show that constitutive endothelial deletion of ERG (Erg(cEC-KO)) in mice causes embryonic lethality with vascular defects. Inducible endothelial deletion of ERG (Erg(iEC-KO)) results in defective physiological and pathological angiogenesis in the postnatal retina and tumors, with decreased vascular stability. ERG controls the Wnt/β-catenin pathway by promoting β-catenin stability, through signals mediated by VE-cadherin and the Wnt receptor Frizzled-4. Wnt signaling is decreased in ERG-deficient endothelial cells; activation of Wnt signaling with lithium chloride, which stabilizes β-catenin levels, corrects vascular defects in Erg(cEC-KO) embryos. Finally, overexpression of ERG in vivo reduces permeability and increases stability of VEGF-induced blood vessels. These data demonstrate that ERG is an essential regulator of angiogenesis and vascular stability through Wnt signaling. PMID:25584796

  11. Dexa Body Composition Assessment in 10-11 Year Healthy Children

    PubMed Central

    Doodeman, H. J.; Struijf, E.; Houdijk, A. P. J.

    2016-01-01

    Introduction Obesity is a growing health problem associated with metabolic derangements and cardiovascular disease. Accumulating evidence links the accumulation of visceral adipose tissue (VAT) to these obesity related health risks in adults. Childhood obesity is associated with a lifetime risk of cardiovascular disease and poses a serious challenge to future health care. In children, there is much less data on the prevalence and gender differences of visceral obesity than in adults. This study aims to provide reference values for VAT in children 10–11 years of age. Methods In a cross-sectional study performed in the north western part of theNetherlands, healthy children of 10–11 years of age, were recruited from primary schools. Anthropometric data consisting of height, weight, waist circumference (WC) and BMI were measured. Body composition was measured using DXA, providing measures for bone mineral content, total fat mass (TFM), lean body mass (LBM) and VAT. Results 217 children were eligible for this study. Girls appeared to have a greater TFM (31.4% vs 27.5% of total body weight (TBW); P < .01) but lower VAT (0.3% vs 0.5% of TBW;P < .01) than boys, whereas boys had higher LBM (65.4% vs 69.3% TBW;P < .01). Median VAT area (cm2) was 41.1 for boys and 22.4 for girls (P < .01). Moderate to strong correlations were found for WC and BMI with VAT (boys: r = .664 and r = .630; Girls r = .699 and r = .546 respectively all P < .001). Discussion This study shows gender specific differences in VAT percentiles in healthy non-obese 10–11 year old children as measured by DXA that may serve as reference values in children. Independent of BMI and WC, girls tend to have more TFM but less VAT and LBM than boys. PMID:27788168

  12. [A new mode of recording retinal activity: multifocal ERG].

    PubMed

    Mack, G; Dollfus, H; Flament, J; Mohand-Said, S; Sahel, J

    1999-03-01

    Global ERG recordings are only modified in conditions with diffuse or extensive retinal involvement. The use, over the last 6 months, of a new functional testing device: VERIS (visual evoked response imaging system) allows accurate detection and quantification of localized retinal function defects. Our preliminary experience shows that a careful preparation of subjects, standardized testing protocols and a good understanding of the device technology, especially software parameters are mandatory. We report our results on a series of 28 normal volunteers, grouped by age and describe the various graphic presentation of data collected. This technology should allow accurate detection and quantification of retinal functional defects in patients with age related macular degeneration as well as evaluation of visual function in retinitis pigmentosa patients before and after photoreceptor transplantation.

  13. Mechanism and pharmacological rescue of berberine-induced hERG channel deficiency

    PubMed Central

    Yan, Meng; Zhang, Kaiping; Shi, Yanhui; Feng, Lifang; Lv, Lin; Li, Baoxin

    2015-01-01

    Berberine (BBR), an isoquinoline alkaloid mainly isolated from plants of Berberidaceae family, is extensively used to treat gastrointestinal infections in clinics. It has been reported that BBR can block human ether-a-go-go-related gene (hERG) potassium channel and inhibit its membrane expression. The hERG channel plays crucial role in cardiac repolarization and is the target of diverse proarrhythmic drugs. Dysfunction of hERG channel can cause long QT syndrome. However, the regulatory mechanisms of BBR effects on hERG at cell membrane level remain unknown. This study was designed to investigate in detail how BBR decreased hERG expression on cell surface and further explore its pharmacological rescue strategies. In this study, BBR decreases caveolin-1 expression in a concentration-dependent manner in human embryonic kidney 293 (HEK293) cells stably expressing hERG channel. Knocking down the basal expression of caveolin-1 alleviates BBR-induced hERG reduction. In addition, we found that aromatic tyrosine (Tyr652) and phenylalanine (Phe656) in S6 domain mediate the long-term effect of BBR on hERG by using mutation techniques. Considering both our previous and present work, we propose that BBR reduces hERG membrane stability with multiple mechanisms. Furthermore, we found that fexofenadine and resveratrol shorten action potential duration prolongated by BBR, thus having the potential effects of alleviating the cardiotoxicity of BBR. PMID:26543354

  14. Development of a peptide-based vaccine targeting TMPRSS2:ERG fusion positive prostate cancer

    PubMed Central

    Kissick, Haydn Thomas; Sanda, Martin George; Dunn, Laura Kathleen; Arredouani, Mohamed Simo

    2013-01-01

    Identification of novel vaccine targets is critical for the design and advancement of prostate cancer (PCa) immunotherapy. Ideal targets are proteins that are abundant in prostate tumors while absent in extra-prostatic tissues. The fusion of the androgen-regulated TMPRSS2 gene with the ETS transcription factor ERG occurs in approximately 50% of prostate cancer cases and results in aberrant ERG expression. Because expression of ERG is very low in peripheral tissue, we evaluated the suitability of this protein as an antigen target in PCa vaccines. ERG-derived HLA-A*0201-restricted immunogenic epitopes were identified through a 3-step strategy that included in silico, in vitro, and in vivo validation. Algorithms were used to predict potential HLA-A*0201-binding epitopes. High scoring epitopes were tested for binding to HLA-A*0201 using the T2-based stabilization assay in vitro. Five peptides were found to bind HLA-A*0201 and were subsequently tested for immunogenicity in humanized HLA-A*0201 transgenic mice. The in vivo screening identified three immunogenic peptides. One of these peptides, ERG295, overcame peripheral tolerance in HLA-A*0201 mice that expressed prostate restricted ERG. Also, this peptide induced an antigen specific response against ERG-expressing human prostate tumor cells. Finally, tetramer assay showed detectable and responsive ERG295-specific cytotoxic lymphocytes in peripheral blood of HLA-A*0201+ prostate cancer patients. Detection of ERG-specific CTLs in both mice and the blood of prostate cancer patients indicates that ERG-specific tolerance can be overcome. Additionally, these data suggest that ERG is a suitable target antigen for PCa immunotherapy. PMID:24149465

  15. Identification of quaternary ammonium compounds as potent inhibitors of hERG potassium channels

    SciTech Connect

    Xia Menghang; Shahane, Sampada A.; Huang, Ruili; Titus, Steven A.; Shum, Enoch; Zhao Yong; Southall, Noel; Zheng, Wei; Witt, Kristine L.; Tice, Raymond R.; Austin, Christopher P.

    2011-05-01

    The human ether-a-go-go-related gene (hERG) channel, a member of a family of voltage-gated potassium (K{sup +}) channels, plays a critical role in the repolarization of the cardiac action potential. The reduction of hERG channel activity as a result of adverse drug effects or genetic mutations may cause QT interval prolongation and potentially leads to acquired long QT syndrome. Thus, screening for hERG channel activity is important in drug development. Cardiotoxicity associated with the inhibition of hERG channels by environmental chemicals is also a public health concern. To assess the inhibitory effects of environmental chemicals on hERG channel function, we screened the National Toxicology Program (NTP) collection of 1408 compounds by measuring thallium influx into cells through hERG channels. Seventeen compounds with hERG channel inhibition were identified with IC{sub 50} potencies ranging from 0.26 to 22 {mu}M. Twelve of these compounds were confirmed as hERG channel blockers in an automated whole cell patch clamp experiment. In addition, we investigated the structure-activity relationship of seven compounds belonging to the quaternary ammonium compound (QAC) series on hERG channel inhibition. Among four active QAC compounds, tetra-n-octylammonium bromide was the most potent with an IC{sub 50} value of 260 nM in the thallium influx assay and 80 nM in the patch clamp assay. The potency of this class of hERG channel inhibitors appears to depend on the number and length of their aliphatic side-chains surrounding the charged nitrogen. Profiling environmental compound libraries for hERG channel inhibition provides information useful in prioritizing these compounds for cardiotoxicity assessment in vivo.

  16. ERG Cooperates with Androgen Receptor in Regulating Trefoil Factor 3 in Prostate Cancer Disease Progression123

    PubMed Central

    Rickman, David S; Chen, Ying-bei; Banerjee, Samprit; Pan, Yihang; Yu, Jindan; Vuong, Terry; Perner, Sven; Lafargue, Christopher J; Mertz, Kirsten D; Setlur, Sunita R; Sircar, Kanishka; Chinnaiyan, Arul M; Bismar, Tarek A; Rubin, Mark A; Demichelis, Francesca

    2010-01-01

    To elucidate the role of ETS gene fusions in castration-resistant prostate cancer (CRPC), we characterized the transcriptome of 54 CRPC tumor samples from men with locally advanced or metastatic disease. Trefoil factor 3 (TFF3) emerged as the most highly differentially regulated gene with respect to ERG rearrangement status and resistance to hormone ablation therapy. Conventional chromatin immunoprecipitation (ChIP)-polymerase chain reaction and ChIP followed by DNA sequencing (ChIP-seq) revealed direct binding of ERG to ETS binding sites in the TFF3 promoter in ERG-rearranged prostate cancer cell lines. These results were confirmed in ERG-rearranged hormone-naive prostate cancer (HNPC) and CRPC tissue samples. Functional studies demonstrated that ERG has an inhibitory effect on TFF3 expression in hormone-naive cancer but not in the castration-resistant state. In addition, we provide evidence suggesting an effect of androgen receptor signaling on ERG-regulated TFF3 expression. Furthermore, TFF3 overexpression enhances ERG-mediated cell invasion in CRPC prostate cancer cells. Taken together, our findings reveal a novel mechanism for enhanced tumor cell aggressiveness resulting from ERG rearrangement in the castration-resistant setting through TFF3 gene expression. PMID:21170267

  17. ERG cooperates with androgen receptor in regulating trefoil factor 3 in prostate cancer disease progression.

    PubMed

    Rickman, David S; Chen, Ying-Bei; Banerjee, Samprit; Pan, Yihang; Yu, Jindan; Vuong, Terry; Perner, Sven; Lafargue, Christopher J; Mertz, Kirsten D; Setlur, Sunita R; Sircar, Kanishka; Chinnaiyan, Arul M; Bismar, Tarek A; Rubin, Mark A; Demichelis, Francesca

    2010-12-01

    To elucidate the role of ETS gene fusions in castration-resistant prostate cancer (CRPC), we characterized the transcriptome of 54 CRPC tumor samples from men with locally advanced or metastatic disease. Trefoil factor 3 (TFF3) emerged as the most highly differentially regulated gene with respect to ERG rearrangement status and resistance to hormone ablation therapy. Conventional chromatin immunoprecipitation (ChIP)-polymerase chain reaction and ChIP followed by DNA sequencing (ChIP-seq) revealed direct binding of ERG to ETS binding sites in the TFF3 promoter in ERG-rearranged prostate cancer cell lines. These results were confirmed in ERG-rearranged hormone-naive prostate cancer (HNPC) and CRPC tissue samples. Functional studies demonstrated that ERG has an inhibitory effect on TFF3 expression in hormone-naive cancer but not in the castration-resistant state. In addition, we provide evidence suggesting an effect of androgen receptor signaling on ERG-regulated TFF3 expression. Furthermore, TFF3 overexpression enhances ERG-mediated cell invasion in CRPC prostate cancer cells. Taken together, our findings reveal a novel mechanism for enhanced tumor cell aggressiveness resulting from ERG rearrangement in the castration-resistant setting through TFF3 gene expression.

  18. IL-6 Overexpression in ERG-Positive Prostate Cancer Is Mediated by Prostaglandin Receptor EP2.

    PubMed

    Merz, Constanze; von Mässenhausen, Anne; Queisser, Angela; Vogel, Wenzel; Andrén, Ove; Kirfel, Jutta; Duensing, Stefan; Perner, Sven; Nowak, Michael

    2016-04-01

    Prostate cancer is the most diagnosed cancer in men and multiple risk factors and genetic alterations have been described. The TMPRSS2-ERG fusion event and the overexpression of the transcription factor ERG are present in approximately 50% of all prostate cancer patients, however, the clinical outcome is still controversial. Prostate tumors produce various soluble factors, including the pleiotropic cytokine IL-6, regulating cellular processes such as proliferation and metastatic segregation. Here, we used prostatectomy samples in a tissue microarray format and analyzed the co-expression and the clinicopathologic data of ERG and IL-6 using immunohistochemical double staining and correlated the read-out with clinicopathologic data. Expression of ERG and IL-6 correlated strongly in prostate tissue samples. Forced expression of ERG in prostate tumor cell lines resulted in significantly increased secretion of IL-6, whereas the down-regulation of ERG decreased IL-6 secretion. By dissecting the underlying mechanism in prostate tumor cell lines we show the ERG-mediated up-regulation of the prostanoid receptors EP2 and EP3. The prostanoid receptor EP2 was overexpressed in human prostate cancer tissue. Furthermore, the proliferation rate and IL-6 secretion in DU145 cells was reduced after treatment with EP2-receptor antagonist. Collectively, our study shows that the expression of ERG in prostate cancer is linked to the expression of IL-6 mediated by the prostanoid receptor EP2.

  19. Evidence, from Pioneer 10/11, Galileo, and Ulysses Data, for an Anomalous, Weak, Long-Range Acceleration

    NASA Technical Reports Server (NTRS)

    Anderson, J. D.; Laing, P. A.; Lau, E. L.; Liu, A. S.; Nieto, M. M.; Turyshev, S. G.

    1998-01-01

    Radio metric data from the Pioneer 10/11, Galileo, and Ulysses Spacecraft indicate an apparent anomalous, constant, acceleration acting on the spacecraft with a magnitude 8.5 x 10(sup -8) cm/s(sup 2), directed towards the Sun.

  20. Study Of Reaction Mechanisms For {sup 9,10,11}Be+{sup 64}Zn Systems Around The Coulomb Barrier

    SciTech Connect

    Scuderi, V.; Amorini, F.; Fisichella, M.; Lattuada, M.; Rizzo, F.; Torresi, D.; Di Pietro, A.; Figuera, P.; Papa, M.; Pellegriti, M. G.; Santonocito, D.; Scalia, G.; Acosta, L.; Martel, I.; Borge, M. J. G.; Sanchez, E. M. R.; Tengblad, O.; Vidal, A. M.; Fraile, L. M.; Jeppesen, H.

    2010-04-26

    The reactions {sup 9,10,11}Be+{sup 64}Zn have been studied at energies around the Coulomb barrier in order to better understand the role played by the halo features on the reaction dynamics. Preliminary results on such studies will be reported in this paper.

  1. Studio in Sculpture, Ceramics, Jewelry. Advanced Elective Courses in Art for Grades 10, 11, or 12: Volume 2.

    ERIC Educational Resources Information Center

    New York State Education Dept., Albany. Bureau of Secondary Curriculum Development.

    This is the second volume in a series that includes the syllabi for the advanced elective courses in the New York state art program for grades 10, 11, and 12. The first volume is described in ED 100 747. The guide consists of the following three sections: (1) Studio in Ceramics, (2) Studio in Sculpture, and (3) Studio in Jewelry and…

  2. Phytoremediation of carbamazepine and its metabolite 10,11-epoxycarbamazepine by C3 and C4 plants.

    PubMed

    Ryšlavá, Helena; Pomeislová, Alice; Pšondrová, Šárka; Hýsková, Veronika; Smrček, Stanislav

    2015-12-01

    The anticonvulsant drug carbamazepine is considered as an indicator of sewage water pollution: however, its uptake by plants and effect on metabolism have not been sufficiently documented, let alone its metabolite (10,11-epoxycarbamazepine). In a model system of sterile, hydroponically cultivated Zea mays (as C4 plant) and Helianthus annuus (as C3 plant), the uptake and effect of carbamazepine and 10,11-epoxycarbamazepine were studied in comparison with those of acetaminophen and ibuprofen. Ibuprofen and acetaminophen were effectively extracted from drug-supplemented media by both plants, while the uptake of more hydrophobic carbamazepine was much lower. On the other hand, the carbamazepine metabolite, 10,11-epoxycarbamazepine, was, unlike sunflower, willingly taken up by maize plants (after 96 h 88 % of the initial concentration) and effectively stored in maize tissues. In addition, the effect of the studied pharmaceuticals on the plant metabolism (enzymes of Hatch-Slack cycle, peroxidases) was followed. The activity of bound peroxidases, which could cause xylem vessel lignification and reduction of xenobiotic uptake, was at the level of control plants in maize leaves contrary to sunflower. Therefore, our results indicate that maize has the potential to remove 10,11-epoxycarbamazepine from contaminated soils. PMID:26310701

  3. Evaluation of Low-Cost, Objective Instruments for Assessing Physical Activity in 10-11-Year-Old Children

    ERIC Educational Resources Information Center

    Hart, Teresa L.; Brusseau, Timothy; Kulinna, Pamela Hodges; McClain, James J.; Tudor-Locke, Catrine

    2011-01-01

    This study compared step counts detected by four, low-cost, objective, physical-activity-assessment instruments and evaluated their ability to detect moderate-to-vigorous physical activity (MVPA) compared to the ActiGraph accelerometer (AG). Thirty-six 10-11-year-old children wore the NL-1000, Yamax Digiwalker SW 200, Omron HJ-151, and Walk4Life…

  4. Studio in Drawing and Painting; Graphics, Photography; Advanced Electric Courses in Art for Grades 10, 11, and 12, Volume 1.

    ERIC Educational Resources Information Center

    New York State Education Dept., Albany. Bureau of Secondary Curriculum Development.

    This is the first volume in a series that includes the syllabi for advanced elective courses in art education for grades 10, 11, and 12. The course objective is to provide a multiplicity of visual experiences in the drawing and painting areas of the graphic arts and photography that are broad in scope and that will challenge the student's ability…

  5. Phytoremediation of carbamazepine and its metabolite 10,11-epoxycarbamazepine by C3 and C4 plants.

    PubMed

    Ryšlavá, Helena; Pomeislová, Alice; Pšondrová, Šárka; Hýsková, Veronika; Smrček, Stanislav

    2015-12-01

    The anticonvulsant drug carbamazepine is considered as an indicator of sewage water pollution: however, its uptake by plants and effect on metabolism have not been sufficiently documented, let alone its metabolite (10,11-epoxycarbamazepine). In a model system of sterile, hydroponically cultivated Zea mays (as C4 plant) and Helianthus annuus (as C3 plant), the uptake and effect of carbamazepine and 10,11-epoxycarbamazepine were studied in comparison with those of acetaminophen and ibuprofen. Ibuprofen and acetaminophen were effectively extracted from drug-supplemented media by both plants, while the uptake of more hydrophobic carbamazepine was much lower. On the other hand, the carbamazepine metabolite, 10,11-epoxycarbamazepine, was, unlike sunflower, willingly taken up by maize plants (after 96 h 88 % of the initial concentration) and effectively stored in maize tissues. In addition, the effect of the studied pharmaceuticals on the plant metabolism (enzymes of Hatch-Slack cycle, peroxidases) was followed. The activity of bound peroxidases, which could cause xylem vessel lignification and reduction of xenobiotic uptake, was at the level of control plants in maize leaves contrary to sunflower. Therefore, our results indicate that maize has the potential to remove 10,11-epoxycarbamazepine from contaminated soils.

  6. Functional analysis of the TMPRSS2:ERG fusion gene in cisplatin‑induced cell death.

    PubMed

    Wu, Junqi; Chi, Linfeng; Chen, Zhanghui; Lu, Xianghong; Xiao, Suping; Zhang, Guanglin; Luo, Jindan; Chen, Ge-Ming; Yang, Jun

    2016-04-01

    The TMPRSS2:E‑twenty‑six (ETS) gene fusion occurs frequently in a high proportion of patients with prostate cancer (PCa) in Western countries, and the aberrant expression of TMPRSS2: v‑ETS avian erythroblastosis virus E26 oncogene homolog (ERG), the most common form of the corresponding protein, can regulate cell migration and contribute to tumor invasion and metastasis. However, its association with other cellular events, and in particular, cell death, remain unknown. To examine the function of such fusion genes, an expression plasmid containing the TMPRSS2:ERG (T1/E5) sequence (ΔERG) from a patient sample was constructed and transiently transfected into DU145 cells, which do not express the fusion gene. It was found that the overexpression of ΔERG significantly inhibited the ability of cisplatin to induce apoptosis in DU145 cells. By contrast, VCaP cells, which do contain TMPRSS2:ERG, were sensitized to cisplatin‑induced apoptosis through siRNA inhibition of the fusion gene. To elucidate the underlying mechanism, a stable cell line expressing the ΔERG gene was constructed. Expression of ΔERG did not affect cell migration, but did protect cells from DNA damage and apoptosis induced by cisplatin. Furthermore, knockdown of ΔERG by short interfering RNA resulted in cells regaining their sensitivity to cisplatin. Finally, the gene coding for activating transcription factor 5, which is important for cell survival, may be upregulated by ΔERG. Taken together, these data point to a new function of the TMPRSS2:ERG fusion gene in regulating the apoptotic pathway. PMID:26935606

  7. Heterogeneity and chronology of 6q15 deletion and ERG-fusion in prostate cancer

    PubMed Central

    Krohn, Antje; Freudenthaler, Fabian; Bauer, Melanie; Salomon, Georg; Heinzer, Hans; Michl, Uwe; Steurer, Stefan; Simon, Ronald; Sauter, Guido; Schlomm, Thorsten; Minner, Sarah

    2016-01-01

    Prostate cancer is notorious for its heterogeneity, which poses a problem for the applicability of diagnostic molecular markers. However, heterogeneity analysis can provide valuable information on the chronology in which molecular alterations arise. Here, we constructed a heterogeneity tissue microarray (TMA) comprising samples from 10 different tumor areas of 189 prostate cancers each in order to study the sequence of two frequent molecular alterations, i.e. 6q15 deletion and TMPRSS2:ERG fusion. Previous work shows a marked inverse relationship between these alterations, suggesting that presence of one of these alterations might impact development of the other. 6q15 deletion was analyzed by fluorescence in situ hybridization and ERG-expression by immunohistochemistry. Only 6.6% of 334 ERG-positive but 28.4% of 440 ERG-negative TMA spots showed 6q15 deletions (p < 0.0001). A breakdown of these data to the level of tumor foci revealed 6q deletions in 138 tumor foci that were large enough to have at least 3 analyzable TMA spots. These included 42 tumor foci with homogeneous ERG positivity and 16 with homogeneous 6q15 deletions. Remarkably, six of the 42 homogeneously ERG-positive tumor foci (14.3%) harbored small 6q15-deleted areas, but none of the 34 6q15-deleted foci showed areas of ERG positivity (p = 0.022). In conclusion, our data suggest that ERG-fusion can precede 6q15 deletion, but not vice versa. The complete absence of ERG-positive tumor areas in 6q15-deleted tumor foci further suggest that the functional consequences of 6q15 deletions may prevent the development of TMPRSS2:ERG fusions. PMID:26684029

  8. Functional decomposition of the human ERG based on the discrete wavelet transform.

    PubMed

    Gauvin, Mathieu; Little, John M; Lina, Jean-Marc; Lachapelle, Pierre

    2015-01-01

    The morphology of the electroretinogram (ERG) can be altered as a result of normal and pathological processes of the retina. However, given that the ERG is almost solely assessed in terms of its amplitude and timing, defining the shape of the ERG waveform so that subtle, physiologically driven, morphological changes can be systematically and reproducibly detected remains a challenging problem. We examined if the discrete wavelet transform (DWT) could meet this challenge. Normal human photopic ERGs evoked to a broad range of luminance intensities (to yield waveforms of various shapes, amplitudes, and timings) were analyzed using DWT descriptors of the ERG. Luminance-response curves that were generated using the various DWT descriptors revealed distinct (p < 0.05) luminance-dependence patterns, indicating that the stimulus luminance differently modulates the various time-frequency components of the ERG and thus its morphology. The latter represents the first attempt to study the luminance-dependence of ERG descriptors obtained with the DWT. Analyses of ERGs obtained from patients affected with ON or OFF retinal pathway anomalies were also presented. We show here for the first time that distinct time-frequency descriptors can be specifically associated to the function of the ON and OFF cone pathway. Therefore, in this study, the DWT revealed reproducible, physiologically meaningful and diagnostically relevant descriptors of the ERG over a wide range of signal amplitudes and morphologies. The DWT analysis thus represents a valuable addition to the electrophysiologist's armamentarium that will improve the quantification and interpretation of normal and pathological ERG responses. PMID:26746684

  9. The Shift of ERG B-Wave Induced by Hours' Dark Exposure in Rodents

    PubMed Central

    Li, Dake; Fang, Qi; Yu, Hongbo

    2016-01-01

    Purpose Dark adaptation can induce a rapid functional shift in the retina, and after that, the retinal function is believed to remain stable during the continuous dark exposure. However, we found that electroretinograms (ERG) b-waves gradually shifted during 24 hours’ dark exposure in rodents. Detailed experiments were designed to explore this non-classical dark adaptation. Methods In vivo ERG recording in adult and developing rodents after light manipulations. Results We revealed a five-fold decrease in ERG b-waves in adult rats that were dark exposed for 24 hours. The ERG b-waves significantly increased within the first hour’s dark exposure, but after that decreased continuously and finally attained steady state after 1 day’s dark exposure. After 3 repetitive, 10 minutes’ light exposure, the dark exposed rats fully recovered. This recovery effect was eye-specific, and light exposure to one eye could not restore the ERGs in the non-exposed eye. The prolonged dark exposure-induced functional shift was also reflected in the down-regulation on the amplitude of intensity-ERG response curve, but the dynamic range of the responsive light intensity remained largely stable. Furthermore, the ERG b-wave shifts occurred in and beyond classical critical period, and in both rats and mice. Importantly, when ERG b-wave greatly shifted, the amplitude of ERG a-wave did not change significantly after the prolonged dark exposure. Conclusions This rapid age-independent ERG change demonstrates a generally existing functional shift in the retina, which is at the entry level of visual system. PMID:27517462

  10. Clinical application of simultaneous pattern VEP and pattern ERG recording.

    PubMed

    Song, H S; Ku, W C; Yeh, S F

    1995-06-01

    Thirteen eyes of optic neuropathy and 13 eyes of maculopathy during Sep. 1990-May 1992 were studied by simultaneous pattern VEP (PVEP) and pattern ERG (PERG) recording. In optic neuropathy, the P100 of PVEP was delayed in 7 eyes (ave. 108.87 msec; normal 94.41 +/- 3.51 msec), absent in 5 eyes, normal in 1 eye. Their PERG showed normal P50 amplitude (either normal or delayed latency) but small or absent N95 in 8 eyes. In maculopathy, the P100 of PVEP was delayed in 2 eyes (ave. 103.59msec), absent in 7 eyes, normal in 4 eyes. However, their PERG showed 12 eyes had small or absent P50. Combined PVEP & PERG test, when compared to PVEP alone, increased the diagnostic value from 57.1% to 100% for optic neuropathy and from 42.9% to 80% for maculopathy in this study. Thus, simultaneous PVEP & PERG recording is highly recommended in evaluation of anterior visual pathway disorders. PMID:7641105

  11. High yield purification of full-length functional hERG K+ channels produced in Saccharomyces cerevisiae.

    PubMed

    Molbaek, Karen; Scharff-Poulsen, Peter; Helix-Nielsen, Claus; Klaerke, Dan A; Pedersen, Per Amstrup

    2015-01-01

    The hERG potassium channel is essential for repolarization of the cardiac action potential. Due to this vital function, absence of unintended and potentially life-threatening interactions with hERG is required for approval of new drugs. The structure of hERG is therefore one of the most sought-after. To provide purified hERG for structural studies and new hERG biomimetic platforms for detection of undesirable interactions, we have developed a hERG expression platform generating unprecedented amounts of purified and functional hERG channels. Full-length hERG, with or without a C-terminally fused green fluorescent protein (GFP) His 8-tag was produced from a codon-optimized hERG cDNA in Saccharomyces cerevisiae. Both constructs complemented the high potassium requirement of a knock-out Saccharomyces cerevisiae strain, indicating correct tetramer assembly in vivo. Functionality was further demonstrated by Astemizole binding to membrane embedded hERG-GFP-His 8 with a stoichiometry corresponding to tetramer assembly. The 156 kDa hERG-GFP protein accumulated to a membrane density of 1.6%. Fluorescence size exclusion chromatography of hERG-GFP-His 8 solubilized in Fos-Choline-12 supplemented with cholesteryl-hemisuccinate and Astemizole resulted in a monodisperse elution profile demonstrating a high quality of the hERG channels. hERG-GFP-His 8 purified by Ni-affinity chromatography maintained the ability to bind Astemizole with the correct stoichiometry indicating that the native, tetrameric structure was preserved. To our knowledge this is the first reported high-yield production and purification of full length, tetrameric and functional hERG. This significant breakthrough will be paramount in obtaining hERG crystal structures, and in establishment of new high-throughput hERG drug safety screening assays. PMID:25656388

  12. FR171456 is a specific inhibitor of mammalian NSDHL and yeast Erg26p

    PubMed Central

    Helliwell, Stephen B.; Karkare, Shantanu; Bergdoll, Marc; Rahier, Alain; Leighton-Davis, Juliet R.; Fioretto, Celine; Aust, Thomas; Filipuzzi, Ireos; Frederiksen, Mathias; Gounarides, John; Hoepfner, Dominic; Hofmann, Andreas; Imbert, Pierre-Eloi; Jeker, Rolf; Knochenmuss, Richard; Krastel, Philipp; Margerit, Anais; Memmert, Klaus; Miault, Charlotte V.; Rao Movva, N.; Muller, Alban; Naegeli, Hans-Ulrich; Oberer, Lukas; Prindle, Vivian; Riedl, Ralph; Schuierer, Sven; Sexton, Jessica A.; Tao, Jianshi; Wagner, Trixie; Yin, Hong; Zhang, Juan; Roggo, Silvio; Reinker, Stefan; Parker, Christian N.

    2015-01-01

    FR171456 is a natural product with cholesterol-lowering properties in animal models, but its molecular target is unknown, which hinders further drug development. Here we show that FR171456 specifically targets the sterol-4-alpha-carboxylate-3-dehydrogenase (Saccharomyces cerevisiae—Erg26p, Homo sapiens—NSDHL (NAD(P) dependent steroid dehydrogenase-like)), an essential enzyme in the ergosterol/cholesterol biosynthesis pathway. FR171456 significantly alters the levels of cholesterol pathway intermediates in human and yeast cells. Genome-wide yeast haploinsufficiency profiling experiments highlight the erg26/ERG26 strain, and multiple mutations in ERG26 confer resistance to FR171456 in growth and enzyme assays. Some of these ERG26 mutations likely alter Erg26 binding to FR171456, based on a model of Erg26. Finally, we show that FR171456 inhibits an artificial Hepatitis C viral replicon, and has broad antifungal activity, suggesting potential additional utility as an anti-infective. The discovery of the target and binding site of FR171456 within the target will aid further development of this compound. PMID:26456460

  13. Imaging Erg and Jun transcription factor interaction in living cells using fluorescence resonance energy transfer analyses

    SciTech Connect

    Camuzeaux, Barbara; Heliot, Laurent; Coll, Jean . E-mail: martine.duterque@ibl.fr

    2005-07-15

    Physical interactions between transcription factors play important roles in modulating gene expression. Previous in vitro studies have shown a transcriptional synergy between Erg protein, an Ets family member, and Jun/Fos heterodimer, members of the bZip family, which requires direct Erg-Jun protein interactions. Visualization of protein interactions in living cells is a new challenge in biology. For this purpose, we generated fusion proteins of Erg, Fos, and Jun with yellow and cyan fluorescent proteins, YFP and CFP, respectively. After transient expression in HeLa cells, interactions of the resulting fusion proteins were explored by fluorescence resonance energy transfer microscopy (FRET) in fixed and living cells. FRET between YFP-Erg and CFP-Jun was monitored by using photobleaching FRET and fluorescence lifetime imaging microscopy. Both techniques revealed the occurrence of intermolecular FRET between YFP-Erg and CFP-Jun. This is stressed by loss of FRET with an YFP-Erg version carrying a point mutation in its ETS domain. These results provide evidence for the interaction of Erg and Jun proteins in living cells as a critical prerequisite of their transcriptional synergy, but also for the essential role of the Y371 residue, conserved in most Ets proteins, in this interaction.

  14. hERG1 Potassium Channels: Novel Biomarkers in Human Solid Cancers

    PubMed Central

    Lastraioli, Elena; Lottini, Tiziano; Bencini, Lapo; Bernini, Marco; Arcangeli, Annarosa

    2015-01-01

    Because of their high incidence and mortality solid cancers are a major health problem worldwide. Although several new biomarkers and potential targets for therapy have been identified through biomolecular research in the last years, the effects on patients' outcome are still unsatisfactory. Increasing evidence indicates that hERG1 potassium channels are overexpressed in human primary cancers of different origin and several associations between hERG1 expression and clinicopathological features and/or outcome are emerging. Aberrant hERG1 expression may be exploited either for early diagnosis (especially in those cancers where it is expressed in the initial steps of tumor progression) or for therapy purposes. Indeed, hERG1 blockage impairs tumor cell growth both in vitro and in vivo in preclinical mouse model. hERG1-based tumor therapy in humans, however, encounters the major hindrance of the potential cardiotoxicity that many hERG1 blockers exert. In this review we focus on recent advances in translational research in some of the most frequent human solid cancers (breast, endometrium, ovary, pancreas, esophagus, stomach, and colorectum) that have been shown to express hERG1 and that are a major health problem. PMID:26339650

  15. Global Analysis Reveals Families of Chemical Motifs Enriched for hERG Inhibitors

    PubMed Central

    Du, Fang; Babcock, Joseph J.; Yu, Haibo; Zou, Beiyan; Li, Min

    2015-01-01

    Promiscuous inhibition of the human ether-à-go-go-related gene (hERG) potassium channel by drugs poses a major risk for life threatening arrhythmia and costly drug withdrawals. Current knowledge of this phenomenon is derived from a limited number of known drugs and tool compounds. However, in a diverse, naïve chemical library, it remains unclear which and to what degree chemical motifs or scaffolds might be enriched for hERG inhibition. Here we report electrophysiology measurements of hERG inhibition and computational analyses of >300,000 diverse small molecules. We identify chemical ‘communities’ with high hERG liability, containing both canonical scaffolds and structurally distinctive molecules. These data enable the development of more effective classifiers to computationally assess hERG risk. The resultant predictive models now accurately classify naïve compound libraries for tendency of hERG inhibition. Together these results provide a more complete reference map of characteristic chemical motifs for hERG liability and advance a systematic approach to rank chemical collections for cardiotoxicity risk. PMID:25700001

  16. ERG is a novel and reliable marker for endothelial cells in central nervous system tumors.

    PubMed

    Haber, Matthew A; Iranmahboob, Amir; Thomas, Cheddhi; Liu, Mengling; Najjar, Amanda; Zagzag, David

    2015-01-01

    ETS-related gene (ERG) is a transcription factor that has been linked to angiogenesis. Very little research has been done to assess ERG expression in central nervous system (CNS) tumors. We evaluated 57 CNS tumors, including glioblastomas (GBMs) and hemangioblastomas (HBs), as well as two arteriovenous malformations and four samples of normal brain tissue with immunohistochemistry using a specific ERG rabbit monoclonal antibody. In addition, immunostains for CD31, CD34, and α-smooth muscle actin (α-SMA) were performed on all samples. CD31 demonstrated variable and sometimes weak immunoreactivity for endothelial cells. Furthermore, in 1 case of a GBM, CD34 stained not only endothelial cells, but also tumor cells. In contrast, we observed that ERG was only expressed in the nuclei of endothelial cells, for example, in the hyperplastic vascular complexes that comprise the glomeruloid microvascular proliferation seen in GBMs. Conversely, α-SMA immunoreactivity was identified in the abluminal cells of these hyperplastic vessels. Quantitative evaluation with automated methodology and custom Matlab 2008b software was used to calculate percent staining of ERG in each case. We observed significantly higher quantitative expression of ERG in HBs than in other CNS tumors. Our results show that ERG is a novel, reliable, and specific marker for endothelial cells within CNS tumors that can be used to better study the process of neovascularization.

  17. ERG signaling in prostate cancer is driven through PRMT5-dependent methylation of the Androgen Receptor

    PubMed Central

    Mounir, Zineb; Korn, Joshua M; Westerling, Thomas; Lin, Fallon; Kirby, Christina A; Schirle, Markus; McAllister, Gregg; Hoffman, Greg; Ramadan, Nadire; Hartung, Anke; Feng, Yan; Kipp, David Randal; Quinn, Christopher; Fodor, Michelle; Baird, Jason; Schoumacher, Marie; Meyer, Ronald; Deeds, James; Buchwalter, Gilles; Stams, Travis; Keen, Nicholas; Sellers, William R; Brown, Myles; Pagliarini, Raymond A

    2016-01-01

    The TMPRSS2:ERG gene fusion is common in androgen receptor (AR) positive prostate cancers, yet its function remains poorly understood. From a screen for functionally relevant ERG interactors, we identify the arginine methyltransferase PRMT5. ERG recruits PRMT5 to AR-target genes, where PRMT5 methylates AR on arginine 761. This attenuates AR recruitment and transcription of genes expressed in differentiated prostate epithelium. The AR-inhibitory function of PRMT5 is restricted to TMPRSS2:ERG-positive prostate cancer cells. Mutation of this methylation site on AR results in a transcriptionally hyperactive AR, suggesting that the proliferative effects of ERG and PRMT5 are mediated through attenuating AR’s ability to induce genes normally involved in lineage differentiation. This provides a rationale for targeting PRMT5 in TMPRSS2:ERG positive prostate cancers. Moreover, methylation of AR at arginine 761 highlights a mechanism for how the ERG oncogene may coax AR towards inducing proliferation versus differentiation. DOI: http://dx.doi.org/10.7554/eLife.13964.001 PMID:27183006

  18. ERG is a novel and reliable marker for endothelial cells in central nervous system tumors.

    PubMed

    Haber, Matthew A; Iranmahboob, Amir; Thomas, Cheddhi; Liu, Mengling; Najjar, Amanda; Zagzag, David

    2015-01-01

    ETS-related gene (ERG) is a transcription factor that has been linked to angiogenesis. Very little research has been done to assess ERG expression in central nervous system (CNS) tumors. We evaluated 57 CNS tumors, including glioblastomas (GBMs) and hemangioblastomas (HBs), as well as two arteriovenous malformations and four samples of normal brain tissue with immunohistochemistry using a specific ERG rabbit monoclonal antibody. In addition, immunostains for CD31, CD34, and α-smooth muscle actin (α-SMA) were performed on all samples. CD31 demonstrated variable and sometimes weak immunoreactivity for endothelial cells. Furthermore, in 1 case of a GBM, CD34 stained not only endothelial cells, but also tumor cells. In contrast, we observed that ERG was only expressed in the nuclei of endothelial cells, for example, in the hyperplastic vascular complexes that comprise the glomeruloid microvascular proliferation seen in GBMs. Conversely, α-SMA immunoreactivity was identified in the abluminal cells of these hyperplastic vessels. Quantitative evaluation with automated methodology and custom Matlab 2008b software was used to calculate percent staining of ERG in each case. We observed significantly higher quantitative expression of ERG in HBs than in other CNS tumors. Our results show that ERG is a novel, reliable, and specific marker for endothelial cells within CNS tumors that can be used to better study the process of neovascularization. PMID:25881913

  19. hERG1 channels drive tumour malignancy and may serve as prognostic factor in pancreatic ductal adenocarcinoma

    PubMed Central

    Lastraioli, E; Perrone, G; Sette, A; Fiore, A; Crociani, O; Manoli, S; D'Amico, M; Masselli, M; Iorio, J; Callea, M; Borzomati, D; Nappo, G; Bartolozzi, F; Santini, D; Bencini, L; Farsi, M; Boni, L; Di Costanzo, F; Schwab, A; Onetti Muda, A; Coppola, R; Arcangeli, A

    2015-01-01

    Background: hERG1 channels are aberrantly expressed in human cancers. The expression, functional role and clinical significance of hERG1 channels in pancreatic ductal adenocarcinoma (PDAC) is lacking. Methods: hERG1 expression was tested in PDAC primary samples assembled as tissue microarray by immunohistochemistry using an anti-hERG1 monoclonal antibody (α-hERG1-MoAb). The functional role of hERG1 was studied in PDAC cell lines and primary cultures. ERG1 expression during PDAC progression was studied in Pdx-1-Cre,LSL-KrasG12D/+,LSL-Trp53R175H/+ transgenic (KPC) mice. ERG1 expression in vivo was determined by optical imaging using Alexa-680-labelled α-hERG1-MoAb. Results: (i) hERG1 was expressed at high levels in 59% of primary PDAC; (ii) hERG1 blockade decreased PDAC cell growth and migration; (iii) hERG1 was physically and functionally linked to the Epidermal Growth Factor-Receptor pathway; (iv) in transgenic mice, ERG1 was expressed in PanIN lesions, reaching high expression levels in PDAC; (v) PDAC patients whose primary tumour showed high hERG1 expression had a worse prognosis; (vi) the α-hERG1-MoAb could detect PDAC in vivo. Conclusions: hERG1 regulates PDAC malignancy and its expression, once validated in a larger cohort also comprising of late-stage, non-surgically resected cases, may be exploited for diagnostic and prognostic purposes in PDAC either ex vivo or in vivo. PMID:25719829

  20. Epitaxial growth of large area single-crystalline few-layer MoS2 with high space charge mobility of 192 cm2 V-1 s-1

    NASA Astrophysics Data System (ADS)

    Ma, Lu; Nath, Digbijoy N.; Lee, Edwin W.; Lee, Choong Hee; Yu, Mingzhe; Arehart, Aaron; Rajan, Siddharth; Wu, Yiying

    2014-08-01

    We report on the vapor-solid growth of single crystalline few-layer MoS2 films on (0001)-oriented sapphire with excellent structural and electrical properties over centimeter length scale. High-resolution X-ray diffraction scans indicated that the films had good out-of-plane ordering and epitaxial registry. A carrier density of ˜2 × 1011 cm-2 and a room temperature mobility of 192 cm2/Vs were extracted from space-charge limited transport regime in the films. The electron mobility was found to exhibit in-plane anisotropy with a ratio of ˜1.8. Theoretical estimates of the temperature-dependent electron mobility including optical phonon, acoustic deformation potential, and remote ionized impurity scattering were found to satisfactorily match the measured data. The synthesis approach reported here demonstrates the feasibility of device quality few-layer MoS2 films with excellent uniformity and high quality.

  1. Is H2O present on Io? The detection of a new strong band near 3590/cm (2.79 microns)

    NASA Astrophysics Data System (ADS)

    Salama, F.; Allamandola, L. J.; Sandford, S. A.; Bregman, J. D.; Witteborn, F. C.; Cruikshank, D. P.

    1994-02-01

    A strong absorption band at 3590 +/- 20/cm (2.790 +/- 0.015 microns) has been discovered in the spectrum of Io using the Kuiper Airborne Observatory (KAO). The 2nu1 + nu3 combination mode of solid SO2 falls at this position. Since SO2 is abundant on Io it must contribute to the new band. However, a band due to H2O was predicted near this frequency in Io's spectrum based on laboratory experiments of H2O:SO2 mixed Io ice analogs which were used to assign the two weak, variable features at 3370 and 3170/cm (2.97 and 3.15 microns) to trace amounts of H2O frozen in solid SO2 on Io. The new band probably originates from both SO2 and H2O. Unfortunately, the spectral resolution of the data is insufficient to settle the issue of whether there are two resolvable components.

  2. Schottky barrier diodes of corundum-structured gallium oxide showing on-resistance of 0.1 mΩ·cm2 grown by MIST EPITAXY®

    NASA Astrophysics Data System (ADS)

    Oda, Masaya; Tokuda, Rie; Kambara, Hitoshi; Tanikawa, Tomochika; Sasaki, Takahiro; Hitora, Toshimi

    2016-02-01

    Thin-film corundum-structured gallium oxide (α-Ga2O3) Schottky barrier diodes (SBDs) were fabricated by growing α-Ga2O3 layers on sapphire substrates by the safe, low-cost, and energy-saving MIST EPITAXY® technique, followed by lifting off the α-Ga2O3 layers from the substrates. The SBDs exhibited on-resistance and breakdown voltage of 0.1 mΩ·cm2 and 531 V (SBD1) or 0.4 mΩ·cm2 and 855 V (SBD2), respectively. These results will encourage the future evolution of low-cost and high-performance SBDs with α-Ga2O3.

  3. Thermal inertia and radar reflectivity of the Martian north polar ERG: Low-density aggregates

    NASA Technical Reports Server (NTRS)

    Herkenhoff, K. E.

    1993-01-01

    The north polar layered deposits on Mars appear to be the source of the dark material that comprises the north polar erg. The physical properties and chemical composition of the erg material therefore have important implications for the origin and evolution of the Martian layered deposits. Viking bistatic radar and infrared thermal mapping (IRTM) data indicate that the bulk density of the erg material is lower than that of the average Martian surface. These data are consistent with hypotheses involving formation of filamentary sublimation residue (FSR) particles from erosion of the layered deposits. The color and albedo of the erg and of the layered deposits, and the presence of magnetic material on Mars, suggest that the dark material is composed of low-density aggregates of magnetic dust grains, perhaps similar to FSR particles created in laboratory experiments.

  4. A toxin to nervous, cardiac, and endocrine ERG K+ channels isolated from Centruroides noxius scorpion venom.

    PubMed

    Gurrola, G B; Rosati, B; Rocchetti, M; Pimienta, G; Zaza, A; Arcangeli, A; Olivotto, M; Possani, L D; Wanke, E

    1999-05-01

    Toxins isolated from a variety of venoms are tools for probing the physiological function and structure of ion channels. The ether-a-go-go-related genes (erg) codify for the K+ channels (ERG), which are crucial in neurons and are impaired in human long-QT syndrome and Drosophila 'seizure' mutants. We have isolated a peptide from the scorpion Centruroides noxius Hoffmann that has no sequence homologies with other toxins, and demonstrate that it specifically inhibits (IC50=16+/-1 nM) only ERG channels of different species and distinct histogenesis. These results open up the possibility of investigating ERG channel structure-function relationships and novel pharmacological tools with potential therapeutic efficacy.

  5. A Cofacially Stacked Electron-Deficient Small Molecule with a High Electron Mobility of over 10 cm(2) V(-1) s(-1) in Air.

    PubMed

    Dou, Jin-Hu; Zheng, Yu-Qing; Yao, Ze-Fan; Lei, Ting; Shen, Xingxing; Luo, Xu-Yi; Yu, Zhi-Ao; Zhang, Shi-Ding; Han, Guangchao; Wang, Zhi; Yi, Yuanping; Wang, Jie-Yu; Pei, Jian

    2015-12-22

    A strong, electron-deficient small molecule, F4 -BDOPV, has a lowest unoccupied molecular orbital (LUMO) level down to -4.44 eV and exhibits cofacial packing in single crystals. These features provide F4 -BDOPV with good ambient stability and large charge-transfer integrals for electrons, leading to a high electron mobility of up to 12.6 cm(2) V(-1) s(-1) in air.

  6. hERG Potassium Channel Blockade by the HCN Channel Inhibitor Bradycardic Agent Ivabradine

    PubMed Central

    Melgari, Dario; Brack, Kieran E.; Zhang, Chuan; Zhang, Yihong; El Harchi, Aziza; Mitcheson, John S.; Dempsey, Christopher E.; Ng, G. André; Hancox, Jules C.

    2015-01-01

    Background Ivabradine is a specific bradycardic agent used in coronary artery disease and heart failure, lowering heart rate through inhibition of sinoatrial nodal HCN‐channels. This study investigated the propensity of ivabradine to interact with KCNH2‐encoded human Ether‐à‐go‐go–Related Gene (hERG) potassium channels, which strongly influence ventricular repolarization and susceptibility to torsades de pointes arrhythmia. Methods and Results Patch clamp recordings of hERG current (IhERG) were made from hERG expressing cells at 37°C. IhERG was inhibited with an IC50 of 2.07 μmol/L for the hERG 1a isoform and 3.31 μmol/L for coexpressed hERG 1a/1b. The voltage and time‐dependent characteristics of IhERG block were consistent with preferential gated‐state‐dependent channel block. Inhibition was partially attenuated by the N588K inactivation‐mutant and the S624A pore‐helix mutant and was strongly reduced by the Y652A and F656A S6 helix mutants. In docking simulations to a MthK‐based homology model of hERG, the 2 aromatic rings of the drug could form multiple π‐π interactions with the aromatic side chains of both Y652 and F656. In monophasic action potential (MAP) recordings from guinea‐pig Langendorff‐perfused hearts, ivabradine delayed ventricular repolarization and produced a steepening of the MAPD90 restitution curve. Conclusions Ivabradine prolongs ventricular repolarization and alters electrical restitution properties at concentrations relevant to the upper therapeutic range. In absolute terms ivabradine does not discriminate between hERG and HCN channels: it inhibits IhERG with similar potency to that reported for native If and HCN channels, with S6 binding determinants resembling those observed for HCN4. These findings may have important implications both clinically and for future bradycardic drug design. PMID:25911606

  7. Activation of human ether-a-go-go related gene (hERG) potassium channels by small molecules

    PubMed Central

    Zhou, Ping-zheng; Babcock, Joseph; Liu, Lian-qing; Li, Min; Gao, Zhao-bing

    2011-01-01

    Human ether-a-go-go related gene (hERG) potassium (K+) channels play a critical role in cardiac action potential repolarization. Mutations that reduce hERG conductance or surface expression may cause congenital long QT syndrome (LQTS). However, the channels can be inhibited by structurally diverse small molecules, resulting in an acquired form of LQTS. Consequently, small molecules that increase the hERG current may be of value for treatment for LQTS. So far, nine hERG activators have been reported. The aim of this review is to discuss recent advances concerning the identification and action mechanism of hERG activators. PMID:21623390

  8. The Central Asian ergs: A study by remote sensing and geographic information systems

    NASA Astrophysics Data System (ADS)

    Maman, Shimrit; Blumberg, Dan G.; Tsoar, Haim; Mamedov, Batyr; Porat, Naomi

    2011-12-01

    Ergs are large, relatively flat areas of deserts covered by wind-swept sand and with varying degrees of vegetation cover. The ergs of Central Asia extend from Turkmenistan to the Syr-Darya River in Kazakhstan. They are crossed by the Amu-Darya River, to the north and south of which lie Kyzyl-Kum and Kara-Kum, respectively. This research focuses on identifying and mapping the ergs of Central Asia and analyzing the climate factors that set the dunes in motion and that later stabilize them. The vast area encompassed by the Central Asian ergs and their inaccessibility make traditional mapping methods virtually impossible. A variety of spaceborne imagery with varying spectral and spatial resolutions was used. These images provided the basis for mapping sand distribution, dune forms, and vegetation cover. Wilson (1973) defined the Central Asian ergs as active based on precipitation. Our results, in contrast, show that these ergs are mostly stabilized, with the estimated sand mantled area for the Kara-Kum desert ˜260,000 km 2, and for the Kyzyl-Kum it is ˜195,500 km 2. Meteorological analysis of wind and precipitation data indicate a low wind power environment (DP < 200) and sufficient rainfall (>100 mm) to support vegetation. The age of the sand samples was determined by optically stimulated luminescence (OSL) (˜5-7 Ka), which provides insight about past climate characteristics. GIS analysis was performed in parallel with field work to obtain validation and verification.

  9. Proposed amendments to UN ST/SG/AC.10/11: transport of dangerous goods—lithium batteries

    NASA Astrophysics Data System (ADS)

    Farrington, Michael D.

    UN Document ST/SG/AC.10/11 [ST/SG/AC.10/11, The UN recommendations on the Transport of Dangerous Goods, Manual of Tests and Criteria, 2nd revision] outlines a test plan that is fundamental to the classification for transport of lithium batteries with metallic lithium or lithium alloy anodes. Cells and batteries that fall within its scope are considered dangerous goods. The test plan requires amendment to address many shortcomings. Some tests assess risks that do not exist, other risks are not addressed. This paper outlines the issues we have identified with the test plan, the proposed amendments, the rationale behind the proposed amendments, and issues we have not addressed in the current round of amendments. Transport of lithium batteries has an excellent record. Packaging requirements are essential to continued safe transport. Tests that address known risks relevant to conditions normal to transport are discussed. It is for consideration that non-metallic anode systems such as some polymer and lithium-ion systems should be treated as distinctly different technologies with their own set of transportation risks. The use of the marketing term lithium battery when applied to lithium polymer and lithium-ion products has erroneously lead to the suggestion that they be included in the scope of UN Document ST/SG/AC.10/11. A recommendation to classify such systems under a new UN number is presented. It is suggested that UN 3090 or UN 3091 should be reserved for lithium metal or lithium metal alloy products.

  10. Indication, from Pioneer 10/11, Galileo, and Ulysses Data, of an Apparent Anomalous, Weak, Long-Range Acceleration

    SciTech Connect

    Anderson, J.D.; Lau, E.L.; Turyshev, S.G.; Laing, P.A.; Liu, A.S.; Nieto, M.M.

    1998-10-01

    Radio metric data from the Pioneer 10/11, Galileo, and Ulysses spacecraft indicate an apparent anomalous, constant, acceleration acting on the spacecraft with a magnitude {approximately}8.5{times}10{sup {minus}8} cm/s{sup 2} , directed towards the Sun. Two independent codes and physical strategies have been used to analyze the data. A number of potential causes have been ruled out. We discuss future kinematic tests and possible origins of the signal. {copyright} {ital 1998} {ital The American Physical Society}

  11. Apollo 10 - 11

    NASA Technical Reports Server (NTRS)

    2001-01-01

    This video gives overviews of the Apollo 10 and Apollo 11 missions to the moon, including footage from the launches and landings of the Command Module Columbia, which is used for both flights. The Apollo 10 crewmembers, Commander Thomas Stafford, Command Module Pilot John Young, and Lunar Module Pilot Eugene Cernan, are seen as they suit-up in preparation for launch and then as they experiment with the microgravity environment on their way to the moon. The moon's surface is seen in detail as the Command Module orbits at an altitude of 69 miles. The Apollo 11 crewmembers, Commander Neil Armstrong, Command Module Pilot Michael Collins, and Lunar Module Pilot Buzz Aldrin, are seen during various training activities, including simulated lunar gravity training, practicing collecting lunar material, and using the moonquake detector. Footage shows the approach and landing of the Lunar Module Eagle on the moon. Armstrong and Aldrin descend to the moon's surface, collect a sample of lunar dust, and erect the American flag. Eagle's liftoff from the moon is seen.

  12. Colorimetric TMPRSS2-ERG Gene Fusion Detection in Prostate Cancer Urinary Samples via Recombinase Polymerase Amplification.

    PubMed

    Koo, Kevin M; Wee, Eugene J H; Trau, Matt

    2016-01-01

    TMPRSS2 (Exon 1)-ERG (Exon 4) is the most frequent gene fusion event in prostate cancer (PC), and is highly PC-specific unlike the current serum prostate specific antigen (PSA) biomarker. However, TMPRSS2-ERG levels are currently measured with quantitative reverse-transcription PCR (RT-qPCR) which is time-consuming and requires costly equipment, thus limiting its use in clinical diagnostics. Herein, we report a novel rapid, cost-efficient and minimal-equipment assay named "FusBLU" for detecting TMPRSS2-ERG gene fusions from urine. TMPRSS2-ERG mRNA was amplified by isothermal reverse transcription-recombinase polymerase amplification (RT-RPA), magnetically-isolated, and detected through horseradish peroxidase (HRP)-catalyzed colorimetric reaction. FusBLU was specific for TMPRSS2-ERG mRNA with a low visual detection limit of 10(5) copies. We also demonstrated assay readout versatility on 3 potentially useful platforms. The colorimetric readout was detectable by naked eye for a quick yes/no evaluation of gene fusion presence. On the other hand, a more quantitative TMPRSS2-ERG detection was achievable by absorbance/electrochemical measurements. FusBLU was successfully applied to 12 urinary samples and results were validated by gold-standard RT-qPCR. We also showed that sediment RNA was likely the main source of TMPRSS2-ERG mRNA in urinary samples. We believe that our assay is a potential clinical screening tool for PC and could also have wide applications for other disease-related fusion genes. PMID:27375789

  13. Tuning hERG out: Antitarget QSAR Models for Drug Development

    PubMed Central

    Braga, Rodolpho C.; Alves, Vinícius M.; Silva, Meryck F. B.; Muratov, Eugene; Fourches, Denis; Tropsha, Alexander; Andrade, Carolina H.

    2015-01-01

    Several non-cardiovascular drugs have been withdrawn from the market due to their inhibition of hERG K+ channels that can potentially lead to severe heart arrhythmia and death. As hERG safety testing is a mandatory FDA-required procedure, there is a considerable interest for developing predictive computational tools to identify and filter out potential hERG blockers early in the drug discovery process. In this study, we aimed to generate predictive and well-characterized quantitative structure–activity relationship (QSAR) models for hERG blockage using the largest publicly available dataset of 11,958 compounds from the ChEMBL database. The models have been developed and validated according to OECD guidelines using four types of descriptors and four different machine-learning techniques. The classification accuracies discriminating blockers from non-blockers were as high as 0.83–0.93 on external set. Model interpretation revealed several SAR rules, which can guide structural optimization of some hERG blockers into non-blockers. We have also applied the generated models for screening the World Drug Index (WDI) database and identify putative hERG blockers and non-blockers among currently marketed drugs. The developed models can reliably identify blockers and non-blockers, which could be useful for the scientific community. A freely accessible web server has been developed allowing users to identify putative hERG blockers and non-blockers in chemical libraries of their interest (http://labmol.farmacia.ufg.br/predherg). PMID:24805060

  14. Molecular basis of hERG potassium channel blockade by the class Ic antiarrhythmic flecainide

    PubMed Central

    Melgari, Dario; Zhang, Yihong; El Harchi, Aziza; Dempsey, Christopher E.; Hancox, Jules C.

    2015-01-01

    The class Ic antiarrhythmic drug flecainide inhibits KCNH2-encoded “hERG” potassium channels at clinically relevant concentrations. The aim of this study was to elucidate the underlying molecular basis of this action. Patch clamp recordings of hERG current (IhERG) were made from hERG expressing cells at 37 °C. Wild-type (WT) IhERG was inhibited with an IC50 of 1.49 μM and this was not significantly altered by reversing the direction of K+ flux or raising external [K+]. The use of charged and uncharged flecainide analogues showed that the charged form of the drug accesses the channel from the cell interior to produce block. Promotion of WT IhERG inactivation slowed recovery from inhibition, whilst the N588K and S631A attenuated-inactivation mutants exhibited IC50 values 4–5 fold that of WT IhERG. The use of pore-helix/selectivity filter (T623A, S624A V625A) and S6 helix (G648A, Y652A, F656A) mutations showed < 10-fold shifts in IC50 for all but V625A and F656A, which respectively exhibited IC50s 27-fold and 142-fold their WT controls. Docking simulations using a MthK-based homology model suggested an allosteric effect of V625A, since in low energy conformations flecainide lay too low in the pore to interact directly with that residue. On the other hand, the molecule could readily form π–π stacking interactions with aromatic residues and particularly with F656. We conclude that flecainide accesses the hERG channel from the cell interior on channel gating, binding low in the inner cavity, with the S6 F656 residue acting as a principal binding determinant. PMID:26159617

  15. Colorimetric TMPRSS2-ERG Gene Fusion Detection in Prostate Cancer Urinary Samples via Recombinase Polymerase Amplification

    PubMed Central

    Koo, Kevin M.; Wee, Eugene J.H.; Trau, Matt

    2016-01-01

    TMPRSS2 (Exon 1)-ERG (Exon 4) is the most frequent gene fusion event in prostate cancer (PC), and is highly PC-specific unlike the current serum prostate specific antigen (PSA) biomarker. However, TMPRSS2-ERG levels are currently measured with quantitative reverse-transcription PCR (RT-qPCR) which is time-consuming and requires costly equipment, thus limiting its use in clinical diagnostics. Herein, we report a novel rapid, cost-efficient and minimal-equipment assay named “FusBLU” for detecting TMPRSS2-ERG gene fusions from urine. TMPRSS2-ERG mRNA was amplified by isothermal reverse transcription-recombinase polymerase amplification (RT-RPA), magnetically-isolated, and detected through horseradish peroxidase (HRP)-catalyzed colorimetric reaction. FusBLU was specific for TMPRSS2-ERG mRNA with a low visual detection limit of 105 copies. We also demonstrated assay readout versatility on 3 potentially useful platforms. The colorimetric readout was detectable by naked eye for a quick yes/no evaluation of gene fusion presence. On the other hand, a more quantitative TMPRSS2-ERG detection was achievable by absorbance/electrochemical measurements. FusBLU was successfully applied to 12 urinary samples and results were validated by gold-standard RT-qPCR. We also showed that sediment RNA was likely the main source of TMPRSS2-ERG mRNA in urinary samples. We believe that our assay is a potential clinical screening tool for PC and could also have wide applications for other disease-related fusion genes. PMID:27375789

  16. Molecular determinants of pentamidine-induced hERG trafficking inhibition.

    PubMed

    Dennis, Adrienne T; Wang, Lu; Wan, Hanlin; Nassal, Drew; Deschenes, Isabelle; Ficker, Eckhard

    2012-02-01

    Pentamidine is an antiprotozoal compound that clinically causes acquired long QT syndrome (acLQTS), which is associated with prolonged QT intervals, tachycardias, and sudden cardiac arrest. Pentamidine delays terminal repolarization in human heart by acutely blocking cardiac inward rectifier currents. At the same time, pentamidine reduces surface expression of the cardiac potassium channel I(Kr)/human ether à-go-go-related gene (hERG). This is unusual in that acLQTS is caused most often by direct block of the cardiac potassium current I(Kr)/hERG. The present study was designed to provide a more complete picture of how hERG surface expression is disrupted by pentamidine at the cellular and molecular levels. Using biochemical and electrophysiological methods, we found that pentamidine exclusively inhibits hERG export from the endoplasmic reticulum to the cell surface in a heterologous expression system as well as in cardiomyocytes. hERG trafficking inhibition could be rescued in the presence of the pharmacological chaperone astemizole. We used rescue experiments in combination with an extensive mutational analysis to locate an interaction site for pentamidine at phenylalanine 656, a crucial residue in the canonical drug binding site of terminally folded hERG. Our data suggest that pentamidine binding to a folding intermediate of hERG arrests channel maturation in a conformational state that cannot be exported from the endoplasmic reticulum. We propose that pentamidine is the founding member of a novel pharmacological entity whose members act as small molecule antichaperones. PMID:22046004

  17. Colorimetric TMPRSS2-ERG Gene Fusion Detection in Prostate Cancer Urinary Samples via Recombinase Polymerase Amplification.

    PubMed

    Koo, Kevin M; Wee, Eugene J H; Trau, Matt

    2016-01-01

    TMPRSS2 (Exon 1)-ERG (Exon 4) is the most frequent gene fusion event in prostate cancer (PC), and is highly PC-specific unlike the current serum prostate specific antigen (PSA) biomarker. However, TMPRSS2-ERG levels are currently measured with quantitative reverse-transcription PCR (RT-qPCR) which is time-consuming and requires costly equipment, thus limiting its use in clinical diagnostics. Herein, we report a novel rapid, cost-efficient and minimal-equipment assay named "FusBLU" for detecting TMPRSS2-ERG gene fusions from urine. TMPRSS2-ERG mRNA was amplified by isothermal reverse transcription-recombinase polymerase amplification (RT-RPA), magnetically-isolated, and detected through horseradish peroxidase (HRP)-catalyzed colorimetric reaction. FusBLU was specific for TMPRSS2-ERG mRNA with a low visual detection limit of 10(5) copies. We also demonstrated assay readout versatility on 3 potentially useful platforms. The colorimetric readout was detectable by naked eye for a quick yes/no evaluation of gene fusion presence. On the other hand, a more quantitative TMPRSS2-ERG detection was achievable by absorbance/electrochemical measurements. FusBLU was successfully applied to 12 urinary samples and results were validated by gold-standard RT-qPCR. We also showed that sediment RNA was likely the main source of TMPRSS2-ERG mRNA in urinary samples. We believe that our assay is a potential clinical screening tool for PC and could also have wide applications for other disease-related fusion genes.

  18. Dynamics of cell and tissue growth acquired by means of 25 mm2 to 10 cm2 lens-free imaging

    NASA Astrophysics Data System (ADS)

    Momey, F.; Coutard, J.-G.; Bordy, T.; Navarro, F.; Menneteau, M.; Dinten, J.-M.; Allier, C.

    2015-03-01

    In this paper, we discuss a new methodology based on lens-free imaging to perform wound healing assay with unprecedented statistics. Our video lens-free microscopy setup is a simple optical system featuring only a CMOS sensor and a semi coherent illumination system. Yet it is a powerful means for the real-time monitoring of cultivated cells. It presents several key advantages, e.g., integration into standard incubator, compatibility with standard cell culture protocol, simplicity and ease of use. It can perform the follow-up in a large field of view (25 mm2) of several crucial parameters during the culture of cells i.e. their motility, their proliferation rate or their death. Consequently the setup can gather large statistics both in space and time. But in the case of tissue growth experiments, the field of view of 25 mm2 remains not sufficient and results can be biased depending on the position of the device with respect to the recipient of the cell culture. Hence, to conduct exhaustive wound healing assay, here we propose to enlarge the field of view up to 10 cm2 through two different approaches. The first method consists in performing a scan of the cell culture by moving the source/sensor couple and then stitch the stack of images. The second is to make an acquisition by scanning with a line scan camera. The two approaches are compared in term of resolution, complexity and acquisition time. Next we have performed acquisitions of wound healing assay (keratinocytes HaCaT) both in real-time (25 mm2) and in final point (10 cm2) to assess the combination of these two complementary modalities. In the future, we aim at combining directly super wide field of view acquisitions (>10 cm2) with real time ability inside the incubator.

  19. MgZnO/ZnO heterostructures with electron mobility exceeding 1 × 10(6) cm(2)/Vs.

    PubMed

    Falson, Joseph; Kozuka, Yusuke; Uchida, Masaki; Smet, Jurgen H; Arima, Taka-Hisa; Tsukazaki, Atsushi; Kawasaki, Masashi

    2016-01-01

    The inherently complex chemical and crystallographic nature of oxide materials has suppressed the purities achievable in laboratory environments, obscuring the rich physical degrees of freedom these systems host. In this manuscript we provide a systematic approach to defect identification and management in oxide molecular beam epitaxy grown MgZnO/ZnO heterostructures which host two-dimensional electron systems. We achieve samples displaying electron mobilities in excess of 1 × 10(6) cm(2)/Vs. This data set for the MgZnO/ZnO system firmly establishes that the crystalline quality has become comparable to traditional semiconductor materials. PMID:27229479

  20. MgZnO/ZnO heterostructures with electron mobility exceeding 1 × 106 cm2/Vs

    PubMed Central

    Falson, Joseph; Kozuka, Yusuke; Uchida, Masaki; Smet, Jurgen H.; Arima, Taka-hisa; Tsukazaki, Atsushi; Kawasaki, Masashi

    2016-01-01

    The inherently complex chemical and crystallographic nature of oxide materials has suppressed the purities achievable in laboratory environments, obscuring the rich physical degrees of freedom these systems host. In this manuscript we provide a systematic approach to defect identification and management in oxide molecular beam epitaxy grown MgZnO/ZnO heterostructures which host two-dimensional electron systems. We achieve samples displaying electron mobilities in excess of 1 × 106 cm2/Vs. This data set for the MgZnO/ZnO system firmly establishes that the crystalline quality has become comparable to traditional semiconductor materials. PMID:27229479

  1. MgZnO/ZnO heterostructures with electron mobility exceeding 1 × 106 cm2/Vs

    NASA Astrophysics Data System (ADS)

    Falson, Joseph; Kozuka, Yusuke; Uchida, Masaki; Smet, Jurgen H.; Arima, Taka-Hisa; Tsukazaki, Atsushi; Kawasaki, Masashi

    2016-05-01

    The inherently complex chemical and crystallographic nature of oxide materials has suppressed the purities achievable in laboratory environments, obscuring the rich physical degrees of freedom these systems host. In this manuscript we provide a systematic approach to defect identification and management in oxide molecular beam epitaxy grown MgZnO/ZnO heterostructures which host two-dimensional electron systems. We achieve samples displaying electron mobilities in excess of 1 × 106 cm2/Vs. This data set for the MgZnO/ZnO system firmly establishes that the crystalline quality has become comparable to traditional semiconductor materials.

  2. High-voltage thin-film GaN LEDs fabricated on ceramic substrates: the alleviated droop effect at 670 W/cm(2).

    PubMed

    Tsai, M L; Liao, J H; Yeh, J H; Hsu, T C; Hon, S J; Chung, T Y; Lai, K Y

    2013-11-01

    High-voltage thin-film GaN LEDs with the emission wavelength of 455 nm were fabricated on ceramic substrates (230 W/m · K). The high-voltage operation was achieved by three cascaded sub-LEDs with dielectric passivation and metal bridges conformally deposited on the side walls. Under the driving power of 670 W/cm(2), the high-voltage LEDs exhibit much alleviated efficiency droop and the operative temperature below 80 °C. The excellent performances were attributed to the improved current spreading within each sub-LED and the superior heat sinking of the ceramic substrate.

  3. Widely bandgap tunable amorphous Cd-Ga-O oxide semiconductors exhibiting electron mobilities ≥10 cm2 V-1 s-1

    NASA Astrophysics Data System (ADS)

    Yanagi, Hiroshi; Sato, Chiyuki; Kimura, Yota; Suzuki, Issei; Omata, Takahisa; Kamiya, Toshio; Hosono, Hideo

    2015-02-01

    Amorphous oxide semiconductors exhibit large electron mobilities; however, their bandgaps are either too large for solar cells or too small for deep ultraviolet applications depending on the materials system. Herein, we demonstrate that amorphous Cd-Ga-O semiconductors display bandgaps covering the entire 2.5-4.3 eV region while maintaining large electron mobilities ≥10 cm2 V-1 s-1. The band alignment diagram obtained by ultraviolet photoemission spectroscopy and the bandgap values reveal that these semiconductors form type-II heterojunctions with p-type Cu2O, which is suitable for solar cells and solar-blind ultraviolet sensors.

  4. Reflectance Spectra of CM2 Chondrite Mighei Irradiated with Pulsed Laser and Implications for Low-Albedo Asteroids and Martian Moons

    NASA Technical Reports Server (NTRS)

    Moroz, L. V.; Hiroi, T.; Shingareva, T. V.; Basilevsky, A. T.; Fisenko, A. V.; Semjonova, L. F.; Pieters, C. M.

    2004-01-01

    Micrometeoritic bombardment is an important space weathering process modifying surface optical properties of airless solar system bodies. We have used irradiation with a microsecond pulsed laser as an experimental method to simulate such a process on various targets. The experiment discussed here was performed on a powdered sample of CM2 carbonaceous chondrite Mighei. Shingareva et al. report the details of experimental procedure as well as the results of mineralogical and chemical studies of the irradiated material. Here we present reflectance spectra of irradiated Mighei samples and discuss their spectral properties compared to those of non-irradiated meteorite and low-albedo small solar system bodies.

  5. The A395T mutation in ERG11 gene confers fluconazole resistance in Candida tropicalis causing candidemia.

    PubMed

    Tan, Jingwen; Zhang, Jinqing; Chen, Wei; Sun, Yi; Wan, Zhe; Li, Ruoyu; Liu, Wei

    2015-04-01

    The mechanism of fluconazole resistance in Candida tropicalis is still unclear. Recently, we isolated a fluconazole-resistant strain of C. tropicalis from the blood specimen of a patient with candidemia in China. In vitro antifungal susceptibility of the isolate was determined by using CLSI M27-A3 and E-test methods. The sequence of ERG11 gene was then analyzed, and the three-dimensional model of Erg11p encoded by ERG11 gene was also investigated. The sequencing of ERG11 gene revealed the mutation of A395T in this fluconazole-resistant isolate of C. tropicalis, resulting in the Y132F substitution in Erg11p. Sequence alignment and three-dimensional model comparison of Erg11ps showed high similarity between fluconazole-susceptible isolates of C. tropicalis and Candida albicans. The comparison of the three-dimensional models of Erg11ps demonstrated that the position of the Y132F substitution in this isolate of C. tropicalis is identical to the isolate of C. albicans with fluconazole resistance resulting from Y132F substitution in Erg11p. Hence, we ascertain that the Y132F substitution of Erg11p caused by A395T mutation in ERG11 gene confers the fluconazole resistance in C. tropicalis.

  6. Androgen receptor and gene network: Micromechanics reassemble the signaling machinery of TMPRSS2-ERG positive prostate cancer cells

    PubMed Central

    2014-01-01

    Prostate cancer is a gland tumor in the male reproductive system. It is a multifaceted and genomically complex disease. Transmembrane protease, serine 2 and v-ets erythroblastosis virus E26 homolog (TMPRSS2-ERG) gene fusions are the common molecular signature of prostate cancer. Although tremendous advances have been made in unraveling various facets of TMPRSS2-ERG-positive prostate cancer, many research findings must be sequentially collected and re-interpreted. It is important to understand the activation or repression of target genes and proteins in response to various stimuli and the assembly in signal transduction in TMPRSS2-ERG fusion-positive prostate cancer cells. Accordingly, we divide this multi-component review ofprostate cancer cells into several segments: 1) The role of TMPRSS2-ERG fusion in genomic instability and methylated regulation in prostate cancer and normal cells; 2) Signal transduction cascades in TMPRSS2-ERG fusion-positive prostate cancer; 3) Overexpressed genes in TMPRSS2-ERG fusion-positive prostate cancer cells; 4) miRNA mediated regulation of the androgen receptor (AR) and its associated protein network; 5) Quantitative control of ERG in prostate cancer cells; 6) TMPRSS2-ERG encoded protein targeting; In conclusion, we provide a detailed understanding of TMPRSS2-ERG fusion related information in prostate cancer development to provide a rationale for exploring TMPRSS2-ERG fusion-mediated molecular network machinery. PMID:24739220

  7. A novel assessment of nefazodone-induced hERG inhibition by electrophysiological and stereochemical method

    SciTech Connect

    Shin, Dae-Seop; Park, Myoung Joo; Lee, Hyang-Ae; Lee, Joo Yun; Chung, Hee-Chung; Yoo, Dae Seok; Chae, Chong Hak; Park, Sang-Joon; Kim, Ki-Suk; Bae, Myung Ae

    2014-02-01

    Nefazodone was used widely as an antidepressant until it was withdrawn from the U.S. market in 2004 due to hepatotoxicity. We have investigated methods to predict various toxic effects of drug candidates to reduce the failure rate of drug discovery. An electrophysiological method was used to assess the cardiotoxicity of drug candidates. Small molecules, including withdrawn drugs, were evaluated using a patch-clamp method to establish a database of hERG inhibition. Nefazodone inhibited hERG channel activity in our system. However, nefazodone-induced hERG inhibition indicated only a theoretical risk of cardiotoxicity. Nefazodone inhibited the hERG channel in a concentration-dependent manner with an IC{sub 50} of 45.3 nM in HEK-293 cells. Nefazodone accelerated both the recovery from inactivation and its onset. Nefazodone also accelerated steady-state inactivation, although it did not modify the voltage-dependent character. Alanine mutants of hERG S6 and pore region residues were used to identify the nefazodone-binding site on hERG. The hERG S6 point mutants Y652A and F656A largely abolished the inhibition by nefazodone. The pore region mutant S624A mildly reduced the inhibition by nefazodone but T623A had little effect. A docking study showed that the aromatic rings of nefazodone interact with Y652 and F656 via π–π interactions, while an amine interacted with the S624 residue in the pore region. In conclusion, Y652 and F656 in the S6 domain play critical roles in nefazodone binding. - Highlights: • Nefazodone inhibits hERG channels with an IC{sub 50} of 45.3 nM in HEK-293 cells. • Nefazodone blocks hERG channels by binding to the open channels. • Y652 and F656 are important for binding of nefazodone. • The aromatic rings of nefazodone interact with Y652 and F656 via π–π interactions.

  8. Flunarizine is a highly potent inhibitor of cardiac hERG potassium current.

    PubMed

    Trepakova, Elena S; Dech, Spencer J; Salata, Joseph J

    2006-02-01

    Flunarizine has been widely used for the management of a variety of disorders such as peripheral vascular diseases, migraine, and epilepsy. The majority of its beneficial effects have been attributed to its ability to inhibit voltage-gated Ca2+ channels in the low micromolar range, albeit non-selectively, as flunarizine has been shown to inhibit a variety of ion channels. We examined the effects of flunarizine on potassium currents through cardiac channels encoded by the human ether-a-go-go related gene (hERG) stably expressed in CHO cells. In this study, we have characterized the effect of flunarizine on biophysical properties of hERG potassium currents with standard whole-cell voltage-clamp techniques. Notably, flunarizine is a highly potent inhibitor of hERG current with an IC50 value of 5.7 nM. The effect of flunarizine on hERG potassium current is concentration and time dependent, and displays voltage dependence over the voltage range between -40 and 0 mV. At concentrations near or above the IC50, flunarizine causes a negative shift in the voltage dependence of hERG current activation and accelerates tail current deactivation. Flunarizine preferentially blocks the activated state of the channel and displays weak frequency dependence of inhibition. Flunarizine also inhibits KCNQ1/KCNE1 channel current with an IC50 of 0.76 microM. PMID:16495758

  9. General Purpose 2D and 3D Similarity Approach to Identify hERG Blockers.

    PubMed

    Schyman, Patric; Liu, Ruifeng; Wallqvist, Anders

    2016-01-25

    Screening compounds for human ether-à-go-go-related gene (hERG) channel inhibition is an important component of early stage drug development and assessment. In this study, we developed a high-confidence (p-value < 0.01) hERG prediction model based on a combined two-dimensional (2D) and three-dimensional (3D) modeling approach. We developed a 3D similarity conformation approach (SCA) based on examining a limited fixed number of pairwise 3D similarity scores between a query molecule and a set of known hERG blockers. By combining 3D SCA with 2D similarity ensemble approach (SEA) methods, we achieved a maximum sensitivity in hERG inhibition prediction with an accuracy not achieved by either method separately. The combined model achieved 69% sensitivity and 95% specificity on an independent external data set. Further validation showed that the model correctly picked up documented hERG inhibition or interactions among the Food and Drug Administration- approved drugs with the highest similarity scores-with 18 of 20 correctly identified. The combination of ascertaining 2D and 3D similarity of compounds allowed us to synergistically use 2D fingerprint matching with 3D shape and chemical complementarity matching. PMID:26718126

  10. General Purpose 2D and 3D Similarity Approach to Identify hERG Blockers.

    PubMed

    Schyman, Patric; Liu, Ruifeng; Wallqvist, Anders

    2016-01-25

    Screening compounds for human ether-à-go-go-related gene (hERG) channel inhibition is an important component of early stage drug development and assessment. In this study, we developed a high-confidence (p-value < 0.01) hERG prediction model based on a combined two-dimensional (2D) and three-dimensional (3D) modeling approach. We developed a 3D similarity conformation approach (SCA) based on examining a limited fixed number of pairwise 3D similarity scores between a query molecule and a set of known hERG blockers. By combining 3D SCA with 2D similarity ensemble approach (SEA) methods, we achieved a maximum sensitivity in hERG inhibition prediction with an accuracy not achieved by either method separately. The combined model achieved 69% sensitivity and 95% specificity on an independent external data set. Further validation showed that the model correctly picked up documented hERG inhibition or interactions among the Food and Drug Administration- approved drugs with the highest similarity scores-with 18 of 20 correctly identified. The combination of ascertaining 2D and 3D similarity of compounds allowed us to synergistically use 2D fingerprint matching with 3D shape and chemical complementarity matching.

  11. Effects of common antitussive drugs on the hERG potassium channel current.

    PubMed

    Deisemann, Heike; Ahrens, Nadine; Schlobohm, Irene; Kirchhoff, Christian; Netzer, Rainer; Möller, Clemens

    2008-12-01

    A common over-the-counter (OTC) non-opioid antitussive drug, clobutinol, was recently withdrawn from the market due to its potential to induce cardiac arrhythmias by a blockade of the potassium channel coded by the human ether-à-go-go-related gene (hERG). In this study, we investigated the effects of a number of antitussive compounds on the hERG ion channel current using patch-clamp electrophysiology, and compared the effects to that of clobutinol. The compounds clobutinol, pentoxyverine, dextromethorphan, and codeine inhibited the outward current in hERG transfected cells with half-maximal inhibition concentrations (IC50) of 1.9 microM, 3.0 microM, 5.1 microM, and 97 microM, respectively. For theobromine, no significant effect on the hERG current at a concentration up to 100 microM was detected. Safety margins between the effects of the drugs on the hERG ion channel current and their calculated maximal free therapeutic plasma concentration were calculated. These results were compared to assess potential risks of the compounds to induce torsade de pointes-type arrhythmias.

  12. Pred-hERG: A Novel web-Accessible Computational Tool for Predicting Cardiac Toxicity.

    PubMed

    Braga, Rodolpho C; Alves, Vinicius M; Silva, Meryck F B; Muratov, Eugene; Fourches, Denis; Lião, Luciano M; Tropsha, Alexander; Andrade, Carolina H

    2015-10-01

    The blockage of the hERG K(+) channels is closely associated with lethal cardiac arrhythmia. The notorious ligand promiscuity of this channel earmarked hERG as one of the most important antitargets to be considered in early stages of drug development process. Herein we report on the development of an innovative and freely accessible web server for early identification of putative hERG blockers and non-blockers in chemical libraries. We have collected the largest publicly available curated hERG dataset of 5,984 compounds. We succeed in developing robust and externally predictive binary (CCR≈0.8) and multiclass models (accuracy≈0.7). These models are available as a web-service freely available for public at http://labmol.farmacia.ufg.br/predherg/. Three following outcomes are available for the users: prediction by binary model, prediction by multi-class model, and the probability maps of atomic contribution. The Pred-hERG will be continuously updated and upgraded as new information became available. PMID:27490970

  13. Early identification of hERG liability in drug discovery programs by automated patch clamp

    PubMed Central

    Danker, Timm; Möller, Clemens

    2014-01-01

    Blockade of the cardiac ion channel coded by human ether-à-gogo-related gene (hERG) can lead to cardiac arrhythmia, which has become a major concern in drug discovery and development. Automated electrophysiological patch clamp allows assessment of hERG channel effects early in drug development to aid medicinal chemistry programs and has become routine in pharmaceutical companies. However, a number of potential sources of errors in setting up hERG channel assays by automated patch clamp can lead to misinterpretation of data or false effects being reported. This article describes protocols for automated electrophysiology screening of compound effects on the hERG channel current. Protocol details and the translation of criteria known from manual patch clamp experiments to automated patch clamp experiments to achieve good quality data are emphasized. Typical pitfalls and artifacts that may lead to misinterpretation of data are discussed. While this article focuses on hERG channel recordings using the QPatch (Sophion A/S, Copenhagen, Denmark) technology, many of the assay and protocol details given in this article can be transferred for setting up different ion channel assays by automated patch clamp and are similar on other planar patch clamp platforms. PMID:25228880

  14. Pred-hERG: A Novel web-Accessible Computational Tool for Predicting Cardiac Toxicity.

    PubMed

    Braga, Rodolpho C; Alves, Vinicius M; Silva, Meryck F B; Muratov, Eugene; Fourches, Denis; Lião, Luciano M; Tropsha, Alexander; Andrade, Carolina H

    2015-10-01

    The blockage of the hERG K(+) channels is closely associated with lethal cardiac arrhythmia. The notorious ligand promiscuity of this channel earmarked hERG as one of the most important antitargets to be considered in early stages of drug development process. Herein we report on the development of an innovative and freely accessible web server for early identification of putative hERG blockers and non-blockers in chemical libraries. We have collected the largest publicly available curated hERG dataset of 5,984 compounds. We succeed in developing robust and externally predictive binary (CCR≈0.8) and multiclass models (accuracy≈0.7). These models are available as a web-service freely available for public at http://labmol.farmacia.ufg.br/predherg/. Three following outcomes are available for the users: prediction by binary model, prediction by multi-class model, and the probability maps of atomic contribution. The Pred-hERG will be continuously updated and upgraded as new information became available.

  15. ERG promotes the maintenance of hematopoietic stem cells by restricting their differentiation

    PubMed Central

    Knudsen, Kasper Jermiin; Rehn, Matilda; Hasemann, Marie Sigurd; Rapin, Nicolas; Bagger, Frederik Otzen; Ohlsson, Ewa; Willer, Anton; Frank, Anne-Katrine; Søndergaard, Elisabeth; Jendholm, Johan; Thorén, Lina; Lee, Julie; Rak, Justyna; Theilgaard-Mönch, Kim; Porse, Bo Torben

    2015-01-01

    The balance between self-renewal and differentiation is crucial for the maintenance of hematopoietic stem cells (HSCs). Whereas numerous gene regulatory factors have been shown to control HSC self-renewal or drive their differentiation, we have relatively few insights into transcription factors that serve to restrict HSC differentiation. In the present work, we identify ETS (E-twenty-six)-related gene (ERG) as a critical factor protecting HSCs from differentiation. Specifically, loss of Erg accelerates HSC differentiation by >20-fold, thus leading to rapid depletion of immunophenotypic and functional HSCs. Molecularly, we could demonstrate that ERG, in addition to promoting the expression of HSC self-renewal genes, also represses a group of MYC targets, thereby explaining why Erg loss closely mimics Myc overexpression. Consistently, the BET domain inhibitor CPI-203, known to repress Myc expression, confers a partial phenotypic rescue. In summary, ERG plays a critical role in coordinating the balance between self-renewal and differentiation of HSCs. PMID:26385962

  16. Effects of common antitussive drugs on the hERG potassium channel current.

    PubMed

    Deisemann, Heike; Ahrens, Nadine; Schlobohm, Irene; Kirchhoff, Christian; Netzer, Rainer; Möller, Clemens

    2008-12-01

    A common over-the-counter (OTC) non-opioid antitussive drug, clobutinol, was recently withdrawn from the market due to its potential to induce cardiac arrhythmias by a blockade of the potassium channel coded by the human ether-à-go-go-related gene (hERG). In this study, we investigated the effects of a number of antitussive compounds on the hERG ion channel current using patch-clamp electrophysiology, and compared the effects to that of clobutinol. The compounds clobutinol, pentoxyverine, dextromethorphan, and codeine inhibited the outward current in hERG transfected cells with half-maximal inhibition concentrations (IC50) of 1.9 microM, 3.0 microM, 5.1 microM, and 97 microM, respectively. For theobromine, no significant effect on the hERG current at a concentration up to 100 microM was detected. Safety margins between the effects of the drugs on the hERG ion channel current and their calculated maximal free therapeutic plasma concentration were calculated. These results were compared to assess potential risks of the compounds to induce torsade de pointes-type arrhythmias. PMID:19034038

  17. AMINO ACID ANALYSES OF THE ANTARCTIC CM2 METEORITES ALH 83100 AND LEW 90500 USING LIQUID CHROMATOGRAPHY-TIME OF FLIGHT-MASS SPECTROMETRY

    NASA Technical Reports Server (NTRS)

    Glavin, D. P.; Dworkin, J. P.; Aubrey, A.; Botta, O.; Doty, J. H., III; Bada, J. L.

    2001-01-01

    The investigation of organic compounds in primitive carbonaceous meteorites provides a record of the chemical processes that occurred in the early solar system. In particular, amino acids have been shown to be potential indicators in tracing the nature of carbonaceous chondrite parent bodies [ 13. The delivery of amino acids by carbonaceous chondrites to the early Earth could have been any important source of the Earth's prebiotic organic inventory [2]. Over 80 different amino acids have been detected in the Murchison CM2 meteorite, most of them completely non-existent in the terrestrial biosphere [3]. We have optimized a new liquid chromatography-time-of-flight-mass spectrometry (LC-ToF-MS) technique coupled with OPAMAC derivatization in order to detect amino acids in meteorite extracts by UV fluorescence and exact mass simultaneously. The detection limit of the LC-ToF-MS instrument for amino acids is at least 3 orders of magnitude lower than traditional GC-MS techniques. Here we report on the first analyses of amino acids and their enantiomeric abundances in the CM2 carbonaceous meteorites ALH 83100, LEW 90500, and Murchison using this new LC-ToF-MS instrument configuration. Amino acid analyses of any kind for the CM meteorite ALH 83100 have not previously been reported.

  18. Tailoring gadolinium-doped ceria-based solid oxide fuel cells to achieve 2 W cm(-2) at 550 °C.

    PubMed

    Lee, Jin Goo; Park, Jeong Ho; Shul, Yong Gun

    2014-06-04

    Low-temperature operation is necessary for next-generation solid oxide fuel cells due to the wide variety of their applications. However, significant increases in the fuel cell losses appear in the low-temperature solid oxide fuel cells, which reduce the cell performance. To overcome this problem, here we report Gd0.1Ce0.9O1.95-based low-temperature solid oxide fuel cells with nanocomposite anode functional layers, thin electrolytes and core/shell fibre-structured Ba0.5Sr0.5Co0.8Fe0.2O3-δ-Gd0.1Ce0.9O1.95 cathodes. In particular, the report describes the use of the advanced electrospinning and Pechini process in the preparation of the core/shell-fibre-structured cathodes. The fuel cells show a very high performance of 2 W cm(-2) at 550 °C in hydrogen, and are stable for 300 h even under the high current density of 1 A cm(-2). Hence, the results suggest that stable and high-performance solid oxide fuel cells at low temperatures can be achieved by modifying the microstructures of solid oxide fuel cell components.

  19. Current density and catalyst-coated membrane resistance distribution of hydro-formed metallic bipolar plate fuel cell short stack with 250 cm2 active area

    NASA Astrophysics Data System (ADS)

    Haase, S.; Moser, M.; Hirschfeld, J. A.; Jozwiak, K.

    2016-01-01

    An automotive fuel cell with an active area of 250 cm2 is investigated in a 4-cell short stack with a current and temperature distribution device next to the bipolar plate with 560 current and 140 temperature segments. The electrical conductivities of the bipolar plate and gas diffusion layer assembly are determined ex-situ with this current scan shunt module. The applied fuel cell consists of bipolar plates constructed of 75-μm-thick, welded stainless-steel foils and a graphitic coating. The electrical conductivities of the bipolar plate and gas diffusion layer assembly are determined ex-situ with this module with a 6% deviation in in-plane conductivity. The current density distribution is evaluated up to 2.4 A cm-2. The entire cell's investigated volumetric power density is 4.7 kW l-1, and its gravimetric power density is 4.3 kW kg-1 at an average cell voltage of 0.5 V. The current density distribution is determined without influencing the operating cell. In addition, the current density distribution in the catalyst-coated membrane and its effective resistivity distribution with a finite volume discretisation of Ohm's law are evaluated. The deviation between the current density distributions in the catalyst-coated membrane and the bipolar plate is determined.

  20. Comparison of 10,11-Dehydrocurvularin Polyketide Synthases from Alternaria cinerariae and Aspergillus terreus Highlights Key Structural Motifs.

    PubMed

    Cochrane, Rachel V K; Gao, Zhizeng; Lambkin, Gareth R; Xu, Wei; Winter, Jaclyn M; Marcus, Sandra L; Tang, Yi; Vederas, John C

    2015-11-01

    Iterative type I polyketide synthases (PKSs) from fungi are multifunctional enzymes that use their active sites repeatedly in a highly ordered sequence to assemble complex natural products. A phytotoxic macrolide with anticancer properties, 10,11-dehydrocurvularin (DHC), is produced by cooperation of a highly reducing (HR) iterative PKS and a non-reducing (NR) iterative PKS. We have identified the DHC gene cluster in Alternaria cinerariae, heterologously expressed the active HR PKS (Dhc3) and NR PKS (Dhc5) in yeast, and compared them to corresponding proteins that make DHC in Aspergillus terreus. Phylogenetic analysis and homology modeling of these enzymes identified variable surfaces and conserved motifs that are implicated in product formation.

  1. Absolute frequency list of the ν3-band transitions of methane at a relative uncertainty level of 10(-11).

    PubMed

    Okubo, Sho; Nakayama, Hirotaka; Iwakuni, Kana; Inaba, Hajime; Sasada, Hiroyuki

    2011-11-21

    We determine the absolute frequencies of 56 rotation-vibration transitions of the ν(3) band of CH(4) from 88.2 to 90.5 THz with a typical uncertainty of 2 kHz corresponding to a relative uncertainty of 2.2 × 10(-11) over an average time of a few hundred seconds. Saturated absorption lines are observed using a difference-frequency-generation source and a cavity-enhanced absorption cell, and the transition frequencies are measured with a fiber-laser-based optical frequency comb referenced to a rubidium atomic clock linked to the international atomic time. The determined value of the P(7) F(2)((2)) line is consistent with the International Committee for Weights and Measures recommendation within the uncertainty.

  2. A longitudinal study of grapheme-color synesthesia in childhood: 6/7 years to 10/11 years

    PubMed Central

    Simner, Julia; Bain, Angela E.

    2013-01-01

    Grapheme-color synesthesia is a condition characterized by enduring and consistent associations between letter/digits and colors. This study is the continuation of longitudinal research begun by Simner et al. (2009) which aimed to explore the development of this condition in real time within a childhood population. In that earlier study we randomly sampled over 600 children and tested them aged 6/7 and 7/8 years. We identified the child synesthetes within that cohort and measured their development over 1 year, in comparison to a group of non-synesthetic children with both average and superior memories. We were able to show the beginnings of a developmental progression in which synesthetic associations (e.g., A = red) mature over time from relatively chaotic pairings into a system of fixed consistent associations. In the current study we return to this same population three years later when participants are now 10/11 years. We used the same paired-association memory task to determine the synesthetic status of our participants and to also establish synesthetes' inventories of grapheme-color associations. We compared their inventories to those from age 6/7 and 7/8 years to examine how synesthesia matures over time. Together with earlier findings, our study shows that grapheme-color synesthesia emerges with a protracted trajectory, with 34% of letters/digits fixed at age 6/7 years, 48% fixed at 7/8 years and 71% fixed at 10/11 years. We also show several cases where synesthesia is not developing in the same time-frame as peers, either because it has died out at an older age, or because it was slower to develop than other cases. Our study paints the first picture of the emergence of synesthesia in real-time over four years within a randomly sampled population of child synesthetes. PMID:24312035

  3. A longitudinal study of grapheme-color synesthesia in childhood: 6/7 years to 10/11 years.

    PubMed

    Simner, Julia; Bain, Angela E

    2013-01-01

    Grapheme-color synesthesia is a condition characterized by enduring and consistent associations between letter/digits and colors. This study is the continuation of longitudinal research begun by Simner et al. (2009) which aimed to explore the development of this condition in real time within a childhood population. In that earlier study we randomly sampled over 600 children and tested them aged 6/7 and 7/8 years. We identified the child synesthetes within that cohort and measured their development over 1 year, in comparison to a group of non-synesthetic children with both average and superior memories. We were able to show the beginnings of a developmental progression in which synesthetic associations (e.g., A = red) mature over time from relatively chaotic pairings into a system of fixed consistent associations. In the current study we return to this same population three years later when participants are now 10/11 years. We used the same paired-association memory task to determine the synesthetic status of our participants and to also establish synesthetes' inventories of grapheme-color associations. We compared their inventories to those from age 6/7 and 7/8 years to examine how synesthesia matures over time. Together with earlier findings, our study shows that grapheme-color synesthesia emerges with a protracted trajectory, with 34% of letters/digits fixed at age 6/7 years, 48% fixed at 7/8 years and 71% fixed at 10/11 years. We also show several cases where synesthesia is not developing in the same time-frame as peers, either because it has died out at an older age, or because it was slower to develop than other cases. Our study paints the first picture of the emergence of synesthesia in real-time over four years within a randomly sampled population of child synesthetes.

  4. Speculations on a relativistic strong focusing self-collider with very high luminosity (≥10 40 cm -2s -1): Macroproduction of antinuclei and other micro cross section events and formation of ambiplasma

    NASA Astrophysics Data System (ADS)

    Maglich, Bogdan C.

    1988-08-01

    The luminosity of the weak focusing self-collider (ESCOL) is intrinsically 10 8-10 10 times greater than that of conventional colliding beams, due to the product of the solid angle factor, ˜10 6, and the neutralization factor, ˜10 2 -10 4. We extrapolate to 10-GeV protons the parameters of a recent low energy experiment demonstrating that a 1-MeV deuteron beam, stored in ESCOL as migma, can be neutralized bo oscillating electrons and operate an order of magnitude above the space charge limit without instabilities. With the number density achieved in ESCOL, n = 3.2 × 10 9 ions cm -3, such a relativistic strong focusing self-collider (XYDER) would have a luminosity L ˜ 10 38 cm -2 s -1 for 10-GeV-on-10-GeV protons (equivalent to 250 GeV beam-on-target). At the diamagnetic "limit" density, which for 10 tesla is n = 10 12 ions cm -3, l ˜ 10 43 cm -2 s -1; this would produce 4 × 10 16 antiprotons/s (2 gram of overlinep/year). Other particles, rare nuclei, and rare effects produced with micro- (10 -16), nano- (10 -9 b), and picoscopic (10 -12 b) cross sections will be macro-produced in XYDER. A newly proposed annular magnet would provide a large volume of stored, V = 10 9 cm 3, as well as automatic ejection along the +z and -z axes of the overlinep's and other particles whose momentum is lower than that of the primary proton migma. Antiprotons, being produced with low rapidity, will have energies below 1 GeV in COM, and thus are suitable for beaming, extraction, cooling, abd slowing down to be either stored for space propulsion or used as a source for acceleration. If the magnetic field strength is adjusted for the antiprotons to be confined, an unusual plasma will be formed, consisting of the protons, antiprotons, electrons, and positrons (from pion-muon-electron decays), and similar to Alfvèns "ambiplasman". Its plasmic beta will be unity already at low densities (˜10 11 cm -3 where ωpi/ ωci ≤ 1); the ion-to-electron "temperature" ratio will never achieve

  5. hERG potassium channels and the structural basis of drug-induced arrhythmias.

    PubMed

    Mitcheson, John S

    2008-05-01

    hERG potassium channels have a critical role in the normal electrical activity of the heart. The block of hERG channels can cause the drug-induced form of long QT syndrome, a cardiac disorder that carries an increased risk of cardiac arrhythmias and sudden death. hERG channels are extraordinarily sensitive to block by large numbers of structurally diverse drugs. In previous years, the risk of compounds causing this cardiotoxic side effect has been a common reason for the failure of compounds in preclinical safety trials. Pharmaceutical companies have successfully utilized and developed higher throughput techniques for the early detection of compounds that block hERG, and this has helped reduce the number of compounds that fail in the late stages of development. Nevertheless, this screening-based approach is expensive, consumes chemistry resources, and bypasses the problem rather than shedding light on it. Crystal structures of potassium channels have facilitated studies into the structural basis for the gating and block of hERG channels. Most drugs bind within the inner cavity, and the individual amino acids that form the drug binding site have been identified by site-directed mutagenesis approaches. Gating processes have an important influence on the drug-binding site. Recent advances in our understanding of channel activation and inactivation are providing insight into why hERG channels are more susceptible to block than other K (+) channels. Knowledge of the structure of the drug-binding site and precise nature of interactions with drug molecules should assist efforts to develop drugs without the propensity to cause cardiac arrhythmias. PMID:18447395

  6. External protons destabilize the activated voltage sensor in hERG channels.

    PubMed

    Shi, Yu Patrick; Cheng, Yen May; Van Slyke, Aaron C; Claydon, Tom W

    2014-03-01

    Extracellular acidosis shifts hERG channel activation to more depolarized potentials and accelerates channel deactivation; however, the mechanisms underlying these effects are unclear. External divalent cations, e.g., Ca(2+) and Cd(2+), mimic these effects and coordinate within a metal ion binding pocket composed of three acidic residues in hERG: D456 and D460 in S2 and D509 in S3. A common mechanism may underlie divalent cation and proton effects on hERG gating. Using two-electrode voltage clamp, we show proton sensitivity of hERG channel activation (pKa = 5.6), but not deactivation, was greatly reduced in the presence of Cd(2+) (0.1 mM), suggesting a common binding site for the Cd(2+) and proton effect on activation and separable effects of protons on activation and deactivation. Mutational analysis confirmed that D509 plays a critical role in the pH dependence of activation, as shown previously, and that cooperative actions involving D456 and D460 are also required. Importantly, neutralization of all three acidic residues abolished the proton-induced shift of activation, suggesting that the metal ion binding pocket alone accounts for the effects of protons on hERG channel activation. Voltage-clamp fluorimetry measurements demonstrated that protons shifted the voltage dependence of S4 movement to more depolarized potentials. The data indicate a site and mechanism of action for protons on hERG activation gating; protonation of D456, D460 and D509 disrupts interactions between these residues and S4 gating charges to destabilize the activated configuration of S4.

  7. The oxygen isotope evolution of parent body aqueous solutions as recorded by multiple carbonate generations in the Lonewolf Nunataks 94101 CM2 carbonaceous chondrite

    NASA Astrophysics Data System (ADS)

    Lee, M. R.; Sofe, M. R.; Lindgren, P.; Starkey, N. A.; Franchi, I. A.

    2013-11-01

    The CM2 carbonaceous chondrite LON 94101 contains aragonite and two generations of calcite that provide snapshots of the chemical and isotopic evolution of aqueous solutions during parent body alteration. Aragonite was the first carbonate to crystallize. It is rare, heterogeneously distributed within the meteorite matrix, and its mean oxygen isotope values are δ18O 39.9 ± 0.6‰, Δ17O -0.3 ± 1.0‰ (1σ). Calcite precipitated soon afterwards, and following a fall in solution Mg/Ca ratios, to produce small equant grains with a mean oxygen isotope value of δ18O 37.5 ± 0.7‰, Δ17O 1.4 ± 1.1‰ (1σ). These grains were partially or completely replaced by serpentine and tochilinite prior to precipitation of the second generation of calcite, which occluded an open fracture to form a millimetre-sized vein, and replaced anhydrous silicates within chondrules and the matrix. The vein calcite has a mean composition of δ18O 18.4 ± 0.3‰, Δ17O -0.5 ± 0.5‰ (1σ). Petrographic and isotopic results therefore reveal two discrete episodes of mineralisation that produced calcite generations with contrasting δ18O, and mean Δ17O values. The aragonite and equant calcite crystallized over a relatively brief period early in the aqueous alteration history of the parent body, and from static fluids that were evolving chemically in response to mineral dissolution and precipitation. The second calcite generation crystallized from solutions of a lower Δ17O, and a lower δ18O and/or higher temperature. As two generations of calcite whose petrographic characteristics and oxygen isotopic compositions are similar to those in LON 94101 occur in at least one other CM2, multiphase carbonate mineralisation could be the typical outcome of the sequence of chemical reactions during parent body aqueous alteration. It is equally possible however that the second generation of calcite formed in response to an event such as impact fracturing and concomitant fluid mobilisation that affected

  8. Three-dimensional nanostructured bilayer solid oxide fuel cell with 1.3 W/cm(2) at 450 °C.

    PubMed

    An, Jihwan; Kim, Young-Beom; Park, Joonsuk; Gür, Turgut M; Prinz, Fritz B

    2013-09-11

    Obtaining high power density at low operating temperatures has been an ongoing challenge in solid oxide fuel cells (SOFC), which are efficient engines to generate electrical energy from fuels. Here we report successful demonstration of a thin-film three-dimensional (3-D) SOFC architecture achieving a peak power density of 1.3 W/cm(2) obtained at 450 °C. This is made possible by nanostructuring of the ultrathin (60 nm) electrolyte interposed with a nanogranular catalytic interlayer at the cathode/electrolyte interface. We attribute the superior cell performance to significant reduction in both the ohmic and the polarization losses due to the combined effects of employing an ultrathin film electrolyte, enhancement of effective area by 3-D architecture, and superior catalytic activity by the ceria-based interlayer at the cathode. These insights will help design high-efficiency SOFCs that operate at low temperatures with power densities that are of practical significance.

  9. X-Ray Radiation Measurements With Photodiodes In Plasmas Generated By 1017 W/Cm2 Intensity Krf Excimer Laser Pulses

    NASA Astrophysics Data System (ADS)

    Rácz, E.; Földes, I. B.; Ryć, L.

    2006-01-01

    Experiments were carried out using a prepulse-free hybrid KrF excimer-dye laser system (700fs pulse duration, 248nm wavelength, 15mJ pulse energy). The intensity of the p-polarized, focused laser beam was 1.5ṡ1017 W/cm2. Vacuum ultraviolet (VUV) and x-rays from solid state laser plasmas were generated in the laser-plasma interaction of subpicosecond laser pulses of nonrelativistic laser intensities. An x-ray sensitive FLM photodiode (ITE, Warsaw) was used to detect x-rays between 1-19 keV in front of the targets. The diode was filtered by a 4μm Al foil. The dependence of the x-ray flux on laser intensity and the angular distribution of x-rays for aluminum and copper targets in the half space of the front side of the targets were investigated.

  10. Compositions of Partly Altered Olivine and Replacement Serpentine in the CM2 Chondrites QUE93005 and Nogoya: Implications for Scales of Elemental Redistribution During Aqueous Alteration

    NASA Technical Reports Server (NTRS)

    Velbel, M. A.; Tonui, E. K.; Zolensky, M. E.

    2003-01-01

    Some phyllosilicates in CM carbonaceous chondrites formed by aqueous alteration of anhydrous precursor phases. Although broad trends in the compositions of hydrous phyllosilicates are recognized and believed to be related to trends in degree of aqueous alteration, details of the reactions that formed specific secondary minerals remain obscure. This paper reports compositional relationships between remnants of partially pseudomorphically replaced silicates and their alteration products (serpentine) in the CM2 chondrites QUE93005 and Nogoya and compares both with previously published results for Allan Hills 81002. By focusing on serpentine formed from known reactants (olivines), and on only those instances in which some of the reactant silicate remains, direct compositional relationships between reactants and products, and the elemental mobility required by the reactions, can be established.

  11. Microfluidic Cell Culture and Its Application in High Throughput Drug Screening: Cardiotoxicity Assay for hERG Channels

    PubMed Central

    Su, Xiaojing; Young, Edmond W.K.; Underkofler, Heather A. S.; Kamp, Timothy J.; January, Craig T.; Beebe, David J.

    2011-01-01

    Evaluation of drug cardiotoxicity is essential to the safe development of novel pharmaceuticals. Assessing a compound's risk for prolongation of the surface electrocardiographic QT interval, and hence risk for life threatening arrhythmias is mandated before approval of nearly all new pharmaceuticals. QT prolongation has most commonly been associated with loss of current through hERG (human ether-a-go-go related gene) potassium ion channels due to direct block of the ion channel by drugs or occasionally by inhibition of the plasma membrane expression of the channel protein. To develop an efficient, reliable, and cost-effective hERG screening assay for detecting drug-mediated disruption of hERG membrane trafficking, we demonstrate the use of microfluidic-based systems to improve throughput and lower cost of current methods. We validate our microfluidics array platform in polystyrene (PS), cyclo-olefin polymer (COP) and poly(dimethylsiloxane) (PDMS) microchannels for drug-induced disruption of hERG trafficking by culturing stably transfected HEK cells that overexpressed hERG (WT-hERG), and studying their morphology, proliferation rates, hERG protein expression, and response to drug treatment. Our results show that WT-hERG cells readily proliferate in PS, COP, and PDMS microfluidic channels. We demonstrated that conventional Western blot analysis was possible using cell lysate extracted from a single microchannel. The Western blot analysis also provided important evidence that WT-hERG cells cultured in microchannels maintained regular (well plate-based) expression of hERG. We further showed that experimental procedures can be streamlined by using direct in-channel immunofluorescent staining in conjunction with detection using an infrared scanner. Finally, treatment of WT-hERG cells with five different drugs suggested that PS (and COP) microchannels were more suitable than PDMS microchannels for drug screening applications, particularly for tests involving hydrophobic

  12. Multispacecraft study on the dynamics of the dusk-flank magnetosphere under northward IMF: 10-11 January 1997

    NASA Astrophysics Data System (ADS)

    Stenuit, H.; Fujimoto, M.; Fuselier, S. A.; Sauvaud, J.-A.; Wing, S.; Fedorov, A.; Budnik, E.; Savin, S. P.; Trattner, K. J.; Angelopoulos, V.; Bonnell, J.; Phan, T. D.; Mukai, T.; Pedersen, A.

    2002-10-01

    The latter half of the magnetic cloud event on 10-11 January 1997 is studied in the context of the cold-dense plasma sheet. A fortuitous distribution of spacecraft in key regions allows us to relate the plasma sheet status transition with the boundary layer process. When the interplanetary magnetic field (IMF) was strongly northward and the solar wind density returned to a nominal value from an anomalously large one, two spacecraft, Geotail and Interball-Tail, were in the dusk-flank region and detected a change in the plasma sheet status from hot and tenuous to cold and dense. The change seen by these spacecraft making in situ observations is confirmed to be a global feature by DMSP observations at low altitude. Just around this time, Interball-Aurora and Polar were crossing the dusk-auroral oval, monitoring globally the dynamics of the dusk-flank magnetopause at its footpoint. Injection of magnetosheath-like ions was detected by these spacecraft. We try to relate these observations with the processes that transport the magnetosheath plasma onto the magnetospheric field lines. Three candidate processes are discussed, but none of them turn out to be convincing, indicating the need for further study on this issue.

  13. False carbamazepine positives due to 10,11-dihydro-10-hydroxycarbamazepine breakdown in the GC-MS injector port.

    PubMed

    Lewis, Russell J; Angier, Mike K; Johnson, Robert D

    2014-10-01

    During the investigation of aviation accidents, postmortem specimens from accident victims are submitted to the Federal Aviation Administration's Civil Aerospace Medical Institute (CAMI) for toxicological analysis. A case recently received by CAMI screened positive for the anticonvulsant medication carbamazepine (CBZ; Tegretol(®)) by gas chromatography-mass spectrometry (GC-MS). The CBZ found during this routine screening procedure was subsequently confirmed using a CBZ-specific GC-MS procedure. It was later discovered that the accident victim had been prescribed oxcarbazepine (OXCBZ; Trileptal(®)). OXCBZ is structurally similar to CBZ and is metabolized by cytosolic enzymes in the liver to an active metabolite, 10,11-dihydro-10-hydroxycarbamazepine (DiCBZ). It was determined that the CBZ initially found in this case was present due to the thermal breakdown of DiCBZ in the GC-MS injector port. In the current study, this conversion was investigated and the percentage of CBZ formed at various injector port temperatures was determined. Additionally, these three compounds were quantified in nine fluid and tissue specimens from the case in question. Liquid chromatography-mass spectrometry was also incorporated to further demonstrate the absence/presence of CBZ in these samples.

  14. Second European Round Table on the Future Management of HIV: 10-11 October 2014, Barcelona, Spain.

    PubMed

    Rokx, Casper; Richman, Douglas D; Müller-Trutwin, Michaela; Silvestri, Guido; Lunzen, Jan; Khoo, Saye; Lichterfeld, Mathias; Altfeld, Marcus; Perno, Carlo Federico; Hunt, Peter W; Mallon, Paddy; Rockstroh, Jürgen K; Pozniak, Anton L; Clotet, Bonaventura; Boucher, Charles Ab

    2015-07-01

    The Second European Round Table on the Future Management of HIV took place in Barcelona, 10-11 October 2014 and focused on the HIV-1 reservoir, strategies for HIV cure and primary HIV infection (PHI). Important issues in the HIV-1 reservoir research field are the validity of reservoir measurement techniques and the potential of new drugs to target latently infected cells. Current HIV-1 cure concepts are based on theoretical assumptions of biologically plausible mechanisms, supported by several clinical observations. Three main potential strategies are under investigation in order to achieve a sterilising cure or maintain HIV-1 remission: latency reversal resulting in antigen expression and viral cytolysis or immune targeted cell-death; immunological control of the reservoir; or replacement of the complete autologous haematopoietic and lymphoid stem-cell repertoire by transplantation. An interesting opportunity for restricting the size of the reservoir entails the early initiation of antiretroviral treatment (ART) during PHI. In terms of the reservoir, early treatment limits its size, alters its composition, and restricts the genetic variability of integrated proviral HIV-1 DNA. The challenges ahead involve the identification of patients undergoing seroconversion to HIV-1 and the prompt initiation of treatment. How the seemingly beneficial impact of early treatment will make cure more feasible, and whether the positive effects of the cure efforts outweigh the potentially negative impact of life-long ART, are important aspects of future collaborative research prospects.

  15. Second European Round Table on the Future Management of HIV: 10-11 October 2014, Barcelona, Spain.

    PubMed

    Rokx, Casper; Richman, Douglas D; Müller-Trutwin, Michaela; Silvestri, Guido; Lunzen, Jan; Khoo, Saye; Lichterfeld, Mathias; Altfeld, Marcus; Perno, Carlo Federico; Hunt, Peter W; Mallon, Paddy; Rockstroh, Jürgen K; Pozniak, Anton L; Clotet, Bonaventura; Boucher, Charles Ab

    2015-01-01

    The Second European Round Table on the Future Management of HIV took place in Barcelona, 10-11 October 2014 and focused on the HIV-1 reservoir, strategies for HIV cure and primary HIV infection (PHI). Important issues in the HIV-1 reservoir research field are the validity of reservoir measurement techniques and the potential of new drugs to target latently infected cells. Current HIV-1 cure concepts are based on theoretical assumptions of biologically plausible mechanisms, supported by several clinical observations. Three main potential strategies are under investigation in order to achieve a sterilising cure or maintain HIV-1 remission: latency reversal resulting in antigen expression and viral cytolysis or immune targeted cell-death; immunological control of the reservoir; or replacement of the complete autologous haematopoietic and lymphoid stem-cell repertoire by transplantation. An interesting opportunity for restricting the size of the reservoir entails the early initiation of antiretroviral treatment (ART) during PHI. In terms of the reservoir, early treatment limits its size, alters its composition, and restricts the genetic variability of integrated proviral HIV-1 DNA. The challenges ahead involve the identification of patients undergoing seroconversion to HIV-1 and the prompt initiation of treatment. How the seemingly beneficial impact of early treatment will make cure more feasible, and whether the positive effects of the cure efforts outweigh the potentially negative impact of life-long ART, are important aspects of future collaborative research prospects. PMID:27482415

  16. Quantitative Gene Expression of ERG9 in Model Saccharomyces cerevisiae: Chamomile Extract For Human Cancer Treatment

    PubMed Central

    Hosseinpour, Maryam; Mobini-Dehkordi, Mohsen

    2016-01-01

    Introduction Over expression of squalene synthase gene causes induction of growth tumour and reduction of apoptosis. This gene which is conserved between Saccharomyces cerevisiae yeast and humans, is named (ERG9). Aim In this work, we studied the effect of Matricaria recutita extract on ERG9 gene (squalene synthase) expression in S.cerevisiae which was used as organism model in cancer therapy. Materials and Methods S. cerevisiae was cultured in YPD medium plus 0,250, 1000 and 3000 μg/ml of Matricaria recutita extract and we evaluated the (ERG9) gene expression by Real-time RT-PCR method after 24 hours. Statistical analysis used At least 3 independent experiments were done. Data were analyzed using One-way ANOVA and Dunnett’s test. A p-value of less than 0.01 was considered as significant. Results We found that 250, 1000 and 3000 μg/ml of Matricaria recutita extract could reduce expression of ERG9 gene significantly (p<0.01). Interestingly, the expression of this gene was completely inhibited in 1000 and 3000 μg/ml concentrations. Conclusion This study predicted that Matricaria recutita extract produced anti-cancer effects in humans, because it could inhibit the expression of an analogue key gene in this malignant disease. Further investigations should be made, to study its molecular mechanism of action at the mammal cell level.

  17. Quantitative Gene Expression of ERG9 in Model Saccharomyces cerevisiae: Chamomile Extract For Human Cancer Treatment

    PubMed Central

    Hosseinpour, Maryam; Mobini-Dehkordi, Mohsen

    2016-01-01

    Introduction Over expression of squalene synthase gene causes induction of growth tumour and reduction of apoptosis. This gene which is conserved between Saccharomyces cerevisiae yeast and humans, is named (ERG9). Aim In this work, we studied the effect of Matricaria recutita extract on ERG9 gene (squalene synthase) expression in S.cerevisiae which was used as organism model in cancer therapy. Materials and Methods S. cerevisiae was cultured in YPD medium plus 0,250, 1000 and 3000 μg/ml of Matricaria recutita extract and we evaluated the (ERG9) gene expression by Real-time RT-PCR method after 24 hours. Statistical analysis used At least 3 independent experiments were done. Data were analyzed using One-way ANOVA and Dunnett’s test. A p-value of less than 0.01 was considered as significant. Results We found that 250, 1000 and 3000 μg/ml of Matricaria recutita extract could reduce expression of ERG9 gene significantly (p<0.01). Interestingly, the expression of this gene was completely inhibited in 1000 and 3000 μg/ml concentrations. Conclusion This study predicted that Matricaria recutita extract produced anti-cancer effects in humans, because it could inhibit the expression of an analogue key gene in this malignant disease. Further investigations should be made, to study its molecular mechanism of action at the mammal cell level. PMID:27630863

  18. Role of the pH in state-dependent blockade of hERG currents

    NASA Astrophysics Data System (ADS)

    Wang, Yibo; Guo, Jiqing; Perissinotti, Laura L.; Lees-Miller, James; Teng, Guoqi; Durdagi, Serdar; Duff, Henry J.; Noskov, Sergei Yu.

    2016-10-01

    Mutations that reduce inactivation of the voltage-gated Kv11.1 potassium channel (hERG) reduce binding for a number of blockers. State specific block of the inactivated state of hERG block may increase risks of drug-induced Torsade de pointes. In this study, molecular simulations of dofetilide binding to the previously developed and experimentally validated models of the hERG channel in open and open-inactivated states were combined with voltage-clamp experiments to unravel the mechanism(s) of state-dependent blockade. The computations of the free energy profiles associated with the drug block to its binding pocket in the intra-cavitary site display startling differences in the open and open-inactivated states of the channel. It was also found that drug ionization may play a crucial role in preferential targeting to the open-inactivated state of the pore domain. pH-dependent hERG blockade by dofetilie was studied with patch-clamp recordings. The results show that low pH increases the extent and speed of drug-induced block. Both experimental and computational findings indicate that binding to the open-inactivated state is of key importance to our understanding of the dofetilide’s mode of action.

  19. Role of the pH in state-dependent blockade of hERG currents

    PubMed Central

    Wang, Yibo; Guo, Jiqing; Perissinotti, Laura L.; Lees-Miller, James; Teng, Guoqi; Durdagi, Serdar; Duff, Henry J.; Noskov, Sergei Yu.

    2016-01-01

    Mutations that reduce inactivation of the voltage-gated Kv11.1 potassium channel (hERG) reduce binding for a number of blockers. State specific block of the inactivated state of hERG block may increase risks of drug-induced Torsade de pointes. In this study, molecular simulations of dofetilide binding to the previously developed and experimentally validated models of the hERG channel in open and open-inactivated states were combined with voltage-clamp experiments to unravel the mechanism(s) of state-dependent blockade. The computations of the free energy profiles associated with the drug block to its binding pocket in the intra-cavitary site display startling differences in the open and open-inactivated states of the channel. It was also found that drug ionization may play a crucial role in preferential targeting to the open-inactivated state of the pore domain. pH-dependent hERG blockade by dofetilie was studied with patch-clamp recordings. The results show that low pH increases the extent and speed of drug-induced block. Both experimental and computational findings indicate that binding to the open-inactivated state is of key importance to our understanding of the dofetilide’s mode of action. PMID:27731415

  20. ERG--Energy Resources Game: Simulation Gaming of Regional Energy Management

    ERIC Educational Resources Information Center

    Wolf, Lyle P.; Laessig, Robert E.

    1973-01-01

    ERG--the Energy Resources Game--is a computer based game which explores questions regarding regional energy supply and demand, such as population and economic growth goals; acceptable levels of dependence on imported energy; and acceptable levels of environmental impact. (JA)

  1. Effect of Voriconazole on Candida tropicalis Biofilms: Relation with ERG Genes Expression.

    PubMed

    Fernandes, Tânia; Silva, Sónia; Henriques, Mariana

    2016-10-01

    Candida tropicalis has emerged as the third most prevalent fungal pathogens and its ability to form biofilms has been considered one of the most important virulence factors, since biofilms represent high tolerance to antifungal agents. However, the mechanisms of C. tropicalis biofilm resistance to antifungals remain poorly understood. Thus, the main aim of this work was to infer about the effect of voriconazole on the formation and control of C. tropicalis biofilms and disclose its relationship with ERG genes' expression. Planktonic cells tolerance of several C. tropicalis clinical isolates to voriconazole was determined through of antifungal susceptibility test, and the effect of this azole against C. tropicalis biofilm formation and pre-formed biofilms was evaluated by cultivable cells determination and total biomass quantification. ERG genes expression was analyzed by quantitative real-time polymerase chain reaction. This work showed that C. tropicalis resistance to voriconazole is strain dependent and that voriconazole was able to partially control biofilm formation, but was unable to eradicate C. tropicalis pre-formed biofilms. Moreover, C. tropicalis biofilms resistance to voriconazole seems to be associated with alterations of sterol content in the cell membrane, resulting in ERG genes overexpression. Voriconazole is unable to control C. tropicalis biofilms, and the overexpression of ERG genes is a possible mechanism of biofilm resistance. PMID:27260519

  2. Effect of Voriconazole on Candida tropicalis Biofilms: Relation with ERG Genes Expression.

    PubMed

    Fernandes, Tânia; Silva, Sónia; Henriques, Mariana

    2016-10-01

    Candida tropicalis has emerged as the third most prevalent fungal pathogens and its ability to form biofilms has been considered one of the most important virulence factors, since biofilms represent high tolerance to antifungal agents. However, the mechanisms of C. tropicalis biofilm resistance to antifungals remain poorly understood. Thus, the main aim of this work was to infer about the effect of voriconazole on the formation and control of C. tropicalis biofilms and disclose its relationship with ERG genes' expression. Planktonic cells tolerance of several C. tropicalis clinical isolates to voriconazole was determined through of antifungal susceptibility test, and the effect of this azole against C. tropicalis biofilm formation and pre-formed biofilms was evaluated by cultivable cells determination and total biomass quantification. ERG genes expression was analyzed by quantitative real-time polymerase chain reaction. This work showed that C. tropicalis resistance to voriconazole is strain dependent and that voriconazole was able to partially control biofilm formation, but was unable to eradicate C. tropicalis pre-formed biofilms. Moreover, C. tropicalis biofilms resistance to voriconazole seems to be associated with alterations of sterol content in the cell membrane, resulting in ERG genes overexpression. Voriconazole is unable to control C. tropicalis biofilms, and the overexpression of ERG genes is a possible mechanism of biofilm resistance.

  3. Allosteric modulators of the hERG K{sup +} channel

    SciTech Connect

    Yu, Zhiyi Klaasse, Elisabeth Heitman, Laura H. IJzerman, Adriaan P.

    2014-01-01

    Drugs that block the cardiac K{sup +} channel encoded by the human ether-à-go-go gene (hERG) have been associated with QT interval prolongation leading to proarrhythmia, and in some cases, sudden cardiac death. Because of special structural features of the hERG K{sup +} channel, it has become a promiscuous target that interacts with pharmaceuticals of widely varying chemical structures and a reason for concern in the pharmaceutical industry. The structural diversity suggests that multiple binding sites are available on the channel with possible allosteric interactions between them. In the present study, three reference compounds and nine compounds of a previously disclosed series were evaluated for their allosteric effects on the binding of [{sup 3}H]astemizole and [{sup 3}H]dofetilide to the hERG K{sup +} channel. LUF6200 was identified as an allosteric inhibitor in dissociation assays with both radioligands, yielding similar EC{sub 50} values in the low micromolar range. However, potassium ions increased the binding of the two radioligands in a concentration-dependent manner, and their EC{sub 50} values were not significantly different, indicating that potassium ions behaved as allosteric enhancers. Furthermore, addition of potassium ions resulted in a concentration-dependent leftward shift of the LUF6200 response curve, suggesting positive cooperativity and distinct allosteric sites for them. In conclusion, our investigations provide evidence for allosteric modulation of the hERG K{sup +} channel, which is discussed in the light of findings on other ion channels. - Highlights: • Allosteric modulators on the hERG K{sup +} channel were evaluated in binding assays. • LUF6200 was identified as a potent allosteric inhibitor. • Potassium ions were found to behave as allosteric enhancers. • Positive cooperativity and distinct allosteric sites for them were proposed.

  4. Transcription Factor Erg Variants and Functional Diversification of Chondrocytes during Limb Long Bone Development

    PubMed Central

    Iwamoto, Masahiro; Higuchi, Yoshinobu; Koyama, Eiki; Enomoto-Iwamoto, Motomi; Kurisu, Kojiro; Yeh, Helena; Abrams, William R.; Rosenbloom, Joel; Pacifici, Maurizio

    2000-01-01

    During limb development, chondrocytes located at the epiphyseal tip of long bone models give rise to articular tissue, whereas the more numerous chondrocytes in the shaft undergo maturation, hypertrophy, and mineralization and are replaced by bone cells. It is not understood how chondrocytes follow these alternative pathways to distinct fates and functions. In this study we describe the cloning of C-1-1, a novel variant of the ets transcription factor ch-ERG. C-1-1 lacks a short 27–amino acid segment located ∼80 amino acids upstream of the ets DNA binding domain. We found that in chick embryo long bone anlagen, C-1-1 expression characterizes developing articular chondrocytes, whereas ch-ERG expression is particularly prominent in prehypertrophic chondrocytes in the growth plate. To analyze the function of C-1-1 and ch-ERG, viral vectors were used to constitutively express each factor in developing chick leg buds and cultured chondrocytes. We found that virally driven expression of C-1-1 maintained chondrocytes in a stable and immature phenotype, blocked their maturation into hypertrophic cells, and prevented the replacement of cartilage with bone. It also induced synthesis of tenascin-C, an extracellular matrix protein that is a unique product of developing articular chondrocytes. In contrast, virally driven expression of ch-ERG significantly stimulated chondrocyte maturation in culture, as indicated by increases in alkaline phosphatase activity and deposition of a mineralized matrix; however, it had modest effects in vivo. The data show that C-1-1 and ch-ERG have diverse biological properties and distinct expression patterns during skeletogenesis, and are part of molecular mechanisms by which limb chondrocytes follow alternative developmental pathways. C-1-1 is the first transcription factor identified to date that appears to be instrumental in the genesis and function of epiphyseal articular chondrocytes. PMID:10893254

  5. Modified MBE hardware and techniques and role of gallium purity for attainment of two dimensional electron gas mobility >35×106 cm2/V s in AlGaAs/GaAs quantum wells grown by MBE

    NASA Astrophysics Data System (ADS)

    Gardner, Geoffrey C.; Fallahi, Saeed; Watson, John D.; Manfra, Michael J.

    2016-05-01

    We provide evidence that gallium purity is the primary impediment to attainment of ultra-high mobility in a two-dimensional electron gas (2DEG) in AlGaAs/GaAs heterostructures grown by molecular beam epitaxy (MBE). The purity of gallium can be enhanced dramatically by in-situ high temperature outgassing within an operating MBE. Based on analysis of data from an initial growth campaign in a new MBE system and modifications employed for a 2nd growth campaign, we have produced 2DEGs with low temperature mobility μ in excess of 35×106 cm2/V s at density n=3.0×1011/cm2 and μ=18×106 cm2/V s at n=1.1×1011/cm2. Our 2nd campaign data indicate that gallium purity remains the factor currently limiting μ<40×106 cm2/V s. We describe strategies to overcome this limitation.

  6. Knocking Down TMPRSS2-ERG Fusion Oncogene by siRNA Could be an Alternative Treatment to Flutamide.

    PubMed

    Urbinati, Giorgia; de Waziers, Isabelle; Slamiç, Mateja; Foussignière, Tobias; Ali, Hafiz M; Desmaële, Didier; Couvreur, Patrick; Massaad-Massade, Liliane

    2016-01-01

    Our purpose was to develop a new pharmacological approach for the treatment of prostate cancer (PCa), the most common neoplasia in men. Recently, we developed siRNA against the fusion oncogene TMPRSS2-ERG found in 50% of patients and showed an antitumoral activity in animal model. Herein, we want to compare or combine the developed siRNA to flutamide (FLU), one of the gold-standard treatment of PCa. Therefore, concomitant or subsequent association of FLU to siRNA TMPRSS2-ERG was performed in VCaP cells and in SCID mice bearing xenografted VCaP tumors. ERG, androgen receptor, cleaved-caspase-3 as well as phase 1 and 2 drug-metabolizing enzymes were investigated within tumors. We observed similar results in terms of TMPRSS2-ERG knock-down and cell viability impairment for all distinct schedules of administration. The association of siRNA TMPRSS2-ERG-squalene nanoparticles with flutamide displayed similar tumor growth inhibition as mice treated with siRNA TMPRSS2-ERG-squalene nanoparticles alone and was paralleled with modification of expression of ERG, androgen receptor, and cleaved-caspase-3. Phase 1 and 2 enzymes were essentially affected by FLU and reverted when combined with squalenoylated siRNA. In conclusion, these results confirm the therapeutic effectiveness of squalenoyl siRNA nanomedicine for PCa based on siRNA TMPRSS2-ERG. PMID:27023109

  7. Knocking Down TMPRSS2-ERG Fusion Oncogene by siRNA Could be an Alternative Treatment to Flutamide

    PubMed Central

    Urbinati, Giorgia; de Waziers, Isabelle; Slamiç, Mateja; Foussignière, Tobias; Ali, Hafiz M; Desmaële, Didier; Couvreur, Patrick; Massaad-Massade, Liliane

    2016-01-01

    Our purpose was to develop a new pharmacological approach for the treatment of prostate cancer (PCa), the most common neoplasia in men. Recently, we developed siRNA against the fusion oncogene TMPRSS2-ERG found in 50% of patients and showed an antitumoral activity in animal model. Herein, we want to compare or combine the developed siRNA to flutamide (FLU), one of the gold-standard treatment of PCa. Therefore, concomitant or subsequent association of FLU to siRNA TMPRSS2-ERG was performed in VCaP cells and in SCID mice bearing xenografted VCaP tumors. ERG, androgen receptor, cleaved-caspase-3 as well as phase 1 and 2 drug-metabolizing enzymes were investigated within tumors. We observed similar results in terms of TMPRSS2-ERG knock-down and cell viability impairment for all distinct schedules of administration. The association of siRNA TMPRSS2-ERG-squalene nanoparticles with flutamide displayed similar tumor growth inhibition as mice treated with siRNA TMPRSS2-ERG-squalene nanoparticles alone and was paralleled with modification of expression of ERG, androgen receptor, and cleaved-caspase-3. Phase 1 and 2 enzymes were essentially affected by FLU and reverted when combined with squalenoylated siRNA. In conclusion, these results confirm the therapeutic effectiveness of squalenoyl siRNA nanomedicine for PCa based on siRNA TMPRSS2-ERG. PMID:27023109

  8. A physiological basis for definition of the ISCEV ERG standard flash (SF) based on the photopic hill.

    PubMed

    Lachapell, P; Rufiange, M; Dembinska, O

    2001-03-01

    The ISCEV Standard for Clinical Electrophysiology indicates that the ERG standard flash should be defined within a very narrow range of intensities. Yet no information is provided as to how this intensity range was identified. We present evidence that would support a redefinition of the SF based on known photopic ERG properties. PMID:11518458

  9. Unstable nuclei in coherent dissociation of relativistic nuclei 7,9Be, 10B and 10,11C

    NASA Astrophysics Data System (ADS)

    Artemenkov, D. A.; Bradnova, V.; Firu, E.; Kornegrutsa, N. K.; Haiduc, M.; Mamatkulov, K. Z.; Kattabekov, R. R.; Neagu, A.; Rukoyatkin, P. A.; Rusakova, V. V.; Sarkisyan, V. R.; Stanoeva, R.; Zaitsev, A. A.; Zarubin, P. I.; Zarubina, I. G.

    2016-06-01

    Contribution of the unstable nuclei 7Be, 8Be and ®B into coherent dissociation events (“white” stars) of relativistic nuclei 7,9Be, 10B and 10,11C is under study on the basis of a nuclear track emulsion exposed to beams of the JINR Nuclotron. Distributions over the opening angle of α-pairs indicate to a simultaneous presence of virtual 8Beg.s. and 8Be2+ states in the ground states of the 9Be and 10C nuclei. The core 9B is manifested in the 10C nucleus with a probability of (30 ± 4)%, Selection of the 10C “white” stars accompanied by 8Beg.s. (9B) leads to the appearance in the excitation energy distribution of 2α2p “quartets” of the distinct peak with a maximum at 4.1 ± 0.3 MeV. 8Beg.s. decays are presented in 21% 2He + 2H and 19% in the 3He of the all 11C “white” stars. 9Bg.s. decays are identified in “white” stars 11C → 2He + 2H constituting 14% of the 11C “white” stars. The 9B nucleus. is manifested in the “white” stars 10B → 2He + 2H with a probability of (9 ± 1)%. For the 10B case yield of 8Beg.s. nuclei with the respect to 9B is about a factor of 3 higher than 9B.

  10. Scalable high-power (>1kW/cm^2) diode laser stacks based on silicon monolithic micro-channel coolers

    NASA Astrophysics Data System (ADS)

    Reichert, Patrick; Fouksman, Michael; Zhou, Hailong; Nabors, David; Alcala, Jiro; Tolman, Sherry; Toivonen, Mika; Lehkonen, Sami; Haapamaa, Jouko

    2007-02-01

    We describe the performance and reliability of high power vertical diode stacks based on silicon monolithic microchannel coolers (SiMMs) operating at >1000W/cm2 CW at 808 and 940nm. The monolithic nature of these stacks makes them inherently robust and compact. Typical emitting dimensions for a 10-bar stack are ~8.8mm × 10mm with CW output power up to 1.5kW. Originally developed at Lawrence Livermore National Laboratory and now actively being developed for commercial applications at Coherent, this technology offers several advantages over current copper-based micro-channel coolers. These devices do not require use of DI water, strict monitoring and control of the pH level, careful control of the water velocity, or sealed cooling systems. The need for hydrostatic seals is also drastically reduced. A typical ten bar stack requires only 2 o-ring seals, compared to 20 such seals for a similar stack using copper microchannel cooling. Mature and readily available wet etching technology allows for cost effective batch fabrication of the sub-mount structure while achieving repeatable high precision components based on photolithographic fabrication processes.

  11. Performance of a 64-channel, 3.2×3.2 cm2 SiPM tile for TOF-PET application

    NASA Astrophysics Data System (ADS)

    Ferri, Alessandro; Acerbi, Fabio; Gola, Alberto; Piemonte, Claudio; Paternoster, Giovanni; Zorzi, Nicola

    2016-07-01

    In this work, we present a new 3.2×3.2 cm2 detector tile, composed of 8×8 single SiPMs, having a regular 4 mm pitch in both the X and Y directions. The tile fill factor is 85%. We produced two versions of the tile with different SiPM technologies: RGB-HD and NUV. The first one features square micro-cells with 25 μm pitch, a PDE peaked at 550 nm and a DCR of 300 kHz/mm2, at 20 °C and at maximum detection efficiency. The second one features micro-cells with 40 μm pitch and a PDE peaked in the blue part of the spectrum. The dark count rate at 20 °C and at maximum PDE is 100 kHz/mm2. In this work, we show the energy and timing resolution measurements at 511 keV obtained coupling the two tiles to an 8×8 LYSO array with a pixel size of 4×4×22 mm3, perfectly matching the photo-detector array.

  12. Nanostructured multielement (TiHfZrNbVTa)N coatings before and after implantation of N+ ions (1018 cm-2): Their structure and mechanical properties

    NASA Astrophysics Data System (ADS)

    Pogrebnjak, A. D.; Bondar, O. V.; Borba, S. O.; Abadias, G.; Konarski, P.; Plotnikov, S. V.; Beresnev, V. M.; Kassenova, L. G.; Drodziel, P.

    2016-10-01

    Multielement high entropy alloy (HEA) nitride (TiHfZrNbVTa)N coatings were deposited by vacuum arc and their structural and mechanical stability after implantation of high doses of N+ ions, 1018 cm-2, were investigated. The crystal structure and phase composition were characterized by X-ray diffraction (XRD) and Transmission Electron Microscopy, while depth-resolved nanoindentation tests were used to determine the evolution of hardness and elastic modulus along the implantation depth. XRD patterns show that coatings exhibit a main phase with fcc structure, which preferred orientation varies from (1 1 1) to (2 0 0), depending on the deposition conditions. First-principles calculations reveal that the presence of Nb atoms could favor the formation of solid solution with fcc structure in multielement HEA nitride. TEM results showed that amorphous and nanostructured phases were formed in the implanted coating sub-surface layer (∼100 nm depth). Concentration of nitrogen reached 90 at% in the near-surface layer after implantation, and decreased at higher depth. Nanohardness of the as-deposited coatings varied from 27 to 38 GPa depending on the deposition conditions. Ion implantation led to a significant decrease of the nanohardness to 12 GPa in the implanted region, while it reaches 24 GPa at larger depths. However, the H/E ratio is ⩾0.1 in the sub-surface layer due to N+ implantation, which is expected to have beneficial effect on the wear properties.

  13. Characterization of thin pixel sensor modules interconnected with SLID technology irradiated to a fluence of 2ṡ1015 neq/cm2.

    NASA Astrophysics Data System (ADS)

    Weigell, P.; Andricek, L.; Beimforde, M.; Macchiolo, A.; Moser, H.-G.; Nisius, R.; Richter, R.-H.

    2011-12-01

    A new module concept for future ATLAS pixel detector upgrades is presented, where thin n-in-p silicon sensors are connected to the front-end chip exploiting the novel Solid Liquid Interdiffusion technique (SLID) and the signals are read out via Inter Chip Vias (ICV) etched through the front-end. This should serve as a proof of principle for future four-side buttable pixel assemblies for the ATLAS upgrades, without the cantilever presently needed in the chip for the wire bonding. The SLID interconnection, developed by the Fraunhofer EMFT, is a possible alternative to the standard bump-bonding. It is characterized by a very thin eutectic Cu-Sn alloy and allows for stacking of different layers of chips on top of the first one, without destroying the pre-existing bonds. This paves the way for vertical integration technologies. Results of the characterization of the first pixel modules interconnected through SLID as well as of one sample irradiated to 2ṡ1015 neq/cm2 are discussed. Additionally, the etching of ICV into the front-end wafers was started. ICVs will be used to route the signals vertically through the front-end chip, to newly created pads on the backside. In the EMFT approach the chip wafer is thinned to (50-60) μm.

  14. Membraneless, room-temperature, direct borohydride/cerium fuel cell with power density of over 0.25 W/cm2.

    PubMed

    Da Mota, Nicolas; Finkelstein, David A; Kirtland, Joseph D; Rodriguez, Claudia A; Stroock, Abraham D; Abruña, Héctor D

    2012-04-11

    The widespread adoption and deployment of fuel cells as an alternative energy technology have been hampered by a number of formidable technical challenges, including the cost and long-term stability of electrocatalyst and membrane materials. We present a microfluidic fuel cell that overcomes many of these obstacles while achieving power densities in excess of 250 mW/cm(2). The poisoning and sluggish reaction rate associated with CO-contaminated H(2) and methanol, respectively, are averted by employing the promising, high-energy density fuel borohydride. The high-overpotential reaction of oxygen gas at the cathode is supplanted by the high-voltage reduction of cerium ammonium nitrate. Expensive, ineffective membrane materials are replaced with laminar flow and a nonselective, porous convection barrier to separate the fuel and oxidant streams. The result is a Nafion-free, room-temperature fuel cell that has the highest power density per unit mass of Pt catalyst employed for a non-H(2) fuel cell, and exceeds the power density of a typical H(2) fuel cell by 50%.

  15. Aging characteristics of blue InGaN micro-light emitting diodes at an extremely high current density of 3.5 kA cm-2

    NASA Astrophysics Data System (ADS)

    Tian, Pengfei; Althumali, Ahmad; Gu, Erdan; Watson, Ian M.; Dawson, Martin D.; Liu, Ran

    2016-04-01

    The aging characteristics of blue InGaN micro-light emitting diodes (micro-LEDs) with different sizes have been studied at an extremely high current density 3.5 kA cm-2 for emerging micro-LED applications including visible light communication (VLC), micro-LED pumped organic lasers and optogenetics. The light output power of micro-LEDs first increases and then decreases due to the competition of Mg activation in p-GaN layer and defect generation in the active region. The smaller micro-LEDs show less light output power degradation compared with larger micro-LEDs, which is attributed to the lower junction temperature of smaller micro-LEDs. It is found that the high current density without additional junction temperature cannot induce significant micro-LED degradation at room temperature but the combination of the high current density and high junction temperature leads to strong degradation. Furthermore, the cluster LEDs, composed of a micro-LED array, have been developed with both high light output power and less light output degradation for micro-LED applications in solid state lighting and VLC.

  16. A sterol C-14 reductase encoded by FgERG24B is responsible for the intrinsic resistance of Fusarium graminearum to amine fungicides.

    PubMed

    Liu, Xin; Fu, Jing; Yun, Yingzi; Yin, Yanni; Ma, Zhonghua

    2011-06-01

    Fusarium graminearum, the causal agent of wheat head blight, shows intrinsic resistance to amine fungicides. It is commonly accepted that the amines target sterol C-14 reductase and sterol Δ(8)-Δ(7) isomerase of ergosterol biosynthesis, encoded by the genes ERG24 and ERG2, respectively. Analysis of the genome sequence of F. graminearum revealed that the fungus contains two paralogous FgERG24 genes (FgERG24A and FgERG24B), which are homologous to the ERG24 of Saccharomyces cerevisiae. In this study, we disrupted FgERG24A and FgERG24B in F. graminearum. Compared to the wild-type strain HN9-1, FgERG24A and FgERG24B deletion mutants did not show recognizable phenotypic changes in mycelial growth on potato dextrose agar or in virulence on wheat heads. HPLC analysis showed that the amount of ergosterol in FgERG24A or FgERG24B deletion mutants was not significantly different from that in the wild-type strain. These results indicate that neither of the two genes is essential for growth, pathogenicity or ergosterol biosynthesis in F. graminearum. FgERG24B deletion mutants exhibited significantly increased sensitivity to amine fungicides, including tridemorph, fenpropidin and spiroxamine, but not to non-amine fungicides. In contrast, FgERG24A deletion mutants did not show changed sensitivity to any amine tested. The resistance of the FgERG24B deletion mutant to amines was restored by genetic complementation of the mutant with wild-type FgERG24B. These results indicate that FgERG24B controls the intrinsic resistance of F. graminearum to amines. The finding of this study provides new insights into amine resistance in filamentous fungi.

  17. Analytical platform evaluation for quantification of ERG in prostate cancer using protein and mRNA detection methods

    SciTech Connect

    He, Jintang; Schepmoes, Athena A.; Shi, Tujin; Wu, Chaochao; Fillmore, Thomas L.; Gao, Yuqian; Smith, Richard D.; Qian, Weijun; Rodland, Karin D.; Liu, Tao; Camp, David G.; Rastogi, Anshu; Tan, Shyh-Han; Yan, Wusheng; Mohamed, Ahmed A.; Huang, Wei; Banerjee, Sreedatta; Kagan, Jacob; Srivastava, Sudhir; McLeod, David; Srivastava, Shiv; Petrovics, Gyorgy; Dobi, Albert; Srinivasan, Alagarsamy

    2015-01-01

    Background: The established methods for detecting prostate cancer (CaP) are based on tests using PSA (blood), PCA3 (urine), and AMACR (tissue) as biomarkers in patient samples. The demonstration of ERG oncoprotein overexpression due to gene fusion in CaP has thus provided ERG as an additional biomarker. Based on this, we hypothesized that ERG protein quantification methods can be of use in the diagnosis of prostate cancer. Methods: Therefore, an antibody-free assay for ERG3 protein detection was developed based on PRISM (high-pressure high-resolution separations with intelligent selection and multiplexing)-SRM (selected reaction monitoring) mass spectrometry. We utilized TMPRSS2-ERG positive VCaP and TMPRSS2-ERG negative LNCaP cells to simulate three different sample types (cells, tissue, and post-DRE urine sediment). Results: Recombinant ERG3 protein spiked into LNCaP cell lysates could be detected at levels as low as 20 pg by PRISM-SRM analysis. The sensitivity of the PRISM-SRM assay was around approximately 10,000 VCaP cells in a mixed cell population model of VCaP and LNCaP cells. Interestingly, ERG protein could be detected in as few as 600 VCaP cells spiked into female urine. The sensitivity of the in-house enzyme-linked immunosorbent assay (ELISA) was similar to the PRISM-SRM assay, with detection of 30 pg of purified recombinant ERG3 protein and 10,000 VCaP cells. On the other hand, qRT-PCR exhibited a higher sensitivity, as TMPRSS2-ERG transcripts were detected in as few as 100 VCaP cells, in comparison to NanoString methodologies which detected ERG from 10,000 cells. Conclusions: Based on this data, we propose that the detection of both ERG transcriptional products with RNA-based assays, as well as protein products of ERG using PRISM-SRM assays, may be of clinical value in developing diagnostics and prognostics assays for prostate cancer given their sensitivity, specificity, and reproducibility.

  18. Ranolazine inhibition of hERG potassium channels: Drug–pore interactions and reduced potency against inactivation mutants

    PubMed Central

    Du, Chunyun; Zhang, Yihong; El Harchi, Aziza; Dempsey, Christopher E.; Hancox, Jules C.

    2014-01-01

    The antianginal drug ranolazine, which combines inhibitory actions on rapid and sustained sodium currents with inhibition of the hERG/IKr potassium channel, shows promise as an antiarrhythmic agent. This study investigated the structural basis of hERG block by ranolazine, with lidocaine used as a low potency, structurally similar comparator. Recordings of hERG current (IhERG) were made from cell lines expressing wild-type (WT) or mutant hERG channels. Docking simulations were performed using homology models built on MthK and KvAP templates. In conventional voltage clamp, ranolazine inhibited IhERG with an IC50 of 8.03 μM; peak IhERG during ventricular action potential clamp was inhibited ~ 62% at 10 μM. The IC50 values for ranolazine inhibition of the S620T inactivation deficient and N588K attenuated inactivation mutants were respectively ~ 73-fold and ~ 15-fold that for WT IhERG. Mutations near the bottom of the selectivity filter (V625A, S624A, T623A) exhibited IC50s between ~ 8 and 19-fold that for WT IhERG, whilst the Y652A and F656A S6 mutations had IC50s ~ 22-fold and 53-fold WT controls. Low potency lidocaine was comparatively insensitive to both pore helix and S6 mutations, but was sensitive to direction of K+ flux and particularly to loss of inactivation, with an IC50 for S620T-hERG ~ 49-fold that for WT IhERG. Docking simulations indicated that the larger size of ranolazine gives it potential for a greater range of interactions with hERG pore side chains compared to lidocaine, in particular enabling interaction of its two aromatic groups with side chains of both Y652 and F656. The N588K mutation is responsible for the SQT1 variant of short QT syndrome and our data suggest that ranolazine is unlikely to be effective against IKr/hERG in SQT1 patients. PMID:24877995

  19. The Influence of Deep Cumulus Convection on Larger - Flow during Ave/sesame i, 10-11 April 1979

    NASA Astrophysics Data System (ADS)

    Carney, Thomas Quentin

    A new formulation of the Eulerian kinetic energy budget equation which contains terms representing interactions between features on different scales of motion is developed and applied to a high-resolution upper air data set. The data were observed in the central United States over a 24-h period during the Atmospheric Variability Experiment -Severe Environmental Storms and Mesoscale Experiment (AVE/SESAME) on 10-11 April 1979. Three-hourly soundings were taken. Two data sets were produced using Barnes' (1964, 1973) objective analysis scheme: one based on observations from 39 stations (SES), which included 23 NWS and 16 supplementary stations, and the other based on observations only at the NWS stations. Kinetic energy budget results are examined for five regions: the total analysis area; the whole convection area which is fixed and contains most of the convective activity during the 24-h period; and three sub-areas, one containing the most intense convection (CB1), one containing weaker convection downwind of CB1 (CB2), and one containing no convection downwind of CB2 (NC). Results are produced for the total (SES) and large-scale (NWS) fields, and for the interacting scale between these two ((delta)-scale). The most energetically-active regions are those containing convective systems. In most cases, large-scale processes dominate; however, scale-interaction processes are important in the generation and dissipation terms throughout the period and in the horizontal transport term after intense convection is occurring. Furthermore, the significant scale-interaction effects generally occur in the upper troposphere (400-100 mb). Results show that scale-interaction processes are causing significant generation of kinetic energy in CB1 and CB2, as well as dissipation of energy to subgrid scales. The major interaction horizontal advection term is contributing to export of energy away from CB1 and CB2. The NC area is characterized by much weaker scale-interaction processes

  20. Investigation of rat bone fracture healing using pulsed 1.5 MHz, 30 mW/cm(2) burst ultrasound--axial distance dependency.

    PubMed

    Fung, Chak-Hei; Cheung, Wing-Hoi; Pounder, Neill M; de Ana, F Javier; Harrison, Andrew; Leung, Kwok-Sui

    2014-03-01

    This study investigated the effect of LIPUS on fracture healing when fractures were exposed to ultrasound at three axial distances: z=0 mm, 60 mm, and 130 mm. We applied LIPUS to rat fracture at these three axial distances mimicking the exposure condition of human fractures at different depths under the soft tissue. Measurement of LIPUS shows pressure variations in near field (nearby transducer); uniform profile was found beyond it (far field). We asked whether different positions of the fracture within the ultrasound field cause inconsistent biological effect during the healing process. Closed femoral fractured Sprague-Dawley rats were randomized into control, near-field (0mm), mid-near field (60 mm) or far-field (130 mm) groups. Daily LIPUS treatment (plane, but apodized source, see details in the text; 2.2 cm in diameter; 1.5 MHz sine waves repeating at 1 kHz PRF; spatial average temporal average intensity, ISATA=30 mW/cm(2)) was given to fracture site at the three axial distances. Weekly radiographs and endpoint microCT, histomorphometry, and mechanical tests were performed. The results showed that the 130 mm group had the highest tissue mineral density; and significantly higher mechanical properties than control at week 4. The 60 mm and 0 mm groups had significantly higher (i.e. p<0.05) woven bone percentage than control group in radiological, microCT and histomorphometry measurements. In general, LIPUS at far field augmented callus mineralization and mechanical properties; while near field and mid-near field enhanced woven bone formation. Our results indicated the therapeutic effect of LIPUS is dependent on the axial distance of the ultrasound beam. Therefore, the depth of fracture under the soft tissue affects the biological effect of LIPUS. Clinicians have to be aware of the fracture depth when LIPUS is applied transcutaneously.

  1. Blisters on the Anterior Shin in 3 Research Subjects After a 1-MHz, 1.5-W/cm 2, Continuous Ultrasound Treatment: A Case Series

    PubMed Central

    Frye, Jamie L; Johns, Lennart D; Tom, James A; Ingersoll, Christopher D

    2007-01-01

    Context: Clinicians should consider multiple factors when estimating tissue-heating rates. Objective: To report 3 separate occurrences of blisters during an ultrasound treatment experiment. Background: While we were conducting a research experiment comparing the measurement capabilities of 2 different intramuscular temperature devices, 3 female participants (age = 26.33 ± 3.79 years, height = 169.34 ± 3.89 cm, mass = 63.39 ± 3.81 kg) out of 16 healthy volunteers (7 men: age = 22.83 ± 1.17 years, height = 170.61 ± 7.77 cm, mass = 74.62 ± 19.24 kg; 9 women: age = 24.22 ± 2.73 years, height = 171.88 ± 6.35 cm, mass = 73.99 ± 18.55 kg) developed blisters on the anterior shin after a 1-MHz, 1.5-W/cm 2 continuous ultrasound treatment delivered to the triceps surae muscle. Differential Diagnosis: Allergies; chemical reaction with cleaning agents; sunburn; negative interaction between the temperature measurement instruments and the ultrasound field; the ultrasound transducer not being calibrated properly, producing a nonuniform field and creating a hot spot or heating differently when compared with other ultrasound devices; the smaller anatomy of our female subjects; or a confounding interaction among these factors. Treatment: Participants were given standard minor burn care by a physician. Uniqueness: (1) The development of blisters on the anterior aspect of the shin as a result of an ultrasound treatment to the posterior aspect of the triceps surae muscle and (2) muscle tissue heating rates ranging from 0.19°C to 1.1°C/min, when ultrasound researchers have suggested tissue heating in the range of 0.3°C/min with these settings. Conclusions: These adverse events raise important questions regarding treatment application and potential differences in heating and quality control among different ultrasound devices from different manufacturers. PMID:18060000

  2. One-year Outcomes of Pachymetry and Epithelium Thicknesses after Accelerated (45 mW/cm(2)) Transepithelial Corneal Collagen Cross-linking for Keratoconus Patients.

    PubMed

    Zhang, Xiaoyu; Sun, Ling; Chen, Yingjun; Li, Meiyan; Tian, Mi; Zhou, Xingtao

    2016-01-01

    The thickness of corneal pachymetry and the epithelium after accelerated (45 mW/cm(2)) transepithelial corneal collagen cross-linking (CXL) for keratoconus were assessed in this prospective case series study. Twenty-eight patients were treated for keratoconus. The mean Kmax was 56.18 ± 7.90. The thinnest point, as assessed by optical coherence tomography (OCT), was 443.18 ± 39.75 μm. Accelerated transepithelial CXL was performed, and corrected distance visual acuity (CDVA), corneal topography, and OCT were recorded at 1 week postoperatively as well as at 1, 3, 6, and 12 months. The surgery was uneventful in all eyes. Postoperative epithelial edema was observed and faded in 3 days. The postoperative Kmax was 54.56 ± 8.81, 55.78 ± 8.11, 56.37 ± 8.71, 55.80 ± 7.92, and 55.47 ± 8.24 at 1 week, 1 month, 3 months, 6 months, and 12 months, respectively (all, P > 0.05). The thinnest postoperative corneal point, 439.04 ± 44.99 μm, was observed at 12 months (P = 0.109). The epithelial thickness decreased during the first postoperative week then showed a gradual recovery. Postoperative pachymetry thickness showed no significant changes for up to 12 months. Postoperative epithelial thickness decreased temporarily, then stabilized at month 12. Accelerated transepithelial CXL was shown to be effective and safe for the treatment of keratoconus. PMID:27597655

  3. Hydrogen and carbon isotopic ratios of polycyclic aromatic compounds in two CM2 carbonaceous chondrites and implications for prebiotic organic synthesis

    NASA Astrophysics Data System (ADS)

    Huang, Yongsong; Aponte, José C.; Zhao, Jiaju; Tarozo, Rafael; Hallmann, Christian

    2015-09-01

    Study of meteoritic organic compounds offers a unique opportunity to understand the origins of the organic matter in the early Solar System. Meteoritic polycyclic aromatic hydrocarbons (PAHs) and heteropolycyclic aromatic compounds (HACs) have been studied for over fifty years, however; their hydrogen stable isotopic ratios (δD) have never been reported. Compound-specific δD measurements of PAHs and HACs are important, in part because the carbon isotopic ratios (δ13C) of various meteoritic PAHs cannot be readily distinguished from their terrestrial counterparts and it is difficult to rule out terrestrial contamination based on carbon isotopic ratios alone. In this study, we have extracted and identified more than sixty PAHs and HACs present in two CM2 carbonaceous chondrites Murchison and LON 94101. Their carbon and hydrogen stable isotopic ratios (δ13C and δD) were measured and used to discuss about their synthetic environments and formation mechanisms. The concentration of aromatic compounds is ∼30% higher in Murchison than in the Antarctic meteorite LON 94101, but both samples contained similar suites of PAHs and HACs. All PAHs and HACs found exhibited positive δD values (up to 1100‰) consistent with an extraterrestrial origin, indicating the relatively low δ13C values are indeed an inherent feature of the meteoritic aromatic compounds. The hydrogen isotopic data suggest aromatic compounds in carbonaceous chondrites were mainly formed in the cold interstellar environments. Molecular level variations in hydrogen and carbon isotopic values offer new insights to the formation pathways for the aromatic compounds in carbonaceous chondrites.

  4. Aqueous Alteration of Carbonaceous Chondrites: New Insights from Comparative Studies of Two Unbrecciated CM2 Chondrites, Y 791198 and ALH 81002

    NASA Technical Reports Server (NTRS)

    Chizmadia, L. J.; Brearley, A. J.

    2004-01-01

    Carbonaceous chondrites are an important resource for understanding the physical and chemical conditions in the early solar system. In particular, a long-standing question concerns the role of water in the cosmochemical evolution of carbonaceous chondrites. It is well established that extensive hydration of primary nebular phases occurred in the CM and CI chondrites, but the location where this alteration occurred remains controversial. In the CM2 chondrites, hydration formed secondary phases such as serpentine, tochilinite, pentlandite, carbonate and PCP. There are several textural observations which suggest that alteration occurred before the accretion of the final CM parent asteroid, i.e. preaccretionary alteration. Conversely, there is a significant body of evidence that supports parent-body alteration. In order to test these two competing hypotheses further, we studied two CM chondrites, Y-791198 and ALH81002, two meteorites that exhibit widely differing degrees of aqueous alteration. In addition, both meteorites have primary accretionary textures, i.e. experienced minimal asteroidal brecciation. Brecciation significantly complicates the task of unraveling alteration histories, mixing components that have been altered to different degrees from different locations on the same asteroidal parent body. Alteration in Y-791198 is mostly confined to chondrule mesostases, FeNi metal and fine-grained matrix and rims. In comparison, the primary chondrule silicates in ALH81002 have undergone extensive replacement by secondary hydrous phases. This study focuses on compositional and textural relationships between chondrule mesostasis and the associated rim materials. Our hypothesis is: both these components are highly susceptible to aqueous alteration and should be sensitive recorders of the alteration process. For parent body alteration, we expect systematic coupled mineralogical and compositional changes in rims and altered mesostasis, as elemental exchange between these

  5. Investigation of rat bone fracture healing using pulsed 1.5 MHz, 30 mW/cm(2) burst ultrasound--axial distance dependency.

    PubMed

    Fung, Chak-Hei; Cheung, Wing-Hoi; Pounder, Neill M; de Ana, F Javier; Harrison, Andrew; Leung, Kwok-Sui

    2014-03-01

    This study investigated the effect of LIPUS on fracture healing when fractures were exposed to ultrasound at three axial distances: z=0 mm, 60 mm, and 130 mm. We applied LIPUS to rat fracture at these three axial distances mimicking the exposure condition of human fractures at different depths under the soft tissue. Measurement of LIPUS shows pressure variations in near field (nearby transducer); uniform profile was found beyond it (far field). We asked whether different positions of the fracture within the ultrasound field cause inconsistent biological effect during the healing process. Closed femoral fractured Sprague-Dawley rats were randomized into control, near-field (0mm), mid-near field (60 mm) or far-field (130 mm) groups. Daily LIPUS treatment (plane, but apodized source, see details in the text; 2.2 cm in diameter; 1.5 MHz sine waves repeating at 1 kHz PRF; spatial average temporal average intensity, ISATA=30 mW/cm(2)) was given to fracture site at the three axial distances. Weekly radiographs and endpoint microCT, histomorphometry, and mechanical tests were performed. The results showed that the 130 mm group had the highest tissue mineral density; and significantly higher mechanical properties than control at week 4. The 60 mm and 0 mm groups had significantly higher (i.e. p<0.05) woven bone percentage than control group in radiological, microCT and histomorphometry measurements. In general, LIPUS at far field augmented callus mineralization and mechanical properties; while near field and mid-near field enhanced woven bone formation. Our results indicated the therapeutic effect of LIPUS is dependent on the axial distance of the ultrasound beam. Therefore, the depth of fracture under the soft tissue affects the biological effect of LIPUS. Clinicians have to be aware of the fracture depth when LIPUS is applied transcutaneously. PMID:24239510

  6. One-year Outcomes of Pachymetry and Epithelium Thicknesses after Accelerated (45 mW/cm2) Transepithelial Corneal Collagen Cross-linking for Keratoconus Patients

    PubMed Central

    Zhang, Xiaoyu; Sun, Ling; Chen, Yingjun; Li, Meiyan; Tian, Mi; Zhou, Xingtao

    2016-01-01

    The thickness of corneal pachymetry and the epithelium after accelerated (45 mW/cm2) transepithelial corneal collagen cross-linking (CXL) for keratoconus were assessed in this prospective case series study. Twenty-eight patients were treated for keratoconus. The mean Kmax was 56.18 ± 7.90. The thinnest point, as assessed by optical coherence tomography (OCT), was 443.18 ± 39.75 μm. Accelerated transepithelial CXL was performed, and corrected distance visual acuity (CDVA), corneal topography, and OCT were recorded at 1 week postoperatively as well as at 1, 3, 6, and 12 months. The surgery was uneventful in all eyes. Postoperative epithelial edema was observed and faded in 3 days. The postoperative Kmax was 54.56 ± 8.81, 55.78 ± 8.11, 56.37 ± 8.71, 55.80 ± 7.92, and 55.47 ± 8.24 at 1 week, 1 month, 3 months, 6 months, and 12 months, respectively (all, P > 0.05). The thinnest postoperative corneal point, 439.04 ± 44.99 μm, was observed at 12 months (P = 0.109). The epithelial thickness decreased during the first postoperative week then showed a gradual recovery. Postoperative pachymetry thickness showed no significant changes for up to 12 months. Postoperative epithelial thickness decreased temporarily, then stabilized at month 12. Accelerated transepithelial CXL was shown to be effective and safe for the treatment of keratoconus. PMID:27597655

  7. Diminished hERG K+ channel activity facilitates strong human labour contractions but is dysregulated in obese women.

    PubMed

    Parkington, Helena C; Stevenson, Janet; Tonta, Mary A; Paul, Jonathan; Butler, Trent; Maiti, Kaushik; Chan, Eng-Cheng; Sheehan, Penelope M; Brennecke, Shaun P; Coleman, Harold A; Smith, Roger

    2014-06-17

    Human ether-a-go-go-related gene (hERG) potassium channels determine cardiac action potential and contraction duration. Human uterine contractions are underpinned by an action potential that also possesses an initial spike followed by prolonged depolarization. Here we show that hERG channel proteins (α-conducting and β-inhibitory subunits) and hERG currents exist in isolated patch-clamped human myometrial cells. We show that hERG channel activity suppresses contraction amplitude and duration before labour, thereby facilitating quiescence. During established labour, expression of β-inhibitory protein is markedly enhanced, resulting in reduced hERG activity that is associated with an increased duration of uterine action potentials and contractions. Thus, changes in hERG channel activity contribute to electrophysiological mechanisms that produce contractions during labour. We also demonstrate that this system fails in women with elevated BMI, who have enhanced hERG activity as a result of low β-inhibitory protein expression, which likely contributes to the weak contractions and poor labour outcomes observed in many obese women necessitating caesarean delivery.

  8. ERG/AKR1C3/AR constitutes a feed-forward loop for AR signaling in prostate cancer cells

    PubMed Central

    Powell, Katelyn; Semaan, Louie; Conley-LaComb, M. Katie; Asangani, Irfan; Wu, Yi-Mi; Ginsburg, Kevin B.; Williams, Julia; Squire, Jeremy A.; Maddipati, Krishna R.; Cher, Michael L.; Chinni, Sreenivasa R.

    2015-01-01

    Purpose Intratumoral androgen synthesis in prostate cancer (PCa) contributes to the development of castration-resistant prostate cancer (CRPC). Several enzymes responsible for androgen biosynthesis have been shown to be overexpressed in CRPC, thus contributing to CRPC in a castrated environment. The TMPRSS2-ERG transcription factor has been shown to be present in primary PCa tumors as well as CRPC tumors. We hypothesize that TMPRSS2-ERG fusions regulate androgen biosynthetic enzyme (ABE) gene expression and the production of androgens, which contributes to the development of CRPC. Experimental design We used a panel of assays including lentivirus transduction, gene expression, chromatin immunoprecipitation and sequencing, Liquid chromatography-Mass spectrometric quantitation, immunocytochemistry, immunohistochemistry and bio-informatics analysis of gene microarray data bases to determine ERG regulation of androgen synthesis. Results We found that ERG regulated the expression of the ABE AKR1C3 in PCa cells via direct binding to the AKR1C3 gene. Knockdown of ERG resulted in reduced AKR1C3 expression, which caused a reduction in both DHT synthesis and PSA expression in VCaP PCa cells treated with 5α-androstanedione, a DHT precursor metabolite. Immunohistochemical staining revealed that ERG was co-expressed with AKR1C3 in PCa tissue samples. Conclusions These data suggest that AKR1C3 catalyzes the biochemical reduction of 5α-Androstanedione to DHT in PCa cells, and that ERG regulates this step through upregulation of AKR1C3 expression. Elucidation of ERG regulation of ABEs in CRPC may help to stratify TMPRSS2-ERG fusion-positive PCa patients in the clinic for anti-AR driven therapies; and AKR1C3 may serve as a valuable therapeutic target in the treatment of CRPC. PMID:25754347

  9. High electrical conductivity in Ni₃(2,3,6,7,10,11-hexaiminotriphenylene)₂, a semiconducting metal-organic graphene analogue.

    PubMed

    Sheberla, Dennis; Sun, Lei; Blood-Forsythe, Martin A; Er, Süleyman; Wade, Casey R; Brozek, Carl K; Aspuru-Guzik, Alán; Dincă, Mircea

    2014-06-25

    Reaction of 2,3,6,7,10,11-hexaaminotriphenylene with Ni(2+) in aqueous NH3 solution under aerobic conditions produces Ni3(HITP)2 (HITP = 2,3,6,7,10,11-hexaiminotriphenylene), a new two-dimensional metal-organic framework (MOF). The new material can be isolated as a highly conductive black powder or dark blue-violet films. Two-probe and van der Pauw electrical measurements reveal bulk (pellet) and surface (film) conductivity values of 2 and 40 S·cm(-1), respectively, both records for MOFs and among the best for any coordination polymer.

  10. Novel point mutations in the ERG11 gene in clinical isolates of azole resistant Candida species.

    PubMed

    Silva, Danielly Beraldo dos Santos; Rodrigues, Luana Mireli Carbonera; Almeida, Adriana Araújo de; Oliveira, Kelly Mari Pires de; Grisolia, Alexéia Barufatti

    2016-03-01

    The azoles are the class of medications most commonly used to fight infections caused by Candida sp. Typically, resistance can be attributed to mutations in ERG11 gene (CYP51) which encodes the cytochrome P450 14α-demethylase, the primary target for the activity of azoles. The objective of this study was to identify mutations in the coding region of theERG11 gene in clinical isolates of Candida species known to be resistant to azoles. We identified three new synonymous mutations in the ERG11 gene in the isolates of Candida glabrata (C108G, C423T and A1581G) and two new nonsynonymous mutations in the isolates of Candida krusei--A497C (Y166S) and G1570A (G524R). The functional consequence of these nonsynonymous mutations was predicted using evolutionary conservation scores. The G524R mutation did not have effect on 14α-demethylase functionality, while the Y166S mutation was found to affect the enzyme. This observation suggests a possible link between the mutation and dose-dependent sensitivity to voriconazole in the clinical isolate of C. krusei. Although the presence of the Y166S in phenotype of reduced azole sensitivity observed in isolate C. krusei demands investigation, it might contribute to the search of new therapeutic agents against resistant Candida isolates. PMID:26982177

  11. FUS-ERG gene fusion in isolated myeloid sarcoma showing uncommon clinical features.

    PubMed

    Ueda, Ryosuke; Maruyama, Dai; Nomoto, Junko; Maeshima, Akiko M; Fukuhara, Suguru; Kitahara, Hideaki; Miyamoto, Ken-Ichi; Munakata, Wataru; Suzuki, Tatsuya; Taniguchi, Hirokazu; Kobayashi, Yukio; Tobinai, Kensei

    2016-01-01

    FUS-ERG gene fusion has not been reported in cases of myeloid sarcoma (MS), a subtype of acute myeloid leukemia involving extramedullary anatomic sites. Here, we report a case of a 48-year-old man with primary isolated MS of the anterior mediastinum, who later developed multiple extramedullary recurrences without bone marrow infiltration throughout the course. G-banding analysis of the cells in pericardial effusion at recurrence showed complex karyotypic abnormalities including t(16;21)(p11.2;q22). FUS break-apart fluorescent in situ hybridization analysis showed split signals in biopsy sections at initial diagnosis and recurrence. Reverse transcriptase polymerase chain reaction and direct sequencing demonstrated the presence of the FUS-ERG chimeric gene transcript. The patient underwent cord blood transplantation, but died of pneumonia on day 64. To our knowledge, this is the first report of isolated MS carrying FUS-ERG gene fusion. In future study, relationship between the fusion gene and uncommon clinical features should be investigated in isolated MS. PMID:26770812

  12. Molecular cloning, characterization, and overexpression of ERG7, the Saccharomyces cerevisiae gene encoding lanosterol synthase.

    PubMed Central

    Corey, E J; Matsuda, S P; Bartel, B

    1994-01-01

    We report the cloning, characterization, and overexpression of Saccharomyces cerevisiae ERG7, which encodes lanosterol synthase [(S)-2,3-epoxysqualene mutase (cyclizing, lanosterol forming), EC 5.4.99.7], the enzyme responsible for the complex cyclization/rearrangement step in sterol biosynthesis. Oligonucleotide primers were designed corresponding to protein sequences conserved between Candida albicans ERG7 and the related Arabidopsis thaliana cycloartenol synthase [(S)-2,3-epoxysqualene mutase (cyclizing, cycloartenol forming), EC 5.4.99.8]. A PCR product was amplified from yeast genomic DNA using these primers and was used to probe yeast libraries by hybridization. Partial-length clones homologous to the two known epoxysqualene mutases were isolated, but a full-length sequence was found neither in cDNA nor genomic libraries, whether in phage or plasmids. Two overlapping clones were assembled to make a functional reconstruction of the gene, which contains a 2196-bp open reading frame capable of encoding an 83-kDa protein. The reconstruction complemented the erg7 mutation when driven from either its native promoter or the strong ADH1 promoter. Images PMID:8134375

  13. Novel point mutations in the ERG11 gene in clinical isolates of azole resistant Candida species.

    PubMed

    Silva, Danielly Beraldo dos Santos; Rodrigues, Luana Mireli Carbonera; Almeida, Adriana Araújo de; Oliveira, Kelly Mari Pires de; Grisolia, Alexéia Barufatti

    2016-03-01

    The azoles are the class of medications most commonly used to fight infections caused by Candida sp. Typically, resistance can be attributed to mutations in ERG11 gene (CYP51) which encodes the cytochrome P450 14α-demethylase, the primary target for the activity of azoles. The objective of this study was to identify mutations in the coding region of theERG11 gene in clinical isolates of Candida species known to be resistant to azoles. We identified three new synonymous mutations in the ERG11 gene in the isolates of Candida glabrata (C108G, C423T and A1581G) and two new nonsynonymous mutations in the isolates of Candida krusei--A497C (Y166S) and G1570A (G524R). The functional consequence of these nonsynonymous mutations was predicted using evolutionary conservation scores. The G524R mutation did not have effect on 14α-demethylase functionality, while the Y166S mutation was found to affect the enzyme. This observation suggests a possible link between the mutation and dose-dependent sensitivity to voriconazole in the clinical isolate of C. krusei. Although the presence of the Y166S in phenotype of reduced azole sensitivity observed in isolate C. krusei demands investigation, it might contribute to the search of new therapeutic agents against resistant Candida isolates.

  14. Erg11 mutations associated with azole resistance in clinical isolates of Candida albicans.

    PubMed

    Xiang, Ming-Jie; Liu, Jin-Yan; Ni, Pei-Hua; Wang, Shengzheng; Shi, Ce; Wei, Bing; Ni, Yu-Xing; Ge, Hai-Liang

    2013-06-01

    The widespread use of azoles has led to increasing azole resistance among Candida albicans strains. One mechanism of azole resistance involves point mutations in the ERG11 gene, which encodes the target enzyme (cytochrome P450 lanosterol 14α-demethylase). In the present study, we amplified and sequenced the ERG11 gene of 23 C. albicans clinical isolates. Seventeen mutations encoding distinct amino acid substitutions were found, of which seven (K143Q, Y205E, A255V, E260V, N435V, G472R, and D502E) were novel. We further verified the contribution of the amino acid substitutions to azole resistance using site-directed mutagenesis of the ERG11 gene to recreate these mutations for heterologous expression in Saccharomyces cerevisiae. We observed that substitutions A114S, Y132H, Y132F, K143R, Y257H, and a new K143Q substitution contributed to significant increases (≧fourfold) in fluconazole and voriconazole resistance; changes in itraconazole resistance were not significant (≦twofold).

  15. Two Clinical Isolates of Candida glabrata Exhibiting Reduced Sensitivity to Amphotericin B Both Harbor Mutations in ERG2

    PubMed Central

    Hull, Claire M.; Bader, Oliver; Parker, Josie E.; Weig, Michael; Gross, Uwe; Warrilow, Andrew G. S.; Kelly, Diane E.

    2012-01-01

    Two novel isolates of Candida glabrata exhibiting reduced sensitivity to amphotericin B (MIC, 8 μg ml−1) were found to be ERG2 mutants, wherein Δ8-sterol intermediates comprised >90% of the total cellular sterol fraction. Both harbored an alteration at Thr121 in ERG2; the corresponding residue (Thr119) in Saccharomyces cerevisiae is essential for sterol Δ8-Δ7 isomerization. This constitutes the first report of C. glabrata harboring mutations in ERG2 and exhibiting reduced sensitivity to amphotericin B. PMID:23027188

  16. Effect of S5P alpha-helix charge mutants on inactivation of hERG K+ channels.

    PubMed

    Clarke, C E; Hill, A P; Zhao, J; Kondo, M; Subbiah, R N; Campbell, T J; Vandenberg, J I

    2006-06-01

    The ether-à-go-go (EAG) family of voltage-gated K(+) channels contains three subfamilies, EAG, ether-à-go-go related (ERG) and ether-à-go-go like (ELK). The human ether-à-go-go related gene (hERG) K(+) channel has been of significant interest because loss of function in the hERG channel is associated with a markedly increased risk of cardiac arrhythmias. The hERG channel has unusual kinetics with slow activation and deactivation but very rapid and voltage-dependent inactivation. The outer pore region of the hERG K(+) channel is predicted to be different from that of other members of the voltage-gated K(+) channel family. HERG has a much longer linker between the fifth transmembrane domain (SS) and the pore helix (S5P linker) compared to other families of voltage-gated K(+) channels (43 amino acids compared to 14-23 amino acids). Further, the S5P linker contains an amphipathic alpha-helix that in hERG channels probably interacts with the mouth of the pore to modulate inactivation. The human EAG and rat ELK2 channels (hEAG and rELK2) show reduced or no inactivation in comparison to hERG channels, yet both channels are predicted to contain a similarly long S5P linker to that of hERG. In this study, we have constructed a series of chimaeric channels consisting of the S1-S6 of hERG but with the S5P alpha-helical region of either hEAG or rELK2, and one consisting of the S1-S6 of rELK2 but with the S5P alpha-helical region of hERG to investigate the role of the S5P linker in inactivation. Our studies show that charged residues on the alpha-helix of the S5P linker contribute significantly to the differences in inactivation characteristics of the EAG family channels. Further, individually mutating each of the hydrophilic residues on the S5P alpha-helix of hERG to a charged residue had significant effects on the voltage dependence of inactivation and the two residues with the greatest affect when mutated to a lysine, N588 and Q592, both lie on the same face of the S5P

  17. Analytical platform evaluation for quantification of ERG in prostate cancer using protein and mRNA detection methods

    DOE PAGES

    He, Jintang; Schepmoes, Athena A.; Shi, Tujin; Wu, Chaochao; Fillmore, Thomas L.; Gao, Yuqian; Smith, Richard D.; Qian, Weijun; Rodland, Karin D.; Liu, Tao; et al

    2015-01-01

    Background: The established methods for detecting prostate cancer (CaP) are based on tests using PSA (blood), PCA3 (urine), and AMACR (tissue) as biomarkers in patient samples. The demonstration of ERG oncoprotein overexpression due to gene fusion in CaP has thus provided ERG as an additional biomarker. Based on this, we hypothesized that ERG protein quantification methods can be of use in the diagnosis of prostate cancer. Methods: Therefore, an antibody-free assay for ERG3 protein detection was developed based on PRISM (high-pressure high-resolution separations with intelligent selection and multiplexing)-SRM (selected reaction monitoring) mass spectrometry. We utilized TMPRSS2-ERG positive VCaP and TMPRSS2-ERGmore » negative LNCaP cells to simulate three different sample types (cells, tissue, and post-DRE urine sediment). Results: Recombinant ERG3 protein spiked into LNCaP cell lysates could be detected at levels as low as 20 pg by PRISM-SRM analysis. The sensitivity of the PRISM-SRM assay was around approximately 10,000 VCaP cells in a mixed cell population model of VCaP and LNCaP cells. Interestingly, ERG protein could be detected in as few as 600 VCaP cells spiked into female urine. The sensitivity of the in-house enzyme-linked immunosorbent assay (ELISA) was similar to the PRISM-SRM assay, with detection of 30 pg of purified recombinant ERG3 protein and 10,000 VCaP cells. On the other hand, qRT-PCR exhibited a higher sensitivity, as TMPRSS2-ERG transcripts were detected in as few as 100 VCaP cells, in comparison to NanoString methodologies which detected ERG from 10,000 cells. Conclusions: Based on this data, we propose that the detection of both ERG transcriptional products with RNA-based assays, as well as protein products of ERG using PRISM-SRM assays, may be of clinical value in developing diagnostics and prognostics assays for prostate cancer given their sensitivity, specificity, and reproducibility.« less

  18. Determining temperature distribution in tissue in the focal plane of the high (>100 W/cm(2)) intensity focused ultrasound beam using phase shift of ultrasound echoes.

    PubMed

    Karwat, Piotr; Kujawska, Tamara; Lewin, Peter A; Secomski, Wojciech; Gambin, Barbara; Litniewski, Jerzy

    2016-02-01

    In therapeutic applications of High Intensity Focused Ultrasound (HIFU) the guidance of the HIFU beam and especially its focal plane is of crucial importance. This guidance is needed to appropriately target the focal plane and hence the whole focal volume inside the tumor tissue prior to thermo-ablative treatment and beginning of tissue necrosis. This is currently done using Magnetic Resonance Imaging that is relatively expensive. In this study an ultrasound method, which calculates the variations of speed of sound in the locally heated tissue volume by analyzing the phase shifts of echo-signals received by an ultrasound scanner from this very volume is presented. To improve spatial resolution of B-mode imaging and minimize the uncertainty of temperature estimation the acoustic signals were transmitted and received by 8 MHz linear phased array employing Synthetic Transmit Aperture (STA) technique. Initially, the validity of the algorithm developed was verified experimentally in a tissue-mimicking phantom heated from 20.6 to 48.6 °C. Subsequently, the method was tested using a pork loin sample heated locally by a 2 MHz pulsed HIFU beam with focal intensity ISATA of 129 W/cm(2). The temperature calibration of 2D maps of changes in the sound velocity induced by heating was performed by comparison of the algorithm-determined changes in the sound velocity with the temperatures measured by thermocouples located in the heated tissue volume. The method developed enabled ultrasound temperature imaging of the heated tissue volume from the very inception of heating with the contrast-to-noise ratio of 3.5-12 dB in the temperature range 21-56 °C. Concurrently performed, conventional B-mode imaging revealed CNR close to zero dB until the temperature reached 50 °C causing necrosis. The data presented suggest that the proposed method could offer an alternative to MRI-guided temperature imaging for prediction of the location and extent of the thermal lesion prior to applying the

  19. Determining temperature distribution in tissue in the focal plane of the high (>100 W/cm(2)) intensity focused ultrasound beam using phase shift of ultrasound echoes.

    PubMed

    Karwat, Piotr; Kujawska, Tamara; Lewin, Peter A; Secomski, Wojciech; Gambin, Barbara; Litniewski, Jerzy

    2016-02-01

    In therapeutic applications of High Intensity Focused Ultrasound (HIFU) the guidance of the HIFU beam and especially its focal plane is of crucial importance. This guidance is needed to appropriately target the focal plane and hence the whole focal volume inside the tumor tissue prior to thermo-ablative treatment and beginning of tissue necrosis. This is currently done using Magnetic Resonance Imaging that is relatively expensive. In this study an ultrasound method, which calculates the variations of speed of sound in the locally heated tissue volume by analyzing the phase shifts of echo-signals received by an ultrasound scanner from this very volume is presented. To improve spatial resolution of B-mode imaging and minimize the uncertainty of temperature estimation the acoustic signals were transmitted and received by 8 MHz linear phased array employing Synthetic Transmit Aperture (STA) technique. Initially, the validity of the algorithm developed was verified experimentally in a tissue-mimicking phantom heated from 20.6 to 48.6 °C. Subsequently, the method was tested using a pork loin sample heated locally by a 2 MHz pulsed HIFU beam with focal intensity ISATA of 129 W/cm(2). The temperature calibration of 2D maps of changes in the sound velocity induced by heating was performed by comparison of the algorithm-determined changes in the sound velocity with the temperatures measured by thermocouples located in the heated tissue volume. The method developed enabled ultrasound temperature imaging of the heated tissue volume from the very inception of heating with the contrast-to-noise ratio of 3.5-12 dB in the temperature range 21-56 °C. Concurrently performed, conventional B-mode imaging revealed CNR close to zero dB until the temperature reached 50 °C causing necrosis. The data presented suggest that the proposed method could offer an alternative to MRI-guided temperature imaging for prediction of the location and extent of the thermal lesion prior to applying the

  20. Estimates of L:M cone ratio from ERG flicker photometry and genetics.

    PubMed

    Carroll, Joseph; Neitz, Jay; Neitz, Maureen

    2002-01-01

    Estimates of L:M cone ratio for males with normal color vision were derived using the flicker-photometric electroretinogram (ERG). These were obtained by best fitting ERG spectral sensitivity functions to a weighted sum of long (L)- and middle (M)-wavelength-sensitive cone spectral absorption curves. Using the ERG, measurements can be made with extremely high precision, which leaves variation in the wavelength of maximal sensitivity (lambda(max)) of the cone photopigments as the major remaining source of inaccuracy in determining the ratio of cone contributions. Here that source of inaccuracy was largely eliminated through the use of individualized L-cone spectral absorption curves deduced from L-pigment gene sequences. The method was used on 62 normal males as part of an effort to obtain a true picture of how normal variations in L:M cone ratio are distributed. The percentage of L cones in the average eye was 65%L [where %L = 100 X L / (L+M)]. There were huge individual differences ranging from 28%-93%L, corresponding to more than a 30-fold range in L:M ratio (0.4-13). However, the most extreme values were relatively rare; 80% of the subjects fell within +/-15 %L of the mean, corresponding to a 4-fold range in L:M ratio (1-4). The method remedies major weaknesses inherent in earlier applications of flicker photometry to estimate cone ratio; however, it continues to depend on the assumption that the average L cone produces a response with an identical amplitude to that of the average M cone. A comparison of the ERG results with the distribution of cone ratios estimated from cone pigment messenger RNA in cadaver eyes indicates that the assumption generally holds true. However, there may be a small number of exceptions in which individuals have normally occurring (but relatively rare) amino acid substitutions in one of their pigments that significantly affect the physiology of the cone class containing that pigment, so as to reduce the amplitude of its contribution

  1. Celastrol Suppresses Tumor Cell Growth through Targeting an AR-ERG-NF-κB Pathway in TMPRSS2/ERG Fusion Gene Expressing Prostate Cancer

    PubMed Central

    Cai, Yi; Castro, Patricia; Dakhov, Olga; Shi, Ping; Bai, Yaoxia; Ji, Huixiang; Shen, Wenhao; Wang, Jianghua

    2013-01-01

    The TMPRSS2/ERG (T/E) fusion gene is present in the majority of all prostate cancers (PCa). We have shown previously that NF-kB signaling is highly activated in these T/E fusion expressing cells via phosphorylation of NF-kB p65 Ser536 (p536). We therefore hypothesize that targeting NF-kB signaling may be an efficacious approach for the subgroup of PCas that carry T/E fusions. Celastrol is a well known NF-kB inhibitor, and thus may inhibit T/E fusion expressing PCa cell growth. We therefore evaluated Celastrol’s effects in vitro and in vivo in VCaP cells, which express the T/E fusion gene. VCaP cells were treated with different concentrations of Celastrol and growth inhibition and target expression were evaluated. To test its ability to inhibit growth in vivo, 0.5 mg/kg Celastrol was used to treat mice bearing subcutaneous VCaP xenograft tumors. Our results show Celastrol can significantly inhibit the growth of T/E fusion expressing PCa cells both in vitro and in vivo through targeting three critical signaling pathways: AR, ERG and NF-kB in these cells. When mice received 0.5 mg/kg Celastrol for 4 times/week, significant growth inhibition was seen with no obvious toxicity or significant weight loss. Therefore, Celastrol is a promising candidate drug for T/E fusion expressing PCa. Our findings provide a novel strategy for the targeted therapy which may benefit the more than half of PCa patients who have T/E fusion expressing PCas. PMID:23554889

  2. Health Curriculum Materials: Grades 10, 11, and 12. Strand IV, Environmental and Community Health; Consumer Health. Special Edition for Evaluation and Discussion.

    ERIC Educational Resources Information Center

    Van Hooft, Gordon E.; And Others

    This publication contains curriculum suggestions for teaching Environmental and Community Health - Consumer Health for grades 10, 11 and 12. Emphasis is placed on the psychological dimension of contemporary quackery and pseudo-scientific practices, and sources of health information and health counsel. In general, the grade 10 through 12 materials…

  3. Localization of the ergtoxin-1 receptors on the voltage sensing domain of hERG K+ channel by AFM recognition imaging.

    PubMed

    Chtcheglova, Lilia A; Atalar, Fatmahan; Ozbek, Ugur; Wildling, Linda; Ebner, Andreas; Hinterdorfer, Peter

    2008-04-01

    The inhibition of the human ether-à-go-go-related (hERG) K+ channels is the major cause of long QT syndromes inducing fatal cardiac arrhythmias. Ergtoxin 1 (ErgTx1) belongs to scorpion-toxins, which are K+ channel-blockers, and binds to hERG channel with 1:1 stoichiometry and high affinity (Kd approximately 10 nM). Nevertheless, patch-clamp recordings recently demonstrated that ErgTx1 does not establish complete blockade of hERG currents, even at high ErgTx1 concentrations. Such phenomenon is supposed to be consistent with highly dynamic conformational changes of the outer pore domain of hERG. In this study, simultaneous topography and recognition imaging (TREC) on hERG HEK 293 cells was used to visualize binding sites on the extracellular part of hERG channel (on S1-S2 region) for Anti-Kv11.1 (hERG-extracellular-antibody). The recognition maps of hERG channels contained recognition spots, haphazardly distributed and organized in clusters. Recognition images after the addition of ErgTx1 at high concentrations ( approximately 1 microM) revealed subsequent partial disappearance of clusters, indicating that ErgTx1 was bound to the S1-S2 region. These results were supported by AFM force spectroscopy data, showing for the first time that voltage sensing domain (S1-S4) of hERG K+ channel might be one of the multiple binding sites of ErgTx1. PMID:18286302

  4. Incremental and decremental L- and M-cone-driven ERG responses: I. Square-wave pulse stimulation.

    PubMed

    McKeefry, Declan; Kremers, Jan; Kommanapalli, Deepika; Challa, Naveen K; Murray, Ian J; Maguire, John; Parry, Neil R A

    2014-04-01

    Electroretinograms (ERGs) elicited by transient, square-wave L- and M-cone isolating stimuli were recorded from human trichromatic (n=19) and dichromatic (n=4) observers. The stimuli were generated on a four primary LED stimulator and were equated in terms of cone modulation (cone contrast=0.11) and retinal illuminance (12,000 trolands). L- and M-cone isolated ERGs had waveforms similar to those observed for luminance responses. However, M-cone ERGs exhibited a phase reversal in their responses to onset and offset stimuli relative to the L-cone responses. This on-off response reversal was observed in trichromats but not dichromats. Simultaneous counterphase and inphase combinations of L- and M-cone isolating stimuli generated responses that reflected chromatic and luminance processing, respectively. We conclude that L- and M-cone specific ERGs provide a measure of how photoreceptors contribute to postreceptoral mechanisms. PMID:24695165

  5. miR-30 as a tumor suppressor connects EGF/Src signal to ERG and EMT

    PubMed Central

    Kao, Chiao-Jung; Martiniez, Anthony; Shi, Xu-Bao; Yang, Joy; Evans, Christopher P.; Dobi, Albert; deVere White, Ralph W.; Kung, Hsing-Jien

    2015-01-01

    Src tyrosine kinase (Src) is implicated in the development of bone metastasis and castration-resistance of prostate cancer. Src inhibitors are currently being tested in clinical trials for such diseases. Understanding the molecular and cellular actions of Src inhibitors holds the key to future improvement of this line of therapy. Here we describe the microRNA (miRNA) expression profiles modulated by two Src inhibitors and demonstrate that the miR-30 family members are the most prominently induced species. Consistent with its tumor suppressor role, miR-30 is downmodulated by oncogenic signals such as epidermal growth factor (EGF) and hepatocyte growth factor (HGF), and is generally underexpressed in prostate cancer specimens. A number of epithelial to mesenchymal transition (EMT)-associated genes are predicted targets of miR-30. Among these genes the Ets Related Gene (ERG) is the most frequently overexpressed-oncogene in prostate cancer activated by genomic fusion events between promoter upstream sequences of the TMPRSS2 and coding sequences of ERG. We showed by ERG 3′UTR-reporter and mutagenesis assays that ERG is a direct target of miR-30. Overexpression of miR-30 in prostate cancer cells suppresses EMT phenotypes and inhibits cell migration and invasion. It also inhibits the in vitro and in vivo growth of VCaP cells, which depends on TMPRSS2-ERG for proliferation. TMPRSS2-ERG is generally regulated by androgen at the transcriptional level. Our finding reveals a new post-transcriptional mechanism of TMPRSS2-ERG regulation by Src and growth signals via miR-30 providing a rationale for targeting ERG positive castration resistant tumors with Src inhibitors. PMID:23728339

  6. Investigation of miscellaneous hERG inhibition in large diverse compound collection using automated patch-clamp assay

    PubMed Central

    Yu, Hai-bo; Zou, Bei-yan; Wang, Xiao-liang; Li, Min

    2016-01-01

    Aim: hERG potassium channels display miscellaneous interactions with diverse chemical scaffolds. In this study we assessed the hERG inhibition in a large compound library of diverse chemical entities and provided data for better understanding of the mechanisms underlying promiscuity of hERG inhibition. Methods: Approximately 300 000 compounds contained in Molecular Library Small Molecular Repository (MLSMR) library were tested. Compound profiling was conducted on hERG-CHO cells using the automated patch-clamp platform–IonWorks Quattro™. Results: The compound library was tested at 1 and 10 μmol/L. IC50 values were predicted using a modified 4-parameter logistic model. Inhibitor hits were binned into three groups based on their potency: high (IC50<1 μmol/L), intermediate (1 μmol/L< IC50<10 μmol/L), and low (IC50>10 μmol/L) with hit rates of 1.64%, 9.17% and 16.63%, respectively. Six physiochemical properties of each compound were acquired and calculated using ACD software to evaluate the correlation between hERG inhibition and the properties: hERG inhibition was positively correlative to the physiochemical properties ALogP, molecular weight and RTB, and negatively correlative to TPSA. Conclusion: Based on a large diverse compound collection, this study provides experimental evidence to understand the promiscuity of hERG inhibition. This study further demonstrates that hERG liability compounds tend to be more hydrophobic, high-molecular, flexible and polarizable. PMID:26725739

  7. ADMET Evaluation in Drug Discovery. 16. Predicting hERG Blockers by Combining Multiple Pharmacophores and Machine Learning Approaches.

    PubMed

    Wang, Shuangquan; Sun, Huiyong; Liu, Hui; Li, Dan; Li, Youyong; Hou, Tingjun

    2016-08-01

    Blockade of human ether-à-go-go related gene (hERG) channel by compounds may lead to drug-induced QT prolongation, arrhythmia, and Torsades de Pointes (TdP), and therefore reliable prediction of hERG liability in the early stages of drug design is quite important to reduce the risk of cardiotoxicity-related attritions in the later development stages. In this study, pharmacophore modeling and machine learning approaches were combined to construct classification models to distinguish hERG active from inactive compounds based on a diverse data set. First, an optimal ensemble of pharmacophore hypotheses that had good capability to differentiate hERG active from inactive compounds was identified by the recursive partitioning (RP) approach. Then, the naive Bayesian classification (NBC) and support vector machine (SVM) approaches were employed to construct classification models by integrating multiple important pharmacophore hypotheses. The integrated classification models showed improved predictive capability over any single pharmacophore hypothesis, suggesting that the broad binding polyspecificity of hERG can only be well characterized by multiple pharmacophores. The best SVM model achieved the prediction accuracies of 84.7% for the training set and 82.1% for the external test set. Notably, the accuracies for the hERG blockers and nonblockers in the test set reached 83.6% and 78.2%, respectively. Analysis of significant pharmacophores helps to understand the multimechanisms of action of hERG blockers. We believe that the combination of pharmacophore modeling and SVM is a powerful strategy to develop reliable theoretical models for the prediction of potential hERG liability.

  8. Sterols of Saccharomyces cerevisiae erg6 Knockout Mutant Expressing the Pneumocystis carinii S-Adenosylmethionine:Sterol C-24 Methyltransferase.

    PubMed

    Kaneshiro, Edna S; Johnston, Laura Q; Nkinin, Stephenson W; Romero, Becky I; Giner, José-Luis

    2015-01-01

    The AIDS-associated lung pathogen Pneumocystis is classified as a fungus although Pneumocystis has several distinct features such as the absence of ergosterol, the major sterol of most fungi. The Pneumocystis carinii S-adenosylmethionine:sterol C24-methyltransferase (SAM:SMT) enzyme, coded by the erg6 gene, transfers either one or two methyl groups to the C-24 position of the sterol side chain producing both C28 and C29 24-alkylsterols in approximately the same proportions, whereas most fungal SAM:SMT transfer only one methyl group to the side chain. The sterol compositions of wild-type Sacchromyces cerevisiae, the erg6 knockout mutant (Δerg6), and Δerg6 expressing the P. carinii or the S. cerevisiae erg6 gene were analyzed by a variety of chromatographic and spectroscopic procedures to examine functional complementation in the yeast expression system. Detailed sterol analyses were obtained using high performance liquid chromatography and proton nuclear magnetic resonance spectroscopy ((1)H-NMR). The P. carinii SAM:SMT in the Δerg6 restored its ability to produce the C28 sterol ergosterol as the major sterol, and also resulted in low levels of C29 sterols. This indicates that while the P. carinii SAM:SMT in the yeast Δerg6 cells was able to transfer a second methyl group to the side chain, the action of Δ(24(28)) -sterol reductase (coded by the erg4 gene) in the yeast cells prevented the formation and accumulation of as many C29 sterols as that found in P. carinii.

  9. Inhibition of hERG potassium channel by the antiarrhythmic agent mexiletine and its metabolite m-hydroxymexiletine.

    PubMed

    Gualdani, Roberta; Tadini-Buoninsegni, Francesco; Roselli, Mariagrazia; Defrenza, Ivana; Contino, Marialessandra; Colabufo, Nicola Antonio; Lentini, Giovanni

    2015-10-01

    Mexiletine is a sodium channel blocker, primarily used in the treatment of ventricular arrhythmias. Moreover, recent studies have demonstrated its therapeutic value to treat myotonic syndromes and to relieve neuropathic pain. The present study aims at investigating the direct blockade of hERG potassium channel by mexiletine and its metabolite m-hydroxymexiletine (MHM). Our data show that mexiletine inhibits hERG in a time- and voltage-dependent manner, with an IC50 of 3.7 ± 0.7 μmol/L. Analysis of the initial onset of current inhibition during a depolarizing test pulse indicates mexiletine binds preferentially to the open state of the hERG channel. Looking for a possible mexiletine alternative, we show that m-hydroxymexiletine (MHM), a minor mexiletine metabolite recently reported to be as active as the parent compound in an arrhythmia animal model, is a weaker hERG channel blocker, compared to mexiletine (IC50 = 22.4 ± 1.2 μmol/L). The hERG aromatic residues located in the S6 helix (Tyr652 and Phe656) are crucial in the binding of mexiletine and the different affinities of mexiletine and MHM with hERG channel are interpreted by modeling their corresponding binding interactions through ab initio calculations. The simulations demonstrate that the introduction of a hydroxyl group on the meta-position of the aromatic portion of mexiletine weakens the interaction of the drug xylyloxy moiety with Tyr652. These results provide further insights into the molecular basis of drug/hERG interactions and, in agreement with previously reported results on clofilium and ibutilide analogs, support the possibility of reducing hERG potency and related toxicity by modifying the aromatic pattern of substitution of clinically relevant compounds. PMID:26516576

  10. Inhibition of hERG potassium channel by the antiarrhythmic agent mexiletine and its metabolite m-hydroxymexiletine

    PubMed Central

    Gualdani, Roberta; Tadini-Buoninsegni, Francesco; Roselli, Mariagrazia; Defrenza, Ivana; Contino, Marialessandra; Colabufo, Nicola Antonio; Lentini, Giovanni

    2015-01-01

    Mexiletine is a sodium channel blocker, primarily used in the treatment of ventricular arrhythmias. Moreover, recent studies have demonstrated its therapeutic value to treat myotonic syndromes and to relieve neuropathic pain. The present study aims at investigating the direct blockade of hERG potassium channel by mexiletine and its metabolite m-hydroxymexiletine (MHM). Our data show that mexiletine inhibits hERG in a time- and voltage-dependent manner, with an IC50 of 3.7 ± 0.7 μmol/L. Analysis of the initial onset of current inhibition during a depolarizing test pulse indicates mexiletine binds preferentially to the open state of the hERG channel. Looking for a possible mexiletine alternative, we show that m-hydroxymexiletine (MHM), a minor mexiletine metabolite recently reported to be as active as the parent compound in an arrhythmia animal model, is a weaker hERG channel blocker, compared to mexiletine (IC50 = 22.4 ± 1.2 μmol/L). The hERG aromatic residues located in the S6 helix (Tyr652 and Phe656) are crucial in the binding of mexiletine and the different affinities of mexiletine and MHM with hERG channel are interpreted by modeling their corresponding binding interactions through ab initio calculations. The simulations demonstrate that the introduction of a hydroxyl group on the meta-position of the aromatic portion of mexiletine weakens the interaction of the drug xylyloxy moiety with Tyr652. These results provide further insights into the molecular basis of drug/hERG interactions and, in agreement with previously reported results on clofilium and ibutilide analogs, support the possibility of reducing hERG potency and related toxicity by modifying the aromatic pattern of substitution of clinically relevant compounds. PMID:26516576

  11. TMPRSS2:ERG Gene Fusion Predicts Subsequent Detection of Prostate Cancer in Patients With High-Grade Prostatic Intraepithelial Neoplasia

    PubMed Central

    Park, Kyung; Dalton, James T.; Narayanan, Ramesh; Barbieri, Christopher E.; Hancock, Michael L.; Bostwick, David G.; Steiner, Mitchell S.; Rubin, Mark A.

    2014-01-01

    Purpose High-grade prostatic intraepithelial neoplasia (HGPIN) is considered a precursor lesion of prostate cancer (PCa). The predictive value of ERG gene fusion in HGPIN for PCa was interrogated as a post hoc analysis in the context of a randomized clinical trial. Patients and Methods The GTx Protocol G300104 randomly assigned 1,590 men with biopsy-diagnosed HGPIN to receive toremifene or placebo for 3 years or until a diagnosis of PCa was made on prostate biopsy. As part of this phase III clinical trial, a central pathologist evaluated biopsies of patients with isolated HGPIN at baseline and 12, 24, and 36 months of follow-up. ERG immunohistochemistry was performed on biopsies from 461 patients and evaluated for protein overexpression. Results ERG expression was detected in 11.1% of patients (51 of 461 patients) with isolated HGPIN. In the first year and during the 3-year clinical trial, 14.7% and 36.9% of 461 patients were diagnosed with PCa, respectively. Patients with ERG expression were more likely to develop PCa, with 27 (53%) of 51 ERG-positive and 143 (35%) of 410 ERG-negative patients experiencing progression to PCa (P = .014, Fisher's exact test). ERG expression was not associated with age, baseline PSA, Gleason score, or tumor volume. Conclusion This study underscores the necessity of more stringent follow-up for men with HGPIN that is also positive for ERG overexpression. Clinicians should consider molecular characterization of HGPIN as a means to improve risk stratification. PMID:24297949

  12. ADMET Evaluation in Drug Discovery. 16. Predicting hERG Blockers by Combining Multiple Pharmacophores and Machine Learning Approaches.

    PubMed

    Wang, Shuangquan; Sun, Huiyong; Liu, Hui; Li, Dan; Li, Youyong; Hou, Tingjun

    2016-08-01

    Blockade of human ether-à-go-go related gene (hERG) channel by compounds may lead to drug-induced QT prolongation, arrhythmia, and Torsades de Pointes (TdP), and therefore reliable prediction of hERG liability in the early stages of drug design is quite important to reduce the risk of cardiotoxicity-related attritions in the later development stages. In this study, pharmacophore modeling and machine learning approaches were combined to construct classification models to distinguish hERG active from inactive compounds based on a diverse data set. First, an optimal ensemble of pharmacophore hypotheses that had good capability to differentiate hERG active from inactive compounds was identified by the recursive partitioning (RP) approach. Then, the naive Bayesian classification (NBC) and support vector machine (SVM) approaches were employed to construct classification models by integrating multiple important pharmacophore hypotheses. The integrated classification models showed improved predictive capability over any single pharmacophore hypothesis, suggesting that the broad binding polyspecificity of hERG can only be well characterized by multiple pharmacophores. The best SVM model achieved the prediction accuracies of 84.7% for the training set and 82.1% for the external test set. Notably, the accuracies for the hERG blockers and nonblockers in the test set reached 83.6% and 78.2%, respectively. Analysis of significant pharmacophores helps to understand the multimechanisms of action of hERG blockers. We believe that the combination of pharmacophore modeling and SVM is a powerful strategy to develop reliable theoretical models for the prediction of potential hERG liability. PMID:27379394

  13. Effects of Tannic Acid, Green Tea and Red Wine on hERG Channels Expressed in HEK293 Cells

    PubMed Central

    Xu, Bingyuan; Li, Wenya; Lin, Yue; Sun, Xiaorun; Ding, Chunhua; Zhang, Xuan

    2015-01-01

    Tannic acid presents in varying concentrations in plant foods, and in relatively high concentrations in green teas and red wines. Human ether-à-go-go-related gene (hERG) channels expressed in multiple tissues (e.g. heart, neurons, smooth muscle and cancer cells), and play important roles in modulating cardiac action potential repolarization and tumor cell biology. The present study investigated the effects of tannic acid, green teas and red wines on hERG currents. The effects of tannic acid, teas and red wines on hERG currents stably transfected in HEK293 cells were studied with a perforated patch clamp technique. In this study, we demonstrated that tannic acid inhibited hERG currents with an IC50 of 3.4 μM and ~100% inhibition at higher concentrations, and significantly shifted the voltage dependent activation to more positive potentials (Δ23.2 mV). Remarkably, a 100-fold dilution of multiple types of tea (green tea, oolong tea and black tea) or red wine inhibited hERG currents by ~90%, and significantly shifted the voltage dependent activation to more positive potentials (Δ30.8 mV and Δ26.0 mV, respectively). Green tea Lung Ching and red wine inhibited hERG currents, with IC50 of 0.04% and 0.19%, respectively. The effects of tannic acid, teas and red wine on hERG currents were irreversible. These results suggest tannic acid is a novel hERG channel blocker and consequently provide a new mechanistic evidence for understanding the effects of tannic acid. They also revealed the potential pharmacological basis of tea- and red wine-induced biology activities. PMID:26625122

  14. Utility of a Monoclonal ERG/FLI1 Antibody for Immunohistochemical Discrimination of Ewing’s Family Tumors

    PubMed Central

    Tomlins, Scott A.; Palanisamy, Nallasivam; Brenner, J. Chad; Stall, Jennifer N.; Siddiqui, Javed; Thomas, Dafydd G.; Lucas, David R.; Chinnaiyan, Arul M.; Kunju, Lakshmi P.

    2013-01-01

    Ewing family tumors (EFTs) and prostate carcinomas (PCa) are characterized by rearrangement of ETS genes, most commonly FLI1 (EFTs) and ERG (PCa). Previously, we characterized an antibody against ERG (EPR3864) for detecting ERG-rearranged PCa. EPR3864 also cross reacts with FLI1, thus, here we evaluated the utility of EPR3864 for discriminating EFTs from other small round blue cell tumors (SRBCTs) by immunohistochemistry. Of 57 evaluable EFTs, 47 (82%) demonstrated at least moderate, diffuse, nuclear ERG/FLI1 staining (including 89% and 100% of cases with confirmed EWSR1:FLI1 and EWSR1:ERG fusions, respectively), of which 1, 3 and 43 showed negative, cytoplasmic or membranous CD99 staining, respectively. Amongst other SRBCTs (n=61 cases, 6 types), at least moderate, diffuse, nuclear EPR3864 staining was seen in all precursor-B-lymphoblastic lymphomas/leukemias and subsets of Burkitt’s lymphomas (10%) and synovial sarcomas (45%). In summary, EPR3864 may have utility for detecting EWSR1:FLI1 and EWSR1:ERG rearranged EFTs, in addition to PCa. PMID:23690120

  15. Use of molecular modeling aided design to dial out hERG liability in adenosine A(2A) receptor antagonists.

    PubMed

    Deng, Qiaolin; Lim, Yeon-Hee; Anand, Rajan; Yu, Younong; Kim, Jae-hun; Zhou, Wei; Zheng, Junying; Tempest, Paul; Levorse, Dorothy; Zhang, Xiaoping; Greene, Scott; Mullins, Deborra; Culberson, Chris; Sherborne, Brad; Parker, Eric M; Stamford, Andrew; Ali, Amjad

    2015-08-01

    Molecular modeling was performed on a triazolo quinazoline lead compound to help develop a series of adenosine A2A receptor antagonists with improved hERG profile. Superposition of the lead compound onto MK-499, a benchmark hERG inhibitor, combined with pKa calculations and measurement, identified terminal fluorobenzene to be responsible for hERG activity. Docking of the lead compound into an A2A crystal structure suggested that this group is located at a flexible, spacious, and solvent-exposed opening of the binding pocket, making it possible to tolerate various functional groups. Transformation analysis (MMP, matched molecular pair) of in-house available experimental data on hERG provided suggestions for modifications in order to mitigate this liability. This led to the synthesis of a series of compounds with significantly reduced hERG activity. The strategy used in the modeling work can be applied to other medicinal chemistry programs to help improve hERG profile. PMID:26048804

  16. Inner retinal contributions to the multifocal electroretinogram: patients with Leber's hereditary optic neuropathy (LHON). Multifocal ERG in patients with LHON.

    PubMed

    Kurtenbach, Anne; Leo-Kottler, Beate; Zrenner, Eberhart

    2004-05-01

    In this study we examine the multifocal electroretinogram (mfERG) recorded from patients suffering from Leber's hereditary optic neuropathy (LHON), a degeneration of the ganglion cell and nerve fibre layers of the retina. We compared the mfERGs recorded from 11 patients with LHON, to those from 11 control subjects. The pattern ERG (PERG) was additionally performed with 9 of the patients. MfERGs were recorded and analysed using the VERIS 3.01 system with a stimulus of 103 equal-sized hexagons. For analysis, hexagons were grouped according to distance from the optic nerve head (ONH) and according to distance from the fovea. Two significant differences were found between the waveforms of the two groups: In the first order kernel, the control group showed a component around 34 ms that decreased with distance from the ONH. This component was reduced in the LHON group of subjects. In the second order (first slice) kernel, the patient group was missing features that decrease with distance from the fovea in the control group. PERG amplitudes showed a significant correlation with the amplitude of the second order mfERG kernel. The results show that the damage to ganglion cells and nerve fibres caused by LHON can be detected in mfERG recordings and indicate that activity from the inner retina can contribute significantly to first and second order waveforms.

  17. The role of TMPRSS2:ERG in molecular stratification of PCa and its association with tumor aggressiveness: a study in Brazilian patients.

    PubMed

    Eguchi, Flávia C; Faria, Eliney F; Scapulatempo Neto, Cristovam; Longatto-Filho, Adhemar; Zanardo-Oliveira, Cleyton; Taboga, Sebastião R; Campos, Silvana G P

    2014-07-10

    Recurrent gene fusions between the genes TMPRSS2 and ERG have been described in prostate cancer (PCa) and are found in 27% to 79% of radical prostatectomy. This fusion transcription results in ERG overexpression, which can be detected by immunohistochemistry (IHC) and provide a potential diagnostic marker for PCa. Three tissue microarrays (TMAs) containing samples from 98 patients with PCa and one TMA of 27 samples from individuals without PCa were tested for ERG immunostaining, and the presence of TMPRSS2:ERG transcripts was confirmed by quantitative real time PCR (qRT-PCR). The results showed that 46.9% of tumors tested positive for ERG immunostaining, and this finding was consistent with the results of qRT-PCR testing (k = 0.694, p < 0.001). IHC had a specificity of 83.3% and a sensitivity of 81% in detecting TMPRSS2:ERG fusion. Patients with PSA < 4.0 ng/mL showed positive immunoreactivity for ERG (p = 0.031). Kaplan-Meier analysis suggested that ERG expression did not influence the time of biochemical recurrence. This study demonstrates that both IHC and qRT-PCR are useful tools in detecting TMPRSS2:ERG fusions. A correlation between ERG expression and clinical and pathological parameters was not found, but the frequency, specificity and recurrence of ERG in PCa suggests that it may be a potential adjunct diagnostic tool.

  18. Sequence of Gating Charge Movement and Pore Gating in hERG Activation and Deactivation Pathways

    PubMed Central

    Goodchild, Samuel J.; Macdonald, Logan C.; Fedida, David

    2015-01-01

    KV11.1 voltage-gated K+ channels are noted for unusually slow activation, fast inactivation, and slow deactivation kinetics, which tune channel activity to provide vital repolarizing current during later stages of the cardiac action potential. The bulk of charge movement in human ether-a-go-go-related gene (hERG) is slow, as is return of charge upon repolarization, suggesting that the rates of hERG channel opening and, critically, that of deactivation might be determined by slow voltage sensor movement, and also by a mode-shift after activation. To test these ideas, we compared the kinetics and voltage dependence of ionic activation and deactivation with gating charge movement. At 0 mV, gating charge moved ∼threefold faster than ionic current, which suggests the presence of additional slow transitions downstream of charge movement in the physiological activation pathway. A significant voltage sensor mode-shift was apparent by 24 ms at +60 mV in gating currents, and return of charge closely tracked pore closure after pulses of 100 and 300 ms duration. A deletion of the N-terminus PAS domain, mutation R4AR5A or the LQT2-causing mutation R56Q gave faster-deactivating channels that displayed an attenuated mode-shift of charge. This indicates that charge movement is perturbed by N- and C-terminus interactions, and that these domain interactions stabilize the open state and limit the rate of charge return. We conclude that slow on-gating charge movement can only partly account for slow hERG ionic activation, and that the rate of pore closure has a limiting role in the slow return of gating charges. PMID:25809256

  19. A comparison among different techniques for human ERG signals processing and classification.

    PubMed

    Barraco, R; Persano Adorno, D; Brai, M; Tranchina, L

    2014-02-01

    Feature detection in biomedical signals is crucial for deepening our knowledge about the involved physiological processes. To achieve this aim, many analytic approaches can be applied but only few are able to deal with signals whose time dependent features provide useful clinical information. Among the biomedical signals, the electroretinogram (ERG), that records the retinal response to a light flash, can improve our comprehension of the complex photoreceptoral activities. The present study is focused on the analysis of the early response of the photoreceptoral human system, known as a-wave ERG-component. This wave reflects the functional integrity of the photoreceptors, rods and cones, whose activation dynamics are not yet completely understood. Moreover, since in incipient photoreceptoral pathologies eventual anomalies in a-wave are not always detectable with a "naked eye" analysis of the traces, the possibility to discriminate pathologic from healthy traces, by means of appropriate analytical techniques, could help in clinical diagnosis. In the present paper, we discuss and compare the efficiency of various techniques of signal processing, such as Fourier analysis (FA), Principal Component Analysis (PCA), Wavelet Analysis (WA) in recognising pathological traces from the healthy ones. The investigated retinal pathologies are Achromatopsia, a cone disease and Congenital Stationary Night Blindness, affecting the photoreceptoral signal transmission. Our findings prove that both PCA and FA of conventional ERGs, don't add clinical information useful for the diagnosis of ocular pathologies, whereas the use of a more sophisticated analysis, based on the wavelet transform, provides a powerful tool for routine clinical examinations of patients. PMID:23590981

  20. 'Unilateral cone dystrophy': ERG changes implicate abnormal signaling by hyperpolarizing bipolar and/or horizontal cells.

    PubMed Central

    Sieving, P A

    1994-01-01

    The two cases described here appear to represent the infrequently reported entity of "unilateral cone (cone-rod) dystrophy." Both cases give the suggestion that daylight vision can be affected by abnormalities in visual signals in the proximal retina, after they leave the cone photoreceptors themselves. The ERG waveform changes in these two cases are consistent with a deficit in signaling by the hyperpolarizing bipolar cells, and the complaint of abnormal color perception in both cases presented here raises the possibility that the OFF-pathway through hyperpolarizing bipolar cells may be important for color processing. PMID:7886877

  1. MicroRNA-224 targets ERG2 and contributes to malignant progressions of meningioma

    SciTech Connect

    Wang, Maomao; Deng, Xiaodong; Ying, Qi; Jin, Tingyan; Li, Ming; Liang, Chong

    2015-05-01

    MicroRNA-224 is overexpressed in various malignant tumors with poor prognosis, which plays a critical role in biological processes including cell proliferation, apoptosis and several developmental and physiological progressions. However, the potential association between miR-224 and clinical outcome in patients with meningiomas remains unknown. Here, we investigate miR-224 expression and biological functions in meningiomas. MiR-224 expression was measured by Northern blot analysis and quantitative reverse transcription-polymerase chain reaction (qRT-PCR) in meningioma and normal brain tissues. Kaplan–Meier analysis and Cox regression analysis were used to exam its correlation with clinicopathological features and prognostic value. The biological effects of miR-224 on the cell proliferation and apoptosis in meningioma cells were examined by MTT assay and apoptosis assay. We found the expression levels of miR-224 were significantly higher in meningioma tissues than that in normal brain, positively correlated with advanced pathological grade. Kaplan–Meier analysis indicated that meningioma patients with low miR-224 expression exhibited significantly prolonged overall and recurrence-free survival. Furthermore, we demonstrated that ERG2 was an identical candidate target gene of MiR-224 in vitro. Our results indicated that downregulation of miR-224 suppressed cell growth and resulted in the enhancement of cell apoptosis through activation of the ERG2-BAK-induced apoptosis pathway. Our findings imply the miR-224 expression could predict the overall survival and recurrence-free survival of patients with meningioma and it might be a promising therapeutic target for treating malignant meningiomas. - Highlights: • MiR-224 expression is correlates with prognosis in meningioma patients. • ERG2 is a novel downstream target of miR-224. • MiR-224 suppressed cell growth and enhanced apoptosis in IOMM-Lee and CH157 cells. • MiR-224 is an upstream regulator of the ERG2

  2. Prostate cancer genes associated with TMPRSS2–ERG gene fusion and prognostic of biochemical recurrence in multiple cohorts

    PubMed Central

    Barwick, B G; Abramovitz, M; Kodani, M; Moreno, C S; Nam, R; Tang, W; Bouzyk, M; Seth, A; Leyland-Jones, B

    2010-01-01

    Background: Recent studies have indicated that prostate cancer patients with the TMPRSS2–ERG gene fusion have a higher risk of recurrence. To identify markers associated with TMPRSS2–ERG fusion and prognostic of biochemical recurrence, we analysed a cohort of 139 men with prostate cancer for 502 molecular markers. Methods: RNA from radical prostatectomy tumour specimens was analysed using cDNA-mediated, annealing, selection, extension and ligation (DASL) to determine mRNAs associated with TMPRSS2–ERG T1/E4 fusion and prognostic of biochemical recurrence. Differentially expressed mRNAs in T1/E4-positive tumours were determined using significance analysis of microarrays (false discovery rate (FDR) <5%). Univariate and multivariate Cox regression determined genes, gene signatures and clinical factors prognostic of recurrence (P-value <0.05, log–rank test). Analysis of two prostate microarray studies (GSE1065 and GSE8402) validated the findings. Results: In the 139 patients from this study and from a 455-patient Swedish cohort, 15 genes in common were differentially regulated in T1/E4 fusion-positive tumours (FDR <0.05). The most significant mRNAs in both cohorts coded ERG. Nine genes were found prognostic of recurrence in this study and in a 596-patient Minnesota cohort. A molecular recurrence score was significant in prognosticating recurrence (P-value 0.000167) and remained significant in multivariate analysis of a mixed clinical model considering Gleason score and TMPRSS2–ERG fusion status. Conclusions: TMPRSS2–ERG T1/E4 fusion-positive tumours had differentially regulated mRNAs observed in multiple studies, the most significant one coded for ERG. Several mRNAs were consistently associated with biochemical recurrence and have potential clinical utility but will require further validation for successful translation. PMID:20068566

  3. ERG AND CHD1 HETEROGENEITY IN PROSTATE CANCER: USE OF CONFOCAL MICROSCOPY IN ASSESSMENT OF MICROSCOPIC FOCI

    PubMed Central

    Tereshchenko; Zhong, H; Santanam, U; Petrosky, W; Stein, MN; Dvorzhinski, D; Ganesan, S; Singer, E; Moore, D; Tischfield, J; DiPaola, RS

    2014-01-01

    Background Biomarkers predicting tumor response are important to emerging targeted therapeutics. Complimentary methods to assess and understand genetic changes and heterogeneity within only few cancer cells in tissue will be a valuable addition for assessment of tumors such as prostate cancer that often have insufficient tumor for next generation sequencing in a single biopsy core. Methods Using confocal microscopy to identify cell-to-cell relationships in situ, we studied the most common gene rearrangement in prostate cancer (TMPRSS2 and ERG) and the tumor suppressor CHD1 in 56 patients who underwent radical prostatectomy. Contingency tables and the chi-square test were used to determine associations between mutation status of the genes and tumor phenotype. Results Wild type ERG was found in 22 of 56 patients; ERG copy number was increased in 10/56, and ERG rearrangements confirmed in 24/56 patients. In 24 patients with ERG rearrangements, the mechanisms of rearrangement were heterogeneous, with deletion in 14/24, a split event in 7/24, and both deletions and split events in the same tumor focus in 3/24 patients. Overall, 14/45 (31.1%) of patients had CHD1 deletion, with the majority of patients with CHD1 deletions (13/14) correlating with ERG-rearrangement negative status (p< 0.01). Conclusions These results demonstrate the ability of confocal microscopy and FISH to identify the cell-to-cell differences in common gene fusions such as TMPRSS2–ERG that may arise independently within the same tumor focus. These data support the need to study complimentary approaches to assess genetic changes that may stratify therapy based on predicted sensitivities. PMID:25175909

  4. Growth of ˜5 cm2V-1s-1 mobility, p-type Copper(I) oxide (Cu2O) films by fast atmospheric atomic layer deposition (AALD) at 225°C and below

    NASA Astrophysics Data System (ADS)

    Muñoz-Rojas, D.; Jordan, M.; Yeoh, C.; Marin, A. T.; Kursumovic, A.; Dunlop, L. A.; Iza, D. C.; Chen, A.; Wang, H.; MacManus Driscoll, J. L.

    2012-12-01

    Phase pure, dense Cu2O thin films were grown on glass and polymer substrates at 225°C by rapid atmospheric atomic layer deposition (AALD). Carrier mobilities of 5 cm2V-1s-1 and carrier concentrations of ˜1016 cm-3 were achieved in films of thickness 50 - 120 nm, over a >10 cm2 area. Growth rates were ˜1 nm.min-1 which is two orders of magnitude faster than conventional ALD.. The high mobilities achieved using the atmospheric, low temperature method represent a significant advance for flextronics and flexible solar cells which require growth on plastic substrates.

  5. Efficient diterpene production in yeast by engineering Erg20p into a geranylgeranyl diphosphate synthase.

    PubMed

    Ignea, Codruta; Trikka, Fotini A; Nikolaidis, Alexandros K; Georgantea, Panagiota; Ioannou, Efstathia; Loupassaki, Sofia; Kefalas, Panagiotis; Kanellis, Angelos K; Roussis, Vassilios; Makris, Antonios M; Kampranis, Sotirios C

    2015-01-01

    Terpenes have numerous applications, ranging from pharmaceuticals to fragrances and biofuels. With increasing interest in producing terpenes sustainably and economically, there has been significant progress in recent years in developing methods for their production in microorganisms. In Saccharomyces cerevisiae, production of the 20-carbon diterpenes has so far proven to be significantly less efficient than production of their 15-carbon sesquiterpene counterparts. In this report, we identify the modular structure of geranylgeranyl diphosphate synthesis in yeast to be a major limitation in diterpene yields, and we engineer the yeast farnesyl diphosphate synthase Erg20p to produce geranylgeranyl diphosphate. Using a combination of protein and genetic engineering, we achieve significant improvements in the production of sclareol and several other isoprenoids, including cis-abienol, abietadiene and β-carotene. We also report the development of yeast strains carrying the engineered Erg20p, which support efficient isoprenoid production and can be used as a dedicated chassis for diterpene production or biosynthetic pathway elucidation. The design developed here can be applied to the production of any GGPP-derived isoprenoid and is compatible with other yeast terpene production platforms.

  6. A functional Kv1.2-hERG chimaeric channel expressed in Pichia pastoris

    NASA Astrophysics Data System (ADS)

    Dhillon, Mandeep S.; Cockcroft, Christopher J.; Munsey, Tim; Smith, Kathrine J.; Powell, Andrew J.; Carter, Paul; Wrighton, David C.; Rong, Hong-Lin; Yusaf, Shahnaz P.; Sivaprasadarao, Asipu

    2014-02-01

    Members of the six-transmembrane segment family of ion channels share a common structural design. However, there are sequence differences between the members that confer distinct biophysical properties on individual channels. Currently, we do not have 3D structures for all members of the family to help explain the molecular basis for the differences in their biophysical properties and pharmacology. This is due to low-level expression of many members in native or heterologous systems. One exception is rat Kv1.2 which has been overexpressed in Pichia pastoris and crystallised. Here, we tested chimaeras of rat Kv1.2 with the hERG channel for function in Xenopus oocytes and for overexpression in Pichia. Chimaera containing the S1-S6 transmembrane region of HERG showed functional and pharmacological properties similar to hERG and could be overexpressed and purified from Pichia. Our results demonstrate that rat Kv1.2 could serve as a surrogate to express difficult-to-overexpress members of the six-transmembrane segment channel family.

  7. Structural insight into the transmembrane segments 3 and 4 of the hERG potassium channel.

    PubMed

    Li, Qingxin; Wong, Ying Lei; Ng, Hui Qi; Gayen, Shovanlal; Kang, CongBao

    2014-12-01

    The hERG (human ether-a-go-go related gene) potassium channel is a voltage-gated potassium channel containing an N-terminal domain, a voltage-sensor domain, a pore domain and a C-terminal domain. The transmembrane segment 4 (S4) is important for sensing changes of membrane potentials through positively charge residues. A construct containing partial S2-S3 linker, S3, S4 and the S4-S5 linker of the hERG channel was purified into detergent micelles. This construct exhibits good quality NMR spectrum when it was purified in lyso-myristoyl phosphatidylglycerol (LMPG) micelles. Structural study showed that S3 contains two short helices with a negatively charged surface. The S4 and S4-S5 linker adopt helical structures. The six positively charged residues in S4 localize at different sides, suggesting that they may have different functions in channel gating. Relaxation studies indicated that S3 is more flexible than S4. The boundaries of S3-S4 and S4-S4-S5 linker were identified. Our results provided structural information of the S3 and S4, which will be helpful to understand their roles in channel gating.

  8. The Human Ether-a-go-go-related Gene (hERG) Potassium Channel Represents an Unusual Target for Protease-mediated Damage.

    PubMed

    Lamothe, Shawn M; Guo, Jun; Li, Wentao; Yang, Tonghua; Zhang, Shetuan

    2016-09-23

    The human ether-a-go-go-related gene (hERG) encodes the pore-forming subunit of the rapidly activating delayed rectifier potassium channel (IKr), which is important for cardiac repolarization. Dysfunction of hERG causes long QT syndrome and sudden death, which occur in patients with cardiac ischemia. Cardiac ischemia is also associated with activation, up-regulation, and secretion of various proteolytic enzymes. Here, using whole-cell patch clamp and Western blotting analysis, we demonstrate that the hERG/IKr channel was selectively cleaved by the serine protease, proteinase K (PK). Using molecular biology techniques including making a chimeric channel between protease-sensitive hERG and insensitive human ether-a-go-go (hEAG), as well as application of the scorpion toxin BeKm-1, we identified that the S5-pore linker of hERG is the target domain for proteinase K cleavage. To investigate the physiological relevance of the unique susceptibility of hERG to proteases, we show that cardiac ischemia in a rabbit model was associated with a reduction in mature ERG expression and an increase in the expression of several proteases, including calpain. Using cell biology approaches, we found that calpain-1 was actively released into the extracellular milieu and cleaved hERG at the S5-pore linker. Using protease cleavage-predicting software and site-directed mutagenesis, we identified that calpain-1 cleaves hERG at position Gly-603 in the S5-pore linker of hERG. Clarification of protease-mediated damage of hERG extends our understanding of hERG regulation. Damage of hERG mediated by proteases such as calpain may contribute to ischemia-associated QT prolongation and sudden cardiac death.

  9. The Human Ether-a-go-go-related Gene (hERG) Potassium Channel Represents an Unusual Target for Protease-mediated Damage.

    PubMed

    Lamothe, Shawn M; Guo, Jun; Li, Wentao; Yang, Tonghua; Zhang, Shetuan

    2016-09-23

    The human ether-a-go-go-related gene (hERG) encodes the pore-forming subunit of the rapidly activating delayed rectifier potassium channel (IKr), which is important for cardiac repolarization. Dysfunction of hERG causes long QT syndrome and sudden death, which occur in patients with cardiac ischemia. Cardiac ischemia is also associated with activation, up-regulation, and secretion of various proteolytic enzymes. Here, using whole-cell patch clamp and Western blotting analysis, we demonstrate that the hERG/IKr channel was selectively cleaved by the serine protease, proteinase K (PK). Using molecular biology techniques including making a chimeric channel between protease-sensitive hERG and insensitive human ether-a-go-go (hEAG), as well as application of the scorpion toxin BeKm-1, we identified that the S5-pore linker of hERG is the target domain for proteinase K cleavage. To investigate the physiological relevance of the unique susceptibility of hERG to proteases, we show that cardiac ischemia in a rabbit model was associated with a reduction in mature ERG expression and an increase in the expression of several proteases, including calpain. Using cell biology approaches, we found that calpain-1 was actively released into the extracellular milieu and cleaved hERG at the S5-pore linker. Using protease cleavage-predicting software and site-directed mutagenesis, we identified that calpain-1 cleaves hERG at position Gly-603 in the S5-pore linker of hERG. Clarification of protease-mediated damage of hERG extends our understanding of hERG regulation. Damage of hERG mediated by proteases such as calpain may contribute to ischemia-associated QT prolongation and sudden cardiac death. PMID:27502273

  10. Loss of miR-449a in ERG-associated prostate cancer promotes the invasive phenotype by inducing SIRT1

    PubMed Central

    Kumar, Parameet; Sharad, Shashwat; Petrovics, Gyorgy; Mohamed, Ahmed; Dobi, Albert; Sreenath, Taduru L.; Srivastava, Shiv; Biswas, Roopa

    2016-01-01

    Epigenetic regulation by SIRT1, a multifaceted NAD+-dependent protein deacetylase, is one of the most common factors modulating cellular processes in a broad range of diseases, including prostate cancer (CaP). SIRT1 is over-expressed in CaP cells, however the associated mechanism is not well understood. To identify whether specific microRNAs might mediate this linkage, we have screened a miRNA library for differential expression in ERG-associated CaP tissues. Of 20 differentially and significantly expressed miRNAs that distinguish ERG-positive tumors from ERG-negative tumors, we find miR-449a is highly suppressed in ERG-positive tumors. We establish that SIRT1 is a direct target of miR-449a and is also induced by ERG in ERG-associated CaP. Our data suggest that attenuation of miR-449a promotes the invasive phenotype of the ERG-positive CaP in part by inducing the expression of SIRT1 in prostate cancer cells. Furthermore, we also find that suppression of SIRT1 results in a significant reduction in ERG expression in ERG-positive CaP cells, indicating a feed-back regulatory loop associated with ERG, miR-449a and SIRT1. We also report that ERG suppresses p53 acetylation perhaps through miR-449a-SIRT1 axis in CaP cells. Our findings provide new insight into the function of miRNAs in regulating ERG-associated CaP. Thus, miR-449a activation or SIRT1 suppression may represent new therapeutic opportunity for ERG-associated CaP. PMID:26988912

  11. Prospective validation of a comprehensive in silico hERG model and its applications to commercial compound and drug databases.

    PubMed

    Doddareddy, Munikumar R; Klaasse, Elisabeth C; Shagufta; Ijzerman, Adriaan P; Bender, Andreas

    2010-05-01

    Ligand-based in silico hERG models were generated for 2 644 compounds using linear discriminant analysis (LDA) and support vector machines (SVM). As a result, the dataset used for the model generation is the largest publicly available (see Supporting Information). Extended connectivity fingerprints (ECFPs) and functional class fingerprints (FCFPs) were used to describe chemical space. All models showed area under curve (AUC) values ranging from 0.89 to 0.94 in a fivefold cross-validation, indicating high model consistency. Models correctly predicted 80 % of an additional, external test set; Y-scrambling was also performed to rule out chance correlation. Additionally models based on patch clamp data and radioligand binding data were generated separately to analyze their predictive ability when compared to combined models. To experimentally validate the models, 50 of the predicted hERG blockers from the Chembridge database and ten of the predicted non-hERG blockers from an in-house compound library were selected for biological evaluation. Out of those 50 predicted hERG blockers, tested at a concentration of 10 microM, 18 compounds showed more than 50 % displacement of [(3)H]astemizole binding to cell membranes expressing the hERG channel. K(i) values of four of the selected binders were determined to be in the micromolar and high nanomolar range (K(i) (VH01)=2.0 microM, K(i) (VH06)=0.15 microM, K(i) (VH19)=1.1 microM and K(i) (VH47)=18 microM). Of these four compounds, VH01 and VH47 showed also a second, even higher affinity binding site with K(i) values of 7.4 nM and 36 nM, respectively. In the case of non-hERG blockers, all ten compounds tested were found to be inactive, showing less than 50 % displacement of [(3)H]astemizole binding at 10 microM. These experimentally validated models were then used to virtually screen commercial compound databases to evaluate whether they contain hERG blockers. 109 784 (23 %) of Chembridge, 133 175 (38 %) of Chemdiv, 111 737 (31

  12. hERG blocking potential of acids and zwitterions characterized by three thresholds for acidity, size and reactivity.

    PubMed

    Nikolov, Nikolai G; Dybdahl, Marianne; Jónsdóttir, Svava Ó; Wedebye, Eva B

    2014-11-01

    Ionization is a key factor in hERG K(+) channel blocking, and acids and zwitterions are known to be less probable hERG blockers than bases and neutral compounds. However, a considerable number of acidic compounds block hERG, and the physico-chemical attributes which discriminate acidic blockers from acidic non-blockers have not been fully elucidated. We propose a rule for prediction of hERG blocking by acids and zwitterionic ampholytes based on thresholds for only three descriptors related to acidity, size and reactivity. The training set of 153 acids and zwitterionic ampholytes was predicted with a concordance of 91% by a decision tree based on the rule. Two external validations were performed with sets of 35 and 48 observations, respectively, both showing concordances of 91%. In addition, a global QSAR model of hERG blocking was constructed based on a large diverse training set of 1374 chemicals covering all ionization classes, externally validated showing high predictivity and compared to the decision tree. The decision tree was found to be superior for the acids and zwitterionic ampholytes classes.

  13. Diverse Anhydrous Silicates in a Fine-Grained Rim in the Weakly Altered CM2 Chondrite Queen Elizabeth Range 97990: Evidence for the Localized Preservation of Pristine Nebular Dust in CM Chondrites.

    NASA Astrophysics Data System (ADS)

    Brearley, A. J.

    2016-08-01

    A fine-grained rim the QUE 97990 CM2 chondrite contains diverse submicron crystalline anhydrous silicates, including olivines, low-Ca and high Ca pyroxenes and represents a more pristine sample of nebular dust than is present in most CM chondrites.

  14. Low-level laser therapy, at 60 J/cm2 associated with a Biosilicate® increase in bone deposition and indentation biomechanical properties of callus in osteopenic rats

    NASA Astrophysics Data System (ADS)

    Fangel, Renan; Sérgio Bossini, Paulo; Cláudia Renno, Ana; Araki Ribeiro, Daniel; Chenwei Wang, Charles; Luri Toma, Renata; Okino Nonaka, Keico; Driusso, Patrícia; Antonio Parizotto, Nivaldo; Oishi, Jorge

    2011-07-01

    We investigate the effects of a novel bioactive material (Biosilicate®) and low-level laser therapy (LLLT), at 60 J/cm2, on bone-fracture consolidation in osteoporotic rats. Forty female Wistar rats are submitted to the ovariectomy, to induce osteopenia. Eight weeks after the ovariectomy, the animals are randomly divided into four groups, with 10 animals each: bone defect control group; bone defect filled with Biosilicate group; bone defect irradiated with laser at 60 J/cm2 group; bone defect filled with Biosilicate and irradiated with LLLT, at 60 J/cm2 group. Laser irradiation is initiated immediately after surgery and performed every 48 h for 14 days. Histopathological analysis points out that bone defects are predominantly filled with the biomaterial in specimens treated with Biosilicate. In the 60-J/cm2 laser plus Biosilicate group, the biomaterial fills all bone defects, which also contained woven bone and granulation tissue. Also, the biomechanical properties are increased in the animals treated with Biosilicate associated to lasertherapy. Our results indicate that laser therapy improves bone repair process in contact with Biosilicate as a result of increasing bone formation as well as indentation biomechanical properties.

  15. Kv11.1 (hERG)-induced cardiotoxicity: a molecular insight from a binding kinetics study of prototypical Kv11.1 (hERG) inhibitors

    PubMed Central

    Yu, Z; IJzerman, A P; Heitman, L H

    2015-01-01

    Background and Purpose Drug-induced arrhythmia due to blockade of the Kv11.1 channel (also known as the hERG K+ channel) is a frequent side effect. Previous studies have primarily focused on equilibrium parameters, i.e. affinity or potency, of drug candidates at the channel. The aim of this study was to determine the kinetics of the interaction with the channel for a number of known Kv11.1 blockers and to explore a possible correlation with the affinity or physicochemical properties of these compounds. Experimental Approach The affinity and kinetic parameters of 15 prototypical Kv11.1 inhibitors were evaluated in a number of [3H]-dofetilide binding assays. The lipophilicity (logKW-C8) and membrane partitioning (logKW-IAM) of these compounds were determined by means of HPLC analysis. Key Results A novel [3H]-dofetilide competition association assay was set up and validated, which allowed us to determine the binding kinetics of the Kv11.1 blockers used in this study. Interestingly, the compounds' affinities (Ki values) were correlated to their association rates rather than dissociation rates. Overall lipophilicity or membrane partitioning of the compounds were not correlated to their affinity or rate constants for the channel. Conclusions and Implications A compound's affinity for the Kv11.1 channel is determined by its rate of association with the channel, while overall lipophilicity and membrane affinity are not. In more general terms, our findings provide novel insights into the mechanism of action for a compound's activity at the Kv11.1 channel. This may help to elucidate how Kv11.1-induced cardiotoxicity is governed and how it can be circumvented in the future. PMID:25296617

  16. Differential effects of blockade of ERG channels on gamma oscillations and excitability in rat hippocampal slices.

    PubMed

    Fano, Silvia; Çalışkan, Gürsel; Heinemann, Uwe

    2012-12-01

    Agents such as sertindole and astemizole affect heart action by inducing long-QT syndrome, suggesting that apart from their neuronal actions through histamine receptors, 5-HT2 serotonin receptors and D2 dopamine receptors they also affect ether-a-go-go channels and particularly ether-a-go-go-related (ERG) potassium (K(+)) channels, comprising the K(v) 11.1, K(v) 11.2 and K(v) 11.3 voltage-gated potassium currents. Changes in ERG K(+) channel expression and activity have been reported and may be linked to schizophrenia [Huffaker, S.J., Chen, J., Nicodemus, K.K., Sambataro, F., Yang, F., Mattay, V., Lipska, B.K., Hyde, T.M., Song, J., Rujescu, D., Giegling, I., Mayilyan, K., Proust, M.J., Soghoyan, A., Caforio, G., Callicott, J.H., Bertolino, A., Meyer-Lindenberg, A., Chang, J., Ji, Y., Egan, M.F., Goldberg, T.E., Kleinman, J.E., Lu, B. & Weinberger DR. (2009). Nat. Med., 15, 509-518; Shepard, P.D., Canavier, C.C. & Levitan, E.S. (2007). Schizophr Bull., 33, 1263-1269]. We have previously shown that histamine H1 blockers augment gamma oscillations (γ) which are thought to be involved in cognition and storage of information. These effects were particularly pronounced for γ induced by acetylcholine. Here we have compared neuronal effects of three agents which interfere with ERG K(+) channels. We found that astemizole and sertindole, but not the K(v) 11 channel blocker E4031, augmented γ induced by acetylcholine in hippocampal slices. Kainate-induced γ were only affected by astemizole. Evoked responses induced by stratum radiatum stimulation in area CA1 revealed that only E4031 augmented stimulus-induced synaptic potentials and neuronal excitability. Our findings suggest that K(v) 11 channels are involved in neuronal excitability without clear effects on γ and that the effect of astemizole is related to actions on H1 receptors. PMID:23050739

  17. De Par en Par, 10 & 11. (Wide Open, 10 & 11.)

    ERIC Educational Resources Information Center

    De Par en Par, 1997

    1997-01-01

    These two magazines, written entirely in Spanish, are designed for classroom use in the elementary grades. Number 10, focuses on ecology, discussing such topics as the greenhouse effect, endangered species, protecting the natural environment, tree planting, earthworms, natural waste, books on environmental subjects, saving the earth, and…

  18. Structural determinants for histamine H(1) affinity, hERG affinity and QTc prolongation in a series of terfenadine analogs.

    PubMed

    Aslanian, Robert; Piwinski, John J; Zhu, Xiaohong; Priestley, Tony; Sorota, Steve; Du, Xiao-Yi; Zhang, Xue-Song; McLeod, Robbie L; West, Robert E; Williams, Shirley M; Hey, John A

    2009-09-01

    In the late 1980's reports linking the non-sedating antihistamines terfenadine and astemizole with torsades de pointes, a form of ventricular tachyarrhythmia that can degenerate into ventricular fibrillation and sudden death, appeared in the clinical literature. A substantial body of evidence demonstrates that the arrhythmogenic effect of these cardiotoxic antihistamines, as well as a number of structurally related compounds, results from prolongation of the QT interval due to suppression of specific delayed rectifier ventricular K+ currents via blockade of the hERG-IKr channel. In order to better understand the structural requirements for hERG and H(1) binding for terfenadine, a series of analogs of terfenadine has been prepared and studied in both in vitro and in vivo hERG and H(1) assays. PMID:19660947

  19. Intrathecal administration of AAV/GALC vectors in 10-11-day-old twitcher mice improves survival and is enhanced by bone marrow transplant.

    PubMed

    Karumuthil-Melethil, Subha; Marshall, Michael S; Heindel, Clifford; Jakubauskas, Benas; Bongarzone, Ernesto R; Gray, Steven J

    2016-11-01

    Globoid cell leukodystrophy (GLD), or Krabbe disease, is an autosomal recessive neurodegenerative disease caused by the deficiency of the lysosomal enzyme galactocerebrosidase (GALC). Hematopoietic stem cell transplantation (HSCT) provides modest benefit in presymptomatic patients but is well short of a cure. Gene transfer experiments using viral vectors have shown some success in extending the survival in the mouse model of GLD, twitcher mice. The present study compares three single-stranded (ss) AAV serotypes, two natural and one engineered (with oligodendrocyte tropism), and a self-complementary (sc) AAV vector, all packaged with a codon-optimized murine GALC gene. The vectors were delivered via a lumbar intrathecal route for global CNS distribution on PND10-11 at a dose of 2 × 10(11) vector genomes (vg) per mouse. The results showed a similar significant extension of life span of the twitcher mice for all three serotypes (AAV9, AAVrh10, and AAV-Olig001) as well as the scAAV9 vector, compared to control cohorts. The rAAV gene transfer facilitated GALC biodistribution and detectable enzymatic activity throughout the CNS as well as in sciatic nerve and liver. When combined with BMT from syngeneic wild-type mice, there was significant improvement in survival for ssAAV9. Histopathological analysis of brain, spinal cord, and sciatic nerve showed significant improvement in preservation of myelin, with ssAAV9 providing the greatest benefit. In summary, we demonstrate that lumbar intrathecal delivery of rAAV/mGALCopt can significantly enhance the life span of twitcher mice treated at PND10-11 and that BMT synergizes with this treatment to improve the survival further. © 2016 Wiley Periodicals, Inc. PMID:27638599

  20. Thermal behavior and ice-table depth within the north polar erg of Mars

    USGS Publications Warehouse

    Putzig, Nathaniel E.; Mellon, Michael T.; Herkenhoff, Kenneth E.; Phillips, Roger J.; Davis, Brian J.; Ewer, Kenneth J.; Bowers, Lauren M.

    2014-01-01

    We fully resolve a long-standing thermal discrepancy concerning the north polar erg of Mars. Several recent studies have shown that the erg’s thermal properties are consistent with normal basaltic sand overlying shallow ground ice or ice-cemented sand. Our findings bolster that conclusion by thoroughly characterizing the thermal behavior of the erg, demonstrating that other likely forms of physical heterogeneity play only a minor role, and obviating the need to invoke exotic materials. Thermal inertia as calculated from orbital temperature observations of the dunes has previously been found to be more consistent with dust-sized materials than with sand. Since theory and laboratory data show that dunes will only form out of sand-sized particles, exotic sand-sized agglomerations of dust have been invoked to explain the low values of thermal inertia. However, the polar dunes exhibit the same darker appearance and color as that of dunes found elsewhere on the planet that have thermal inertia consistent with normal sand-sized basaltic grains, whereas Martian dust deposits are generally lighter and redder. The alternative explanation for the discrepancy as a thermal effect of a shallow ice table is supported by our analysis of observations from the Mars Global Surveyor Thermal Emission Spectrometer and the Mars Odyssey Thermal Emission Imaging System and by forward modeling of physical heterogeneity. In addition, our results exclude a uniform composition of dark dust-sized materials, and they show that the thermal effects of the dune slopes and bright interdune materials evident in high-resolution images cannot account for the erg’s thermal behavior.

  1. MicroRNA-224 targets ERG2 and contributes to malignant progressions of meningioma.

    PubMed

    Wang, Maomao; Deng, Xiaodong; Ying, Qi; Jin, Tingyan; Li, Ming; Liang, Chong

    2015-05-01

    MicroRNA-224 is overexpressed in various malignant tumors with poor prognosis, which plays a critical role in biological processes including cell proliferation, apoptosis and several developmental and physiological progressions. However, the potential association between miR-224 and clinical outcome in patients with meningiomas remains unknown. Here, we investigate miR-224 expression and biological functions in meningiomas. MiR-224 expression was measured by Northern blot analysis and quantitative reverse transcription-polymerase chain reaction (qRT-PCR) in meningioma and normal brain tissues. Kaplan-Meier analysis and Cox regression analysis were used to exam its correlation with clinicopathological features and prognostic value. The biological effects of miR-224 on the cell proliferation and apoptosis in meningioma cells were examined by MTT assay and apoptosis assay. We found the expression levels of miR-224 were significantly higher in meningioma tissues than that in normal brain, positively correlated with advanced pathological grade. Kaplan-Meier analysis indicated that meningioma patients with low miR-224 expression exhibited significantly prolonged overall and recurrence-free survival. Furthermore, we demonstrated that ERG2 was an identical candidate target gene of MiR-224 in vitro. Our results indicated that downregulation of miR-224 suppressed cell growth and resulted in the enhancement of cell apoptosis through activation of the ERG2-BAK-induced apoptosis pathway. Our findings imply the miR-224 expression could predict the overall survival and recurrence-free survival of patients with meningioma and it might be a promising therapeutic target for treating malignant meningiomas.

  2. Detection of TMPRSS2-ERG translocations in human prostate cancer by expression profiling using GeneChip Human Exon 1.0 ST arrays.

    PubMed

    Jhavar, Sameer; Reid, Alison; Clark, Jeremy; Kote-Jarai, Zsofia; Christmas, Timothy; Thompson, Alan; Woodhouse, Christopher; Ogden, Christopher; Fisher, Cyril; Corbishley, Cathy; De-Bono, Johann; Eeles, Rosalind; Brewer, Daniel; Cooper, Colin

    2008-01-01

    Translocation of TMPRSS2 to the ERG gene, found in a high proportion of human prostate cancer, results in overexpression of the 3'-ERG sequences joined to the 5'-TMPRSS2 promoter. The studies presented here were designed to test the ability of expression analysis on GeneChip Human Exon 1.0 ST arrays to detect 5'-TMPRSS2-ERG-3' hybrid transcripts encoded by this translocation. Monitoring the relative expression of each ERG exon revealed altered transcription of the ERG gene in 15 of a series of 27 prostate cancer samples. In all cases, exons 4 to 11 exhibited enhanced expression compared with exons 2 and 3. This pattern of expression indicated that the most abundant hybrid transcripts involve fusions to ERG exon 4, and RT-PCR analyses confirmed the joining of TMPRSS2 exon 1 to ERG exon 4 in all 15 cases. The exon expression patterns also indicated that TMPRSS2-ERG fusion transcripts commonly contain deletion of ERG exon 8. Analysis of gene-level data from the arrays allowed the identification of genes whose expression levels significantly correlated with the presence of the translocation. These studies demonstrate that expression analyses using exon arrays represent a valuable approach for detecting ETS gene translocation in prostate cancer, in parallel with analyses of gene expression profiles.

  3. An investigation of the cosmic radiation in the vicinity of the moon on the Luna 10, 11, and 12 artificial lunar satellites

    NASA Technical Reports Server (NTRS)

    Grigorov, N. L.; Kurt, V. G.; Lutsenko, V. N.; Maduyev, V. L.; Pisarenko, N. F.; Savenko, I. A.

    1974-01-01

    Research on the primary cosmic radiation and solar cosmic rays from the Luna 10, 11, and 12 artificial lunar satellites is reviewed. Data on the vertical distribution of cosmic rays above the moon's surface are presented, and the albedo for the primary radiation is determined. The fluxes of electrons with energies from 30 to 300 keV were registered in the solar cosmic rays. Rapid variations of the electron flux were observed. The angular distributions of 0.5-10 MeV protons moving together with the corpuscular streams responsible for Forbush decreases were investigated.

  4. Conversion of 10-bromo-10,11-dihydrocinchonidine into 8-oxa-1-azabicyclo64.3.09nonane derivatives and related compounds: a structural study

    NASA Astrophysics Data System (ADS)

    Desperak, Danuta; Pawłowski, Jacek; Thiel, Jacek

    2004-11-01

    The structure of dehydrobromination products of 10-bromo-10,11-dihydrocinchonidine 2c has been investigated in order to explore the scope of the conversions so far observed for quinine and cinchonine. The 2c rearranges into a mixture of 4( S)-( E-propenyl)-6( S),7( R)-(quinol-4-yl)-8-oxa-1( R)-azabicyclo[4.3.0]nonane 6 and its Z-propenyl diastereomer 8 in the ratio 3: 1 and also provides Z-3,10-didehydro-10,11-dihydrocinchonidine 18. The mixture of 6 and 8 undergoes catalytic hydrogenation giving 4( S)-propylo-6( S),7( R)-(quinol-4-yl)-8-oxa-1( R)-azabicyclo[4.3.0]nonane 10. On treatment with an acid the alkaloid 6 yields [4( S)- E-propenyl-2( S)-piperidinyl]-4-quinoline α( R)-methanol 14. Its side chain undergoes hydrogenation affording 4( S)-propylo-derivative 12 which also forms on treatment of 10 by acid. The alkaloids 6, 8, 10, 12 and 14 appear as dominating conformers in their equilibrium mixtures.

  5. The transcription factor ERG recruits CCR4-NOT to control mRNA decay and mitotic progression.

    PubMed

    Rambout, Xavier; Detiffe, Cécile; Bruyr, Jonathan; Mariavelle, Emeline; Cherkaoui, Majid; Brohée, Sylvain; Demoitié, Pauline; Lebrun, Marielle; Soin, Romuald; Lesage, Bart; Guedri, Katia; Beullens, Monique; Bollen, Mathieu; Farazi, Thalia A; Kettmann, Richard; Struman, Ingrid; Hill, David E; Vidal, Marc; Kruys, Véronique; Simonis, Nicolas; Twizere, Jean-Claude; Dequiedt, Franck

    2016-07-01

    Control of mRNA levels, a fundamental aspect in the regulation of gene expression, is achieved through a balance between mRNA synthesis and decay. E26-related gene (Erg) proteins are canonical transcription factors whose previously described functions are confined to the control of mRNA synthesis. Here, we report that ERG also regulates gene expression by affecting mRNA stability and identify the molecular mechanisms underlying this function in human cells. ERG is recruited to mRNAs via interaction with the RNA-binding protein RBPMS, and it promotes mRNA decay by binding CNOT2, a component of the CCR4-NOT deadenylation complex. Transcriptome-wide mRNA stability analysis revealed that ERG controls the degradation of a subset of mRNAs highly connected to Aurora signaling, whose decay during S phase is necessary for mitotic progression. Our data indicate that control of gene expression by mammalian transcription factors may follow a more complex scheme than previously anticipated, integrating mRNA synthesis and degradation. PMID:27273514

  6. The ERG of the beagle dog: evidence associating a post b-wave negativity with the Tapetum lucidum.

    PubMed

    Rosolen, Serge G; Chalier, Catherine; Rigaudière, Florence; Lachapelle, Pierre

    2005-01-01

    As previously reported in the literature, the electroretinogram (ERG) of the Beagle dog includes a large post b-wave negativity, the origin of which is not yet established. In the course of our investigations on the electroretinogram in dogs, we examined two Beagle dogs (2 years apart) who had one eye devoid of a Tapetum Lucidum (TL). Photopic (cone-mediated) and scotopic (rod-mediated) ERGs were obtained according to the guidelines for clinical electroretinography in dog. In both dogs the short-latency ERG components (i.e. a- and b-waves) were found to be within the normal range in amplitude, peak time and morphology O.U. However, the large negative component that, in Beagle dogs, normally follow the b-wave was absent from the photopic as well as the scotopic signals obtained from the TL-free eye. Our results thus suggest a possible contribution of the TL to the ERG of Beagle dogs. PMID:16328922

  7. A Drosophila behavioral mutant, down and out (dao), is defective in an essential regulator of Erg potassium channels

    PubMed Central

    Fergestad, Tim; Sale, Harinath; Bostwick, Bret; Schaffer, Ashleigh; Ho, Lingling; Robertson, Gail A.; Ganetzky, Barry

    2010-01-01

    To signal properly, excitable cells must establish and maintain the correct balance of various types of ion channels that increase or decrease membrane excitability. The mechanisms by which this balance is regulated remain largely unknown. Here, we describe a regulatory mechanism uncovered by a Drosophila behavioral mutant, down and out (dao). At elevated temperatures, dao loss-of-function mutants exhibit seizures associated with spontaneous bursts of neural activity. This phenotype closely resembles that of seizure mutations, which impair activity of ether-a-go-go-related gene (Erg)-type potassium channels. Conversely, neural over-expression of wild-type Dao confers dominant temperature-sensitive paralysis with kinetics reminiscent of paralytic sodium-channel mutants. The over-expression phenotype of dao is suppressed in a seizure mutant background, suggesting that Dao acts by an effect on Erg channels. In support of this hypothesis, functional expression of Erg channels in a heterologous system is dependent on the presence of Dao. These results indicate that Dao has an important role in establishing the proper level of neuronal membrane excitability by regulating functional expression of Erg channels. PMID:20212103

  8. A Drosophila behavioral mutant, down and out (dao), is defective in an essential regulator of Erg potassium channels.

    PubMed

    Fergestad, Tim; Sale, Harinath; Bostwick, Bret; Schaffer, Ashleigh; Ho, Lingling; Robertson, Gail A; Ganetzky, Barry

    2010-03-23

    To signal properly, excitable cells must establish and maintain the correct balance of various types of ion channels that increase or decrease membrane excitability. The mechanisms by which this balance is regulated remain largely unknown. Here, we describe a regulatory mechanism uncovered by a Drosophila behavioral mutant, down and out (dao). At elevated temperatures, dao loss-of-function mutants exhibit seizures associated with spontaneous bursts of neural activity. This phenotype closely resembles that of seizure mutations, which impair activity of ether-a-go-go-related gene (Erg)-type potassium channels. Conversely, neural over-expression of wild-type Dao confers dominant temperature-sensitive paralysis with kinetics reminiscent of paralytic sodium-channel mutants. The over-expression phenotype of dao is suppressed in a seizure mutant background, suggesting that Dao acts by an effect on Erg channels. In support of this hypothesis, functional expression of Erg channels in a heterologous system is dependent on the presence of Dao. These results indicate that Dao has an important role in establishing the proper level of neuronal membrane excitability by regulating functional expression of Erg channels. PMID:20212103

  9. Draft Genome Sequence of MCPA-Degrading Sphingomonas sp. Strain ERG5, Isolated from a Groundwater Aquifer in Denmark

    PubMed Central

    Nielsen, Tue Kjærgaard; Sørensen, Sebastian R.; Hansen, Lars Hestbjerg

    2015-01-01

    Sphingomonas sp. strain ERG5 was isolated from a bacterial community, originating from a groundwater aquifer polluted with low pesticide concentrations. This bacterium degrades 2-methyl-4-chlorophenoxyacetic acid (MCPA) in a wide spectrum of concentrations and has been shown to function in bioaugmented sand filters. Genes associated with MCPA degradation are situated on a putative conjugative plasmid. PMID:25676756

  10. Allosteric modulators of the hERG K(+) channel: radioligand binding assays reveal allosteric characteristics of dofetilide analogs.

    PubMed

    Yu, Zhiyi; Klaasse, Elisabeth; Heitman, Laura H; Ijzerman, Adriaan P

    2014-01-01

    Drugs that block the cardiac K(+) channel encoded by the human ether-à-go-go gene (hERG) have been associated with QT interval prolongation leading to proarrhythmia, and in some cases, sudden cardiac death. Because of special structural features of the hERG K(+) channel, it has become a promiscuous target that interacts with pharmaceuticals of widely varying chemical structures and a reason for concern in the pharmaceutical industry. The structural diversity suggests that multiple binding sites are available on the channel with possible allosteric interactions between them. In the present study, three reference compounds and nine compounds of a previously disclosed series were evaluated for their allosteric effects on the binding of [(3)H]astemizole and [(3)H]dofetilide to the hERG K(+) channel. LUF6200 was identified as an allosteric inhibitor in dissociation assays with both radioligands, yielding similar EC50 values in the low micromolar range. However, potassium ions increased the binding of the two radioligands in a concentration-dependent manner, and their EC50 values were not significantly different, indicating that potassium ions behaved as allosteric enhancers. Furthermore, addition of potassium ions resulted in a concentration-dependent leftward shift of the LUF6200 response curve, suggesting positive cooperativity and distinct allosteric sites for them. In conclusion, our investigations provide evidence for allosteric modulation of the hERG K(+) channel, which is discussed in the light of findings on other ion channels. PMID:24200993

  11. NKX3.1 Suppresses TMPRSS2-ERG Gene Rearrangement and Mediates Repair of Androgen Receptor-Induced DNA Damage

    PubMed Central

    Bowen, Cai; Zheng, Tian; Gelmann, Edward P.

    2015-01-01

    TMPRSS2 gene rearrangements occur at DNA breaks formed during androgen receptor-mediated transcription and activate expression of ETS transcription factors at the early stages of more than half of prostate cancers. NKX3.1, a prostate tumor suppressor that accelerates the DNA repair response, binds to androgen receptor at the ERG gene breakpoint and inhibits both the juxtaposition of the TMPRSS2 and ERG gene loci and also their recombination. NKX3.1 acts by accelerating DNA repair after androgen-induced transcriptional activation. NKX3.1 influences the recruitment of proteins that promote homology-directed DNA repair. Loss of NKX3.1 favors recruitment to the ERG gene breakpoint of proteins that promote error-prone nonhomologous end-joining. Analysis of prostate cancer tissues showed that the presence of a TMPRSS2-ERG rearrangement was highly correlated with lower levels of NKX3.1 expression consistent with the role of NKX3.1 as a suppressor of the pathogenic gene rearrangement. PMID:25977336

  12. miRNA and TMPRSS2-ERG do not mind their own business in prostate cancer cells.

    PubMed

    Fayyaz, Sundas; Farooqi, Ammad Ahmad

    2013-05-01

    Oncogenic fusion proteins belong to an important class that disrupts gene expression networks in a cell. Astonishingly, fusion-positive prostate cancer cells enable the multi-gene regulatory capability of miRNAs to remodel the signal transduction landscape, enhancing or antagonizing the transmission of information to downstream effectors. Accumulating evidence substantiates the fact that miRNAs translate into dose-dependent responsiveness of cells to signaling regulators in transmembrane protease serine 2:ETS-related gene (TMPRSS2-ERG)-positive cells. Wide ranging signaling proteins are the targets for the degree of quantitative fluctuations imposed by miRNAs. miRNA signatures are aberrantly expressed in fusion-positive cancer cells, suggesting that they have a cumulative effect on tumor aggressiveness. It seems attractive to note that TMPRSS2:ERG fusion has a stronger effect as tumors positive for the oncogenic TMPRSS2:ERG have dysregulated oncomirs and tumor suppressor miRNA signature. It is undeniable that a comprehensive analysis of the prostate cancer microRNAome is necessary to uncover novel microRNAs and pathways associated with prostate cancer. Moreover, the identification and validation of miRNA signature in TMPRSS2-ERG-positive prostate cancer cells may help to identify novel molecular targets and pathways for personalized therapy.

  13. Enhancement of hERG channel activity by scFv antibody fragments targeted to the PAS domain.

    PubMed

    Harley, Carol A; Starek, Greg; Jones, David K; Fernandes, Andreia S; Robertson, Gail A; Morais-Cabral, João H

    2016-08-30

    The human human ether-à-go-go-related gene (hERG) potassium channel plays a critical role in the repolarization of the cardiac action potential. Changes in hERG channel function underlie long QT syndrome (LQTS) and are associated with cardiac arrhythmias and sudden death. A striking feature of this channel and KCNH channels in general is the presence of an N-terminal Per-Arnt-Sim (PAS) domain. In other proteins, PAS domains bind ligands and modulate effector domains. However, the PAS domains of KCNH channels are orphan receptors. We have uncovered a family of positive modulators of hERG that specifically bind to the PAS domain. We generated two single-chain variable fragments (scFvs) that recognize different epitopes on the PAS domain. Both antibodies increase the rate of deactivation but have different effects on channel activation and inactivation. Importantly, we show that both antibodies, on binding to the PAS domain, increase the total amount of current that permeates the channel during a ventricular action potential and significantly reduce the action potential duration recorded in human cardiomyocytes. Overall, these molecules constitute a previously unidentified class of positive modulators and establish that allosteric modulation of hERG channel function through ligand binding to the PAS domain can be attained. PMID:27516548

  14. Molecular characterization and clinical impact of TMPRSS2-ERG rearrangement on prostate cancer: comparison between FISH and RT-PCR.

    PubMed

    Fernández-Serra, A; Rubio, L; Calatrava, A; Rubio-Briones, J; Salgado, R; Gil-Benso, R; Espinet, B; García-Casado, Z; López-Guerrero, J A

    2013-01-01

    Prostate cancer (PCa) is a very heterogeneous disease, and there are constraints in its current diagnosis. Serum PSA levels, digital rectal examination (DRE), and histopathologic analysis often drive to overdiagnosis and overtreatment. Since 2005, the presence of the genetic rearrangement between transmembrane-serine protease gene (TMPRSS2) and the erythroblast transformation-specific (ETS) member ERG (v-ets erythroblastosis virus E26 oncogene homolog avian) has been demonstrated in almost half of PCa cases. Both FISH and RT-PCR are useful tools for detecting these rearrangements, but very few comparatives between both techniques have been published. In this study, we included FFPE tumors from 294 PCa patients treated with radical prostatectomy with more than 5 years of followup. We constructed a total of 20 tissue microarrays in order to perform break-apart and tricolor probe FISH approaches that were compared with RT-PCR, showing a concordance of 80.6% (P < 0.001). The presence of TMPRSS2-ERG rearrangement was observed in 56.6% of cases. No association between TMPRSS2-ERG status and clinicopathological parameters nor biochemical progression and clinical progression free survival was found. In conclusion, this study demonstrates that both FISH and RT-PCR are useful tools in the assessment of the TMPRSS2-ERG fusion gene status in PCa patients and that this genetic feature per se lacks prognostic value. PMID:23781502

  15. Reduced response to IKr blockade and altered hERG1a/1b stoichiometry in human heart failure.

    PubMed

    Holzem, Katherine M; Gomez, Juan F; Glukhov, Alexey V; Madden, Eli J; Koppel, Aaron C; Ewald, Gregory A; Trenor, Beatriz; Efimov, Igor R

    2016-07-01

    Heart failure (HF) claims 250,000 lives per year in the US, and nearly half of these deaths are sudden and presumably due to ventricular tachyarrhythmias. QT interval and action potential (AP) prolongation are hallmark proarrhythmic changes in the failing myocardium, which potentially result from alterations in repolarizing potassium currents. Thus, we aimed to examine whether decreased expression of the rapid delayed rectifier potassium current, IKr, contributes to repolarization abnormalities in human HF. To map functional IKr expression across the left ventricle (LV), we optically imaged coronary-perfused LV free wall from donor and end-stage failing human hearts. The LV wedge preparation was used to examine transmural AP durations at 80% repolarization (APD80), and treatment with the IKr-blocking drug, E-4031, was utilized to interrogate functional expression. We assessed the percent change in APD80 post-IKr blockade relative to baseline APD80 (∆APD80) and found that ∆APD80s are reduced in failing versus donor hearts in each transmural region, with 0.35-, 0.43-, and 0.41-fold reductions in endo-, mid-, and epicardium, respectively (p=0.008, 0.037, and 0.022). We then assessed hERG1 isoform gene and protein expression levels using qPCR and Western blot. While we did not observe differences in hERG1a or hERG1b gene expression between donor and failing hearts, we found a shift in the hERG1a:hERG1b isoform stoichiometry at the protein level. Computer simulations were then conducted to assess IKr block under E-4031 influence in failing and nonfailing conditions. Our results confirmed the experimental observations and E-4031-induced relative APD80 prolongation was greater in normal conditions than in failing conditions, provided that the cellular model of HF included a significant downregulation of IKr. In human HF, the response to IKr blockade is reduced, suggesting decreased functional IKr expression. This attenuated functional response is associated with

  16. ERG rearrangement as a novel marker for predicting the extra-prostatic extension of clinically localised prostate cancer

    PubMed Central

    LU, LI; ZHANG, HAO; PANG, JUN; HOU, GUO-LIANG; LU, MIN-HUA; GAO, XIN

    2016-01-01

    Currently, there are no well-established preoperative clinicopathological parameters for predicting extra-prostatic extension (EPE) in patients with clinically localised prostate cancer (PCa). The transmembrane protease serine 2 (TMPRSS2)-ETS-related gene (ERG) fusion gene is a specific biomarker of PCa and is considered a prognostic predictor. The aim of the present study was to assess the value of this marker for predicting EPE in patients with clinically localised PCa. In total, 306 PCa patients with clinically localised disease, including 220 patients (71.9%) with organ-confined disease and 86 EPE cases (28.1%), were included in the study. Receiver operating characteristic curves and logistic regression were employed to establish the optimal cut-off value and to investigate whether ERG rearrangement was an independent predictor for the EPE of clinically localised PCa. A leave-one-out cross-validation (LOOCV) model was implemented to validate the predictive power of ERG rearrangement. An increase in ERG rearrangements was identified to be associate'd with EPE, and the optimal cut-off for predicting EPE was determined to be 2.25%, with a sensitivity of 70.24% [95% confidence interval (CI), 62.6–78.9%], a specificity of 80.43% (95% CI, 75.4–85.1%), and an area under the curve (AUC) of 0.781 (95% CI, 0.730–0.826). In the LOOCV model, ERG rearrangement also demonstrated good performance for predicting EPE (sensitivity, 76.923%; specificity, 71.429%; 95% CI for AUC, 0.724–0.958). In addition, a high Gleason score (≥7) and a cT2c classification upon biopsy were independent factors for EPE. PMID:27073512

  17. Modeling of Thermal Perturbations Using Raytracing Method with Preliminary Results for a Test Case Model of the Pioneer 10/11 Radioisotopic Thermal Generators

    NASA Astrophysics Data System (ADS)

    Rievers, Benny; Lämmerzahl, Claus; Dittus, Hansjörg

    2010-03-01

    Electromagnetic radiation emitted from a source carries momentum. Thus, the dissipation of waste thermal energy can produce disturbance forces on spacecraft surfaces if the energy is not dissipated in a symmetric pattern. This force can be computed for a plate element as the quotient of the radiated power in normal direction and the speed of light. Depending on mission and spacecraft design the resulting surface forces have to be included into the disturbance budget. At ZARM an elaborated method for the exact modeling of the disturbances caused by heat radiation was developed which can be used for any satellite mission with high requirements on perturbation knowledge (e.g. LISA, LISA pathfinder, MICROSCOPE). The method which will be presented in this paper is based on raytracing and finite element (FE) thermal analysis. As a demonstration of the potential of the method, preliminary results acquired with a test case model of the Pioneer 10/11 Radioisotopic Thermal Generators (RTGs) will be shown.

  18. [The dynamics of the direct current potentials of the brain during sustained attention in 10-11-year-old children].

    PubMed

    Shimko, I A; Andreev, O A; Ponomareva, N V; Fokin, V F

    2005-01-01

    The dynamics of direct current potentials of the brain was studied in 10-11-year-old children during sustained attention to successive presentation of series of Shulte tables. Children were examined twice: before and after the series of training to fast reading. A gradual increase in the level of direct current potentials during sustained attention was observed. The increase was more pronounced in children with excessive than in children with moderate reactions to the loading. After the series of training to fast reading, the increase in the level of direct current potentials was reduced in both groups. This aftertraining neurophysiological phenomenon was combined with a transformation of psychophysiological characteristics: a decrease in the time of viewing of Shulte tables and increase in the speed of reading. It is suggested that the shifts of direct current potentials reflects the dynamics of intensity of the cerebral energy metabolism.

  19. Is t(10;11)(p11.2;q23) involving MLL and ABI-1 genes associated with congenital acute monocytic leukemia?

    PubMed

    Morerio, Cristina; Rosanda, Cristina; Rapella, Annamaria; Micalizzi, Concetta; Panarello, Claudio

    2002-11-01

    Congenital, or perinatal, leukemias are rarely observed, but retrospective molecular studies seem to suggest a more frequent onset in prenatal life. Myelocytic types are common, and chromosome band 11q23 rearrangements at the MLL locus are characteristic genetic markers. The fusion of the MLL gene with one of its partners, ABI-1, has recently been described in two infant leukemia patients with monocytic involvement and good clinical outcome. We report a case of congenital monocytic leukemia with the same gene involvement and good response to chemotherapy. The blast metaphases were probed by fluorescence in situ hybridization, and t(10;11)(p11.2;q23) involving MLL and ABI-1 genes was demonstrated with the same breakpoint in ABI-1. The congenital presentation of this case suggests a possible relationship of this genetic event with in utero leukemogenesis.

  20. Activation of hERG3 channel stimulates autophagy and promotes cellular senescence in melanoma

    PubMed Central

    Perez-Neut, Mathew; Haar, Lauren; Rao, Vidhya; Santha, Sreevidya; Lansu, Katherine; Rana, Basabi; Jones, Walter K.; Gentile, Saverio

    2016-01-01

    Ion channels play a major factor in maintaining cellular homeostasis but very little is known about the role of these proteins in cancer biology. In this work we have discovered that, the Kv11.3 (hERG3) a plasma-membrane potassium channel plays a critical role in the regulation of autophagy in a cancer cell model. We have found that pharmacologic stimulation of the Kv11.3 channel with a small molecule activator, NS1643 induced autophagy via activation of an AMPK-dependent signaling pathway in melanoma cell line. In addition, we have found that NS1643 produced a strong inhibition of cell proliferation by activating a cellular senescence program. Furthermore, inhibition of autophagy via siRNA targeting AMPK or treatment with hydroxychloroquine an autophagy inhibitor activates apoptosis in NS1643-treated cells. Thus, we propose that, Kv11.3 is a novel mediator of autophagy, autophagy can be a survival mechanism contributing to cellular senescence, and that use of a combinatorial pharmacologic approach of Kv11.3 activator with inhibitors of autophagy represents a novel therapeutic approach against melanoma. PMID:26942884

  1. Candida tropicalis Antifungal Cross-Resistance Is Related to Different Azole Target (Erg11p) Modifications

    PubMed Central

    Forastiero, A.; Mesa-Arango, A. C.; Alastruey-Izquierdo, A.; Alcazar-Fuoli, L.; Bernal-Martinez, L.; Pelaez, T.; Lopez, J. F.; Grimalt, J. O.; Gomez-Lopez, A.; Cuesta, I.; Zaragoza, O.

    2013-01-01

    Candida tropicalis ranks between third and fourth among Candida species most commonly isolated from clinical specimens. Invasive candidiasis and candidemia are treated with amphotericin B or echinocandins as first-line therapy, with extended-spectrum triazoles as acceptable alternatives. Candida tropicalis is usually susceptible to all antifungal agents, although several azole drug-resistant clinical isolates are being reported. However, C. tropicalis resistant to amphotericin B is uncommon, and only a few strains have reliably demonstrated a high level of resistance to this agent. The resistance mechanisms operating in C. tropicalis strains isolated from clinical samples showing resistance to azole drugs alone or with amphotericin B cross-resistance were elucidated. Antifungal drug resistance was related to mutations of the azole target (Erg11p) with or without alterations of the ergosterol biosynthesis pathway. The antifungal drug resistance shown in vitro correlated very well with the results obtained in vivo using the model host Galleria mellonella. Using this panel of strains, the G. mellonella model system was validated as a simple, nonmammalian minihost model that can be used to study in vitro-in vivo correlation of antifungals in C. tropicalis. The development in C. tropicalis of antifungal drug resistance with different mechanisms during antifungal treatment has potential clinical impact and deserves specific prospective studies. PMID:23877676

  2. Integrated Assessment of Hadley Centre (HadCM2) Climate-Change Impacts on Agricultural Productivity and Irrigation Water Supply in the Conterminous United States. Part II. Regional Agricultural Production in 2030 and 2095.

    SciTech Connect

    Izaurralde, R Cesar C.; Rosenberg, Norman J.; Brown, Robert A.; Thomson, Allison M.

    2003-06-30

    This study used scenarios of the HadCM2 GCM and the EPIC agroecosystem model to evaluate climate change impacts on crop yields and ecosystem processes. Baseline climate data were obtained from records for 1961-1990. The scenario runs for 2025-2034 and 2090-2099 were extracted from a HadCM2 run. EPIC was run on 204 representative farms under current climate and two 10-y periods centered on 2030 and 2095, each at CO2 concentrations of 365 and 560 ppm. Texas, New Mexico, Colorado, Utah, Arizona, and California are projected to experience significant temperature increases by 2030. Slight cooling is expected by 2030 in Alabama, Florida, Maine, Montana, Idaho, and Utah. Larger areas are projected to experience increased warming by 2095. Uniform precipitation increases are expected by 2030 in the NE. These increases are predicted to expand to the eastern half of the country by 2095. EPIC simulated yield increases for the Great Lakes, Corn Belt and Northeast regions. Simulated yields of irrigated corn yields were predicted to increase in almost all regions. Soybean yields could decrease in the Northern and Southern Plains, the Corn Belt, Delta, Appalachian, and Southeast regions and increase in the Lakes and Northeast regions. Simulated wheat yields exhibited upward yield trends under scenarios of climate change. National corn production in 2030 and 2095 could be affected by changes in three major producing regions. In 2030, corn production could increase in the Corn Belt and Lakes regions but decrease in the Northern Plains leading to an overall decrease in national production. National wheat production is expected to increase during both future periods. A proxy indicator was developed to provide a sense of where in the country, and when water would be available to satisfy change in irrigation demand for corn and alfalfa production as these are influenced by the HadCM2 scenarios and CO2-fertilization.

  3. Fully Enzymatic Membraneless Glucose|Oxygen Fuel Cell That Provides 0.275 mA cm(-2) in 5 mM Glucose, Operates in Human Physiological Solutions, and Powers Transmission of Sensing Data.

    PubMed

    Ó Conghaile, Peter; Falk, Magnus; MacAodha, Domhnall; Yakovleva, Maria E; Gonaus, Christoph; Peterbauer, Clemens K; Gorton, Lo; Shleev, Sergey; Leech, Dónal

    2016-02-16

    Coimmobilization of pyranose dehydrogenase as an enzyme catalyst, osmium redox polymers [Os(4,4'-dimethoxy-2,2'-bipyridine)2(poly(vinylimidazole))10Cl](+) or [Os(4,4'-dimethyl-2,2'-bipyridine)2(poly(vinylimidazole))10Cl](+) as mediators, and carbon nanotube conductive scaffolds in films on graphite electrodes provides enzyme electrodes for glucose oxidation. The recombinant enzyme and a deglycosylated form, both expressed in Pichia pastoris, are investigated and compared as biocatalysts for glucose oxidation using flow injection amperometry and voltammetry. In the presence of 5 mM glucose in phosphate-buffered saline (PBS) (50 mM phosphate buffer solution, pH 7.4, with 150 mM NaCl), higher glucose oxidation current densities, 0.41 mA cm(-2), are obtained from enzyme electrodes containing the deglycosylated form of the enzyme. The optimized glucose-oxidizing anode, prepared using deglycosylated enzyme coimmobilized with [Os(4,4'-dimethyl-2,2'-bipyridine)2(poly(vinylimidazole))10Cl](+) and carbon nanotubes, was coupled with an oxygen-reducing bilirubin oxidase on gold nanoparticle dispersed on gold electrode as a biocathode to provide a membraneless fully enzymatic fuel cell. A maximum power density of 275 μW cm(-2) is obtained in 5 mM glucose in PBS, the highest to date under these conditions, providing sufficient power to enable wireless transmission of a signal to a data logger. When tested in whole human blood and unstimulated human saliva maximum power densities of 73 and 6 μW cm(-2) are obtained for the same fuel cell configuration, respectively. PMID:26750758

  4. Silencing of hERG1 Gene Inhibits Proliferation and Invasion, and Induces Apoptosis in Human Osteosarcoma Cells by Targeting the NF-κB Pathway

    PubMed Central

    Zeng, Wenrong; Liu, Qingjun; Chen, Zhida; Wu, Xinyu; Zhong, Yuanfu; Wu, Jin

    2016-01-01

    Recently, the human ether à go-go (eag) related gene 1 (hERG1) channel, a member of the voltage-dependent potassium channel (Kv) family, was determined to have a critical role in cancer cell proliferation, invasion, tumorigenesis and apoptosis. However, the expression levels and functions of hERG1 in osteosarcoma cells remain poorly characterized. In this study, hERG1 transcript and protein levels in osteosarcoma cells and tissues were measured using semi-quantitative real time PCR (RT-PCR), Western blot, and immunohistochemistry. The effects of hERG1 knockdown on osteosarcoma cell proliferation, apoptosis and invasion were examined using CCK-8, colony formation, flow cytometry, caspase-3 activity, wound healing and transwell based assays. Furthermore, semi-quantitative RT-PCR, Western blot and a luciferase reporter assay were used to assess the effects of hERG1 inhibition on the nuclear factor-κB (NF-κB) pathway. In addition, the effect of NF-κB p65-siRNA and NF-κB p65 expression on the survival of osteosarcoma cells was investigated. Through this work, a relationship for hERG1 with the NF-κB pathway was identified. Osteosarcoma cells and tissues were found to express high levels of hERG1. Knockdown of hERG1 significantly suppressed cellular proliferation and invasion, and induced apoptosis, while inhibition of hERG1 significantly decreased activation of NF-κB. Overall, hERG1 may stimulate nuclear translocation of p65, thus regulating the NF-κB pathway through the activation of the hERG1/beta1 integrin complex and PI3K/AKT signaling. Taken together, these results demonstrate that hERG1 is necessary for regulation of osteosarcoma cellular proliferation, apoptosis and migration. Furthermore, this regulation by hERG1 is, at least in part, through mediation of the NF-κB pathway. PMID:27076857

  5. Direct total cross section measurement of the {sup 16}O({alpha}, {gamma}){sup 20}Ne reaction at E{sub c.m.}=2.26 MeV

    SciTech Connect

    Hager, U.; Greife, U.; Brown, J. R.; Buchmann, L.; Fallis, J.; Hutcheon, D.; Ottewell, D.; Ruiz, C.; Sjue, S.; Carmona-Gallardo, M.; Erikson, L.; Vockenhuber, C.

    2011-08-15

    In stellar helium burning, {sup 16}O represents the endpoint of the helium-burning sequence due to the low rate of {sup 16}O({alpha},{gamma}){sup 20}Ne. We present a new direct measurement of the total capture reaction rate of {sup 16}O({alpha},{gamma}){sup 20}Ne at E{sub c.m.}=2.26 MeV employing the DRAGON recoil separator. For the first time, the total S factor and its contributing direct capture transitions could be determined in one experiment.

  6. An ambipolar organic field-effect transistor based on an AIE-active single crystal with a high mobility level of 2.0 cm(2) V(-1) s(-1).

    PubMed

    Deng, Jian; Xu, Yuanxiang; Liu, Liqun; Feng, Cunfang; Tang, Jia; Gao, Yu; Wang, Yan; Yang, Bing; Lu, Ping; Yang, Wensheng; Ma, Yuguang

    2016-02-01

    Organic field-effect transistors (OFETs) based on an aggregation-induced emission (AIE) material were fabricated using a calcium-gold asymmetric electrode system. The devices showed very high and balanced mobility, reaching 2.50 and 2.10 cm(2) V(-1) s(-1), respectively, for electron and hole. Strong green electroluminescence from the single-crystal side edge was observed from all the devices. This work demonstrates that AIE active materials could not only achieve high luminescence, but also be used in light emitting transistors and achieve very high mobility. PMID:26730680

  7. Accelerated molecular evolution of insect orthologues of ERG28/C14orf1: a link with ecdysteroid metabolism?

    PubMed

    Veitia, R A; Hurst, L D

    2001-04-01

    We have analysed the evolution of ERG28/C14orf1, a gene coding for a protein involved in sterol biosynthesis. While primary sequence of the protein is well conserved in all organisms able to synthesize sterols de novo, strong divergence is noticed in insects, which are cholesterol auxotrophs. In spite of this virtual acceleration, our analysis suggests that the insect orthologues are evolving today at rates similar to those of the remaining members of the family. A plausible way to explain this acceleration and subsequent stabilization is that Erg28 plays a role in at least two different pathways. Discontinuation of the cholesterogenesis pathway in insects allowed the protein to evolve as much as the function in the other pathway was not compromised.

  8. Obesity and Prostate Cancer Risk According to Tumor TMPRSS2:ERG Gene Fusion Status

    PubMed Central

    Egbers, Lieke; Luedeke, Manuel; Rinckleb, Antje; Kolb, Suzanne; Wright, Jonathan L.; Maier, Christiane; Neuhouser, Marian L.; Stanford, Janet L.

    2015-01-01

    The T2E gene fusion, formed by fusion of the transmembrane protease, serine 2, gene (TMPRSS2) with the erythroblast transformation-specific (ETS)-related gene (ERG), is found in approximately 50% of prostate cancers and may characterize distinct molecular subtypes of prostate cancer with different etiologies. We investigated the relationship between body mass index (BMI; weight (kg)/height (m)2) and prostate cancer risk by T2E status. Study participants were residents of King County, Washington, recruited for 2 population-based case-control studies conducted in 1993–1996 and 2002–2005. Tumor T2E status was determined for 563 prostate cancer patients who underwent radical prostatectomy. Information on weight, height, and covariables was obtained through in-person interviews. We performed polytomous logistic regression to calculate odds ratios and 95% confidence intervals for T2E-positive and -negative prostate cancer. Comparing the highest BMI quartile with the lowest, inverse associations were observed between recent (≥29.7 vs. <24.5: odds ratio = 0.66, 95% confidence interval: 0.45, 0.97) and maximum (≥31.8 vs. <25.9: odds ratio = 0.69, 95% confidence interval: 0.47, 1.02) BMI and the risk of T2E-positive prostate cancer. No significant associations were seen for men with T2E-negative tumors. This study provides evidence that obesity is specifically associated with reduced risk of developing androgen-responsive T2E fusion–positive tumors. The altered steroid hormone profile in obese men may contribute to this inverse association. PMID:25852077

  9. Investigation of ERG11 gene expression among fluconazole-resistant Candida albicans: first report from an Iranian referral paediatric hospital.

    PubMed

    Teymuri, M; Mamishi, S; Pourakbari, B; Mahmoudi, S; Ashtiani, M T; Sadeghi, R H; Yadegari, M H

    2015-01-01

    The multiplicity of mechanisms of resistance to azole antifungal agents has been described. As fluconazole-resistant clinical Candida albicans isolates that constitutively over-express ERG11 have been identified in previous studies, the aim of this study is to investigate this molecular mechanism involved in fluconazole resistance of C. albicans clinical isolates. Fluconazole susceptibility testing was carried out on clinical isolates of Candida spp. obtained from hospitalised children in an Iranian referral children's hospital. A polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) technique was used to differentiate Candida spp. The resistant C. albicans isolates were subjected to RT-qPCR using primers that identify ERG11 gene expression. Of the 142 Candida spp. isolates studied, C. albicans was the most predominant isolate, occurring in 68.3% (97/142) of the patients. According to the CLSI method, the majority of the C. albicans isolates (91.7%, 89/97), categorised as susceptible (minimum inhibitory concentration [MIC] ≤8 μg/mL), five isolates were considered resistant (MIC ≤64 μg/mL) and three had dose-dependent susceptibility (MIC = 8.16-32 μg/mL). The ERG11 gene in the five fluconazole-resistant C. albicans isolates was upregulated 4.15-5.84-fold relative to the ATCC 10231 control strain. In this study, the expression of ERG11 was upregulated in all the fluconazole-resistant C. albicans isolates. There are limited data on the antifungal susceptibility of Candida spp. as well as the molecular mechanism of azole resistance in Iran, especially for isolates causing infections in children. Therefore, the surveillance of antifungal resistance patterns and investigation of other mechanisms of azole resistance in all Candida spp. isolates is recommended.

  10. Low level laser therapy (AlGaInP) applied at 5J/cm2 reduces the proliferation of Staphylococcus aureus MRSA in infected wounds and intact skin of rats*

    PubMed Central

    Silva, Daniela Conceição Gomes Gonçalves e; Plapler, Helio; da Costa, Mateus Matiuzzi; Silva, Silvio Romero Gonçalves e; de Sá, Maria da Conceição Aquino; Silva, Benedito Sávio Lima e

    2013-01-01

    BACKGROUND Laser therapy is a low cost, non-invasive procedure with good healing results. Doubts exist as to whether laser therapy action on microorganisms can justify research aimed at investigating its possible effects on bacteria-infected wounds. OBJECTIVE To assess the effect of low intensity laser on the rate of bacterial contamination in infected wounds in the skin of rats. METHODS An experimental study using 56 male Wistar rats. The animals were randomly divided into eight groups of seven each. Those in the "infected" groups were infected by Staphylococcus aureus MRSA in the dorsal region. Red laser diode (AlGaInP) 658nm, 5J/cm2 was used to treat the animals in the "treated" groups in scan for 3 consecutive days. Samples were drawn before inoculating bacteria and following laser treatment. For statistical analysis we used the nonparametric Wilcoxon (paired data) method with a significance level of p <0.05. RESULTS The statistical analysis of median values showed that the groups submitted to laser treatment had low bacterial proliferation. CONCLUSION The laser (AlGaInP), with a dose of 5J/cm2 in both intact skin and in wounds of rats infected with Staphylococcus aureus MRSA, is shown to reduce bacterial proliferation. PMID:23539003

  11. Regulation of the human ether-a-go-go-related gene (hERG) potassium channel by Nedd4 family interacting proteins (Ndfips).

    PubMed

    Kang, Yudi; Guo, Jun; Yang, Tonghua; Li, Wentao; Zhang, Shetuan

    2015-11-15

    The cardiac electrical disorder long QT syndrome (LQTS) pre-disposes affected individuals to ventricular arrhythmias and sudden death. Dysfunction of the human ether-a-go-go-related gene (hERG)-encoded rapidly activating delayed rectifier K(+) channel (IKr) is a major cause of LQTS. The expression of hERG channels is controlled by anterograde trafficking of newly synthesized channels to and retrograde degradation of existing channels from the plasma membrane. We have previously shown that the E3 ubiquitin (Ub) ligase Nedd4-2 (neural precursor cell expressed developmentally down-regulated protein 4-2) targets the PY motif of hERG channels to initiate channel degradation. Although both immature and mature hERG channels contain the PY motif, Nedd4-2 selectively mediates the degradation of mature hERG channels. In the present study, we demonstrate that Nedd4-2 is directed to specific cellular compartments by the Nedd4 family interacting proteins, Nedd4 family-interacting protein 1 (Ndfip1) and Ndfip2. Ndfip1 is primarily localized in the Golgi apparatus where it recruits Nedd4-2 to mediate the degradation of mature hERG proteins during channel trafficking to the plasma membrane. Although Ndfip2 directs Nedd4-2 to the Golgi apparatus, it also recruits Nedd4-2 to the multivesicular bodies (MVBs), which may impair MVB function and impede the degradation of mature hERG proteins mediated by Nedd4-2. These findings extend our understanding of hERG channel regulation and provide information which may be useful for the rescue of impaired hERG function in LQTS. PMID:26363003

  12. Comorbidity of 9/11-related PTSD and depression in the World Trade Center Health Registry 10-11 years postdisaster.

    PubMed

    Caramanica, Kimberly; Brackbill, Robert M; Liao, Tim; Stellman, Steven D

    2014-12-01

    Many studies report elevated prevalence of posttraumatic stress disorder (PTSD) and depression among persons exposed to the September 11, 2001 (9/11) disaster compared to those unexposed; few have evaluated long-term PTSD with comorbid depression. We examined prevalence and risk factors for probable PTSD, probable depression, and both conditions 10-11 years post-9/11 among 29,486 World Trade Center Health Registry enrollees who completed surveys at Wave 1 (2003-2004), Wave 2 (2006-2007), and Wave 3 (2011-2012). Enrollees reporting physician diagnosed pre-9/11 PTSD or depression were excluded. PTSD was defined as scoring ≥ 44 on the PTSD Checklist and depression as scoring ≥ 10 on the 8-item Patient Health Questionnaire. We examined 4 groups: comorbid PTSD and depression, PTSD only, depression only, and neither. Among enrollees, 15.2% reported symptoms indicative of PTSD at Wave 3, 14.9% of depression, and 10.1% of both. Comorbid PTSD and depression was associated with high 9/11 exposures, low social integration, health-related unemployment, and experiencing ≥ 1 traumatic life event post-9/11. Comorbid persons experienced poorer outcomes on all PTSD-related impairment measures, life satisfaction, overall health, and unmet mental health care need compared to those with only a single condition. These findings highlight the importance of ongoing screening and treatment for both conditions, particularly among those at risk for mental health comorbidity.

  13. Recombination dynamics of excitons with low non-radiative component in semi-polar (10-11)-oriented GaN/AlGaN multiple quantum wells

    SciTech Connect

    Rosales, D.; Gil, B.; Bretagnon, T.; Guizal, B.; Izyumskaya, N.; Monavarian, M.; Zhang, F.; Okur, S.; Avrutin, V.; Özgür, Ü.; Morkoç, H.

    2014-09-07

    Optical properties of GaN/Al{sub 0.2}Ga{sub 0.8}N multiple quantum wells grown with semi-polar (10-11) orientation on patterned 7°-off Si (001) substrates have been investigated. Studies performed at 8 K reveal the in-plane anisotropic behavior of the QW photoluminescence (PL) intensity for this semi-polar orientation. The time resolved PL measurements were carried out in the temperature range from 8 to 295 K to deduce the effective recombination decay times, with respective radiative and non-radiative contributions. The non-radiative component remains relatively weak with increasing temperature, indicative of high crystalline quality. The radiative decay time is a consequence of contribution from both localized and free excitons. We report an effective density of interfacial defects of 2.3 × 10{sup 12} cm{sup −2} and a radiative recombination time of τ{sub loc} = 355 ps for the localized excitons. This latter value is significantly larger than those reported for the non-polar structures, which we attribute to the presence of a weak residual electric field in the semi-polar QW layers.

  14. Microscopic analysis of 10,11Be elastic scattering on protons and 12C and breakup processes of 11Be within the 10Be+n cluster model

    NASA Astrophysics Data System (ADS)

    Spasova, K.; Lukyanov, V. K.; Kadrev, D. N.; Antonov, A. N.; Zemlyanaya, E. V.; Lukyanov, K. V.; Gaidarov, M. K.

    2016-06-01

    The elastic scattering cross-sections of 10,11Be on protons and 12C at energy E < 100 MeV/nucleon using microscopically calculated optical potentials (OP) are presented. The real OP is obtained by a folding procedure with effective NN interactions, while the imaginary OP is estimated within the high energy approximation (HEA). The spin-orbit part of the OP is also included. The characteristics of the breakup processes of 11Be on different nuclear targets are also considered. The cross-sections of diffractive breakup and stripping reactions of 11Be on 9Be, 93Nb, 181Ta and 238U at energy E = 63 MeV/nucleon and the longitudinal momentum distributions of 10Be fragments produced in the breakup of 11Be on these nuclei are presented. The results are in a good agreement with the available experimental data, in particular the obtained widths of about 50 MeV/c are closed to the empirical ones.

  15. Comorbidity of 9/11-related PTSD and depression in the World Trade Center Health Registry 10-11 years postdisaster.

    PubMed

    Caramanica, Kimberly; Brackbill, Robert M; Liao, Tim; Stellman, Steven D

    2014-12-01

    Many studies report elevated prevalence of posttraumatic stress disorder (PTSD) and depression among persons exposed to the September 11, 2001 (9/11) disaster compared to those unexposed; few have evaluated long-term PTSD with comorbid depression. We examined prevalence and risk factors for probable PTSD, probable depression, and both conditions 10-11 years post-9/11 among 29,486 World Trade Center Health Registry enrollees who completed surveys at Wave 1 (2003-2004), Wave 2 (2006-2007), and Wave 3 (2011-2012). Enrollees reporting physician diagnosed pre-9/11 PTSD or depression were excluded. PTSD was defined as scoring ≥ 44 on the PTSD Checklist and depression as scoring ≥ 10 on the 8-item Patient Health Questionnaire. We examined 4 groups: comorbid PTSD and depression, PTSD only, depression only, and neither. Among enrollees, 15.2% reported symptoms indicative of PTSD at Wave 3, 14.9% of depression, and 10.1% of both. Comorbid PTSD and depression was associated with high 9/11 exposures, low social integration, health-related unemployment, and experiencing ≥ 1 traumatic life event post-9/11. Comorbid persons experienced poorer outcomes on all PTSD-related impairment measures, life satisfaction, overall health, and unmet mental health care need compared to those with only a single condition. These findings highlight the importance of ongoing screening and treatment for both conditions, particularly among those at risk for mental health comorbidity. PMID:25470556

  16. [PCA3 AND TMPRSS2:ERG GENES EXPRESSION IN BIOPSIES OF BENIGN PROSTATE HYPERPLASIA, INTRAEPITHELIAL NEOPLASIA, AND PROSTATE CANCER].

    PubMed

    Mikhaylenko, D S; Perepechin, D V; Grigoryeva, M V; Zhinzhilo, T A; Safronova, N Yu; Efremov, G D; Sivkov, A V

    2015-01-01

    Morphological analysis of the biopsies for prostate cancer (PCa) often is a difficult task due to heterogeneity and multifocality of tumors. At the same time, a lot of data exist about the potential molecular genetic markers of PCa. The aim of our study is to determine of PCA3 and TMPRSS2:ERG genes expression in benign hyperplasia (BPH), low and high grade intraepithelial neoplasia (PIN), PCa for revealing of diagnostic value of those genes expression in benign and precancerous changes in prostate. Total RNA was isolated from 53 biopsies, reverse transcription was performed, gene expression was determined by real time PCR (RT-PCR) then deltaCt index was determined as Ct(PCA3)--Ct(KLK3). Average deltaCt and its SD in BPH were 8.28 ± 3.13, low PIN--8.56 ± 2.64, high PIN--8.98 ±1.69, PCa--1.08 ± 2.36. We have demonstarted that deltaCt did not differ in patients with BPH, low and high grade PIN, whereas significantly increased in PCa relative to any of the three groups listed above (p < 0.0001). Expression of TMPRSS2:ERG was absent in BPH, PIN, but it was detected in 40% (4/10) of PCa cases. ROC-analysis showed that the AUC (area under ROC-curve with 95% CI, p < 0.0001) was 0.98 ± 0.02 in the analysis of a combination of overexpression of PCA3 and TMPRSS2:ERG. Thus, the expression analysis of the PCA3 and chimeric oncogene TMPRSS2:ERG in biopsy cannot be used for differential diagnosis of BPH, low and high grade PIN. However, overexpression of PCA3 and expression of TMPRSS2:ERG are characteristic in PCa. Expression analysis of these genes by the proposed RT-PCR modification at the threshold level deltaCt 3,22 has diagnostic accuracy 90% to detect PCa in biopsy specimens. PMID:26859937

  17. Determination of the type of stacking faults in single-crystal high-purity diamond with a low dislocation density of <50 cm-2 by synchrotron X-ray topography

    NASA Astrophysics Data System (ADS)

    Masuya, Satoshi; Hanada, Kenji; Uematsu, Takumi; Moribayashi, Tomoya; Sumiya, Hitoshi; Kasu, Makoto

    2016-04-01

    The properties of stacking faults in a single-crystal high-purity diamond with a very low dislocation density of <50 cm-2 and a very low impurity concentration of <0.1 ppm were investigated by synchrotron X-ray topography. We found stacking faults on the {111} plane and determined the fault vector f of the stacking faults to be \\textbf{f} = a/3< 111> on the basis of the f · g extinction criteria. Furthermore, we have found that the partial dislocations are of the Shockley type on the basis of the b · g extinction criteria. Consequently, we concluded that the stacking faults are of the Shockley type and formed because of the decomposition of dislocations with \\textbf{b} = a/2< 1\\bar{1}0> into dislocations with \\textbf{b} = a/6< 2\\bar{1}1> and a/6< 1\\bar{2}\\bar{1}> .

  18. A simple, rapid, low-cost technique for naked-eye detection of urine-isolated TMPRSS2:ERG gene fusion RNA.

    PubMed

    Koo, Kevin M; Wee, Eugene J H; Mainwaring, Paul N; Trau, Matt

    2016-01-01

    The TMPRSS2:ERG gene fusion is one of a series of highly promising prostate cancer (PCa) biomarker alternatives to the controversial serum PSA. Current methods for detecting TMPRSS2:ERG are limited in terms of long processing time, high cost and the need for specialized equipment. Thus, there is an unmet need for less complex, faster, and cheaper methods to enable gene fusion detection in the clinic. We describe herein a simple, rapid and inexpensive assay which combines robust isothermal amplification technique with a novel visualization method for evaluating urinary TMPRSS2:ERG status at less than USD 5 and with minimal equipment. The assay is sensitive, and rapidly detects as low as 10(5) copies of TMPRSS2:ERG transcripts while maintaining high levels of specificity. PMID:27470540

  19. A simple, rapid, low-cost technique for naked-eye detection of urine-isolated TMPRSS2:ERG gene fusion RNA

    PubMed Central

    Koo, Kevin M.; Wee, Eugene J. H.; Mainwaring, Paul N.; Trau, Matt

    2016-01-01

    The TMPRSS2:ERG gene fusion is one of a series of highly promising prostate cancer (PCa) biomarker alternatives to the controversial serum PSA. Current methods for detecting TMPRSS2:ERG are limited in terms of long processing time, high cost and the need for specialized equipment. Thus, there is an unmet need for less complex, faster, and cheaper methods to enable gene fusion detection in the clinic. We describe herein a simple, rapid and inexpensive assay which combines robust isothermal amplification technique with a novel visualization method for evaluating urinary TMPRSS2:ERG status at less than USD 5 and with minimal equipment. The assay is sensitive, and rapidly detects as low as 105 copies of TMPRSS2:ERG transcripts while maintaining high levels of specificity. PMID:27470540

  20. Successful reduction of off-target hERG toxicity by structural modification of a T-type calcium channel blocker.

    PubMed

    Choi, Yeon Jae; Seo, Jae Hong; Shin, Kye Jung

    2014-02-01

    To obtain an optimized T-type calcium channel blocker with reduced off-target hERG toxicity, we modified the structure of the original compound by introducing a zwitterion and reducing the basicity of the nitrogen. Among the structurally modified compounds we designed, compounds 5 and 6, which incorporate amides in place of the original compound's amines, most appreciably alleviated hERG toxicity while maintaining T-type calcium channel blocking activity. Notably, the benzimidazole amide 5 selectively blocked T-type calcium channels without inhibiting hERG (hERG/T-type⩾220) and L-type channels (L-type/T-type=96), and exhibited an excellent pharmacokinetic profile in rats.

  1. 2-(4-Carbonylphenyl)benzoxazole inhibitors of CETP: attenuation of hERG binding and improved HDLc-raising efficacy.

    PubMed

    Sweis, Ramzi F; Hunt, Julianne A; Sinclair, Peter J; Chen, Ying; Eveland, Suzanne S; Guo, Qiu; Hyland, Sheryl A; Milot, Denise P; Cumiskey, Anne-Marie; Latham, Melanie; Rosa, Raymond; Peterson, Larry; Sparrow, Carl P; Anderson, Matt S

    2011-05-01

    The development of 2-phenylbenzoxazoles as inhibitors of cholesteryl ester transfer protein (CETP) is described. Efforts focused on finding suitable replacements for the central piperidine with the aim of reducing hERG binding: a main liability of our benchmark benzoxazole (1a). Replacement of the piperidine with a cyclohexyl group successfully attenuated hERG binding, but was accompanied by reduced in vivo efficacy. The approach of substituting a piperidine moiety with an oxazolidinone also attenuated hERG binding. Further refinement of this latter scaffold via SAR at the pyridine terminus and methyl branching on the oxazolidinone led to compounds 7e and 7f, which raised HDLc by 33 and 27mg/dl, respectively, in our transgenic mouse PD model and without the hERG liability of previous series.

  2. Preliminary report on the July 10-11, 2015 eruption at Volcán de Colima: Pyroclastic density currents with exceptional runouts and volume

    NASA Astrophysics Data System (ADS)

    Capra, L.; Macías, J. L.; Cortés, A.; Dávila, N.; Saucedo, R.; Osorio-Ocampo, S.; Arce, J. L.; Gavilanes-Ruiz, J. C.; Corona-Chávez, P.; García-Sánchez, L.; Sosa-Ceballos, G.; Vázquez, R.

    2016-01-01

    On July 10-11, 2015 an eruption occurred at Colima volcano produced 10.5 km long pyroclastic density currents (PDCs) along the Montegrande, and 6.5 km long along the San Antonio ravines. The summit dome was destroyed and a new crater excavated and breached to the south. This new breach connects to a narrow channel that descends along Colima's southern flank and was used by a subsequent lava flow. The Montegrande PDCs represent the longest and hottest flow of this type recorded during the past 30 years but are still smaller in comparison to the 15-km long PDCs produced during the 1913 Plinian eruption. Data obtained from field reconnaissance, lahar monitoring stations, and satellite imagery suggest that at least six PDCs occurred. The two largest PDCs (H/L 0.2) were able to surmount topographic barriers or bends. Based on field reconnaissance and digital elevation models extracted from SPOT satellite imageries we estimate a minimum volume for the valley-pond and distal fan deposits of 4.5 × 106 m3. After one week, the deposits were still hot with burning trees on the surface and millimeter-sized holes from which fumes were emanating. The juvenile components of the deposits consist of gray dense blocks and vesicular dark-gray blocks and bombs with bread-crust textures and cooling joints. The mineral association of these rocks consists of plagioclase + clinopyroxene + orthopyroxene + FeTi-oxides ± olivine and resorbed hornblende in a dark glassy matrix that corresponds to an andesitic composition.

  3. Stimulation of hERG1 channel activity promotes a calcium-dependent degradation of cyclin E2, but not cyclin E1, in breast cancer cells.

    PubMed

    Perez-Neut, Mathew; Shum, Andrew; Cuevas, Bruce D; Miller, Richard; Gentile, Saverio

    2015-01-30

    Cyclin E2 gene amplification, but not cyclin E1, has been recently defined as marker for poor prognosis in breast cancer, and appears to play a major role in proliferation and therapeutic resistance in several breast cancer cells. Our laboratory has previously reported that stimulation of the hERG1 potassium channel with selective activators led to down-regulation of cyclin E2 in breast cancer cells. In this work, we demonstrate that stimulation of hERG1 promotes an ubiquitin-proteasome-dependent degradation of cyclin E2 in multiple breast cancer cell lines representing Luminal A, HER2+ and Trastuzumab-resistant breast cancer cells. In addition we have also reveal that hERG1 stimulation induces an increase in intracellular calcium that is required for cyclin E2 degradation. This novel function for hERG1 activity was specific for cyclin E2, as cyclins A, B, D E1 were unaltered by the treatment. Our results reveal a novel mechanism by which hERG1 activation impacts the tumor marker cyclin E2 that is independent of cyclin E1, and suggest a potential therapeutic use for hERG1 channel activators.

  4. The extremely high-energy plasma/particle sensor for electron (XEP-e) of the ERG satellite

    NASA Astrophysics Data System (ADS)

    Higashio, N.; Matsumoto, H.

    2015-12-01

    It is well known that satellites are always in danger in space and especially high-energy radiation damages them. One of the sources that cause them is the radiation belt (the Van Allen belt). It was thought to be static, but in the 1990s it rediscovered the radiation belt fluctuates greatly. There are some reasons to occur this phenomenon, but we have not understood a clear reason of this yet. On the other hand, it is well known that the energetic particle flux vary during geomagnetic disturbances and the relativistic electrons in the other radiation belt change with solar wind speed. Now we are trying to develop the satellite (ERG) to reveal this mechanism. ERG (Energization and Radiation in Geospace) satellite is the small space science platform for rapid investigation and test satellite of JAXA/ISAS. This satellite will be lanched in 2016. Our group is developing the instrument (the XEP-e) to measure high-energy electrons (400keV~20MeV), that is one of many ERG satellite instruments. The XEP-e (eXtremely high Energy Plasma/ particle sensor for electron) is consists of the 5 SSDs (Solid-State Silicon Detectors) and a GSO single crystal scintillator. It has one-way conic sight and an electric part is unified with a part of sensor that is covered with aluminum to protect from contaminationand and an anti-scintillator to detect it. The front part of the SSDs discriminate a radiation enters into the sensor and the back part of the plastic scintillator get the value of its energy. We can get the data of high-energy electron by using this sensor and it will be useful to reveal the detail of the radiation belt's fluctuation.

  5. Regional flexibility in the S4-S5 linker regulates hERG channel closed-state stabilization.

    PubMed

    Hull, Christina M; Sokolov, Stanislav; Van Slyke, Aaron C; Claydon, Tom W

    2014-10-01

    hERG K(+) channel function is vital for normal cardiac rhythm, yet the mechanisms underlying the unique biophysical characteristics of the channel, such as slow activation and deactivation gating, are incompletely understood. The S4-S5 linker is thought to transduce voltage sensor movement to opening of the pore gate, but may also integrate signals from cytoplasmic domains. Previously, we showed that substitutions of G546 within the S4-S5 linker destabilize the closed state of the channel. Here, we present results of a glycine-scan in the background of 546L. We demonstrate site-specific restoration of WT-like activation which suggests that flexibility in the N-terminal portion of the S4-S5 linker is critical for the voltage dependence of hERG channel activation. In addition, we show that the voltage dependence of deactivation, which was recently shown to be left-shifted from that of activation due to voltage sensor mode-shift, is also modulated by the S4-S5 linker. The G546L mutation greatly attenuated the coupling of voltage sensor mode-shift to the pore gate without altering the mode-shift itself. Indeed, all of the S4-S5 linker mutations tested similarly reduced coupling of the mode-shift to the pore gate. These data demonstrate a key role for S4-S5 linker in the unique activation and deactivation gating of hERG channels. Furthermore, uncoupling of the mode-shift to the pore by S4-S5 linker mutations parallels the effects of mutations in the N-terminus suggestive of functional interactions between the two regions.

  6. "I'm on it 24/7 at the moment": A qualitative examination of multi-screen viewing behaviours among UK 10-11 year olds

    PubMed Central

    2011-01-01

    Background Screen-viewing has been associated with increased body mass, increased risk of metabolic syndrome and lower psychological well-being among children and adolescents. There is a shortage of information about the nature of contemporary screen-viewing amongst children especially given the rapid advances in screen-viewing equipment technology and their widespread availability. Anecdotal evidence suggests that large numbers of children embrace the multi-functionality of current devices to engage in multiple forms of screen-viewing at the same time. In this paper we used qualitative methods to assess the nature and extent of multiple forms of screen-viewing in UK children. Methods Focus groups were conducted with 10-11 year old children (n = 63) who were recruited from five primary schools in Bristol, UK. Topics included the types of screen-viewing in which the participants engaged; whether the participants ever engaged in more than one form of screen-viewing at any time and if so the nature of this multiple viewing; reasons for engaging in multi-screen-viewing; the room within the house where multi-screen-viewing took place and the reasons for selecting that room. All focus groups were transcribed verbatim, anonymised and thematically analysed. Results Multi-screen viewing was a common behaviour. Although multi-screen viewing often involved watching TV, TV viewing was often the background behaviour with attention focussed towards a laptop, handheld device or smart-phone. There were three main reasons for engaging in multi-screen viewing: 1) tempering impatience that was associated with a programme loading; 2) multi-screen facilitated filtering out unwanted content such as advertisements; and 3) multi-screen viewing was perceived to be enjoyable. Multi-screen viewing occurred either in the child's bedroom or in the main living area of the home. There was considerable variability in the level and timing of viewing and this appeared to be a function of whether

  7. Changes in cortical cytoskeletal and extracellular matrix gene expression in prostate cancer are related to oncogenic ERG deregulation

    PubMed Central

    2010-01-01

    Background The cortical cytoskeleton network connects the actin cytoskeleton to various membrane proteins, influencing cell adhesion, polarity, migration and response to extracellular signals. Previous studies have suggested changes in the expression of specific components in prostate cancer, especially of 4.1 proteins (encoded by EPB41 genes) which form nodes in this network. Methods Expression of EPB41L1, EPB41L2, EPB41L3 (protein: 4.1B), EPB41L4B (EHM2), EPB41L5, EPB49 (dematin), VIL2 (ezrin), and DLG1 (summarized as „cortical cytoskeleton" genes) as well as ERG was measured by quantitative RT-PCR in a well-characterized set of 45 M0 prostate adenocarcinoma and 13 benign tissues. Hypermethylation of EPB41L3 and GSTP1 was compared in 93 cancer tissues by methylation-specific PCR. Expression of 4.1B was further studied by immunohistochemistry. Results EPB41L1 and EPB41L3 were significantly downregulated and EPB41L4B was upregulated in cancer tissues. Low EPB41L1 or high EPB41L4B expression were associated with earlier biochemical recurrence. None of the other cortical cytoskeleton genes displayed expression changes, in particular EPB49 and VIL2, despite hints from previous studies. EPB41L3 downregulation was significantly associated with hypermethylation of its promoter and strongly correlated with GSTP1 hypermethylation. Protein 4.1B was detected most strongly in the basal cells of normal prostate epithelia. Its expression in carcinoma cells was similar to the weaker one in normal luminal cells. EPB41L3 downregulation and EPB41L4B upregulation were essentially restricted to the 22 cases with ERG overexpression. Expression changes in EPB41L3 and EPB41L4B closely paralleled those previously observed for the extracellular matrix genes FBLN1 and SPOCK1, respectively. Conclusions Specific changes in the cortical cytoskeleton were observed during prostate cancer progression. They parallel changes in the expression of extracellular matrix components and all together

  8. Pharmacological and electrophysiological characterization of nine, single nucleotide polymorphisms of the hERG-encoded potassium channel

    PubMed Central

    Männikkö, R; Overend, G; Perrey, C; Gavaghan, CL; Valentin, J-P; Morten, J; Armstrong, M; Pollard, CE

    2010-01-01

    Background and purpose: Potencies of compounds blocking KV11.1 [human ether-ago-go-related gene (hERG)] are commonly assessed using cell lines expressing the Caucasian wild-type (WT) variant. Here we tested whether such potencies would be different for hERG single nucleotide polymorphisms (SNPs). Experimental approach: SNPs (R176W, R181Q, Del187-189, P347S, K897T, A915V, P917L, R1047L, A1116V) and a binding-site mutant (Y652A) were expressed in Tet-On CHO-K1 cells. Potencies [mean IC50; lower/upper 95% confidence limit (CL)] of 48 hERG blockers was estimated by automated electrophysiology [IonWorks™ HT (IW)]. In phase one, rapid potency comparison of each WT-SNP combination was made for each compound. In phase two, any compound-SNP combinations from phase one where the WT upper/lower CL did not overlap with those of the SNPs were re-examined. Electrophysiological WT and SNP parameters were determined using conventional electrophysiology. Key results: IW detected the expected sixfold potency decrease for propafenone in Y652A. In phase one, the WT lower/upper CL did not overlap with those of the SNPs for 77 compound-SNP combinations. In phase two, 62/77 cases no longer yielded IC50 values with non-overlapping CLs. For seven of the remaining 15 cases, there were non-overlapping CLs but in the opposite direction. For the eight compound-SNP combinations with non-overlapping CLs in the same direction as for phase 1, potencies were never more than twofold apart. The only statistically significant electrophysiological difference was the voltage dependence of activation of R1047L. Conclusion and implications: Potencies of hERG channel blockers defined using the Caucasian WT sequence, in this in vitro assay, were representative of potencies for common SNPs. This article is part of a themed section on QT safety. To view this issue visit http://www3.interscience.wiley.com/journal/121548564/issueyear?year=2010 PMID:19673885

  9. Replacement of olivine by serpentine in the Queen Alexandra Range 93005 carbonaceous chondrite (CM2): Reactant-product compositional relations, and isovolumetric constraints on reaction stoichiometry and elemental mobility during aqueous alteration

    NASA Astrophysics Data System (ADS)

    Velbel, Michael A.; Tonui, Eric K.; Zolensky, Michael E.

    2015-01-01

    Isovolumetric replacement of euhedral and anhedral olivine by serpentine produced both centripetal and meshwork textures in the CM2 chondrites ALH 81002 and Nogoya. The compositions of these textural varieties of serpentine are uniform within narrow limits within each previously studied meteorite, independent of the composition of olivine being replaced, and different between the two meteorites. In QUE 93005 (CM2), coarse olivines of widely varying compositions (Fo<76-99) are replaced in a texturally similar manner by compositionally uniform serpentine (Mg0.73±0.05Fe0.27±0.05)3Si2O5(OH)4. The narrow compositional range of serpentine replacing coarse olivine indicates that the aqueous solution from which the serpentine formed was compositionally uniform on scales at least as large as the meteorite (∼2.5 cm in longest dimension). Isovolumetric textures and compositional observations constrain elemental redistribution from coarse olivine to serpentine and to surrounding phases during serpentinization. Regardless of olivine's composition, isovolumetric replacement of coarse olivines by serpentine of the observed composition released more Mg and Si from olivine than was required to form the serpentine. Excess Mg and Si released by olivine destruction and not retained in serpentine were exported from the replaced volume. Olivines with different Fa/Fo proportions contributed different amounts of Fe and Mg to the serpentine. Ferroan olivines released more Fe than required to form the serpentines replacing them, so some of the Fe released from ferroan olivine was exported from the replaced volumes. Forsteritic olivines released less Fe than required to form the serpentines replacing them, so some Fe was imported into the replaced volumes augmenting the small amount of Fe released from forsteritic olivine. In QUE 93005 Fo83.8 is the threshold composition between Fe-exporting and Fe-importing behavior in individual olivine-serpentine pairs, which released exactly the

  10. A novel four-color fluorescence in situ hybridization assay for the detection of TMPRSS2 and ERG rearrangements in prostate cancer.

    PubMed

    Qu, Xiaoyu; Randhawa, Grace; Friedman, Cynthia; O'Hara-Larrivee, Siobhan; Kroeger, Kathleen; Dumpit, Ruth; True, Larry; Vakar-Lopez, Funda; Porter, Christopher; Vessella, Robert; Nelson, Peter; Fang, Min

    2013-01-01

    Since the identification of the TMPRSS2-ERG rearrangement as the most common fusion event in prostate cancer, various methods have been developed to detect this rearrangement and to study its prognostic significance. We report a novel four-color fluorescence in situ hybridization (FISH) assay that detects not only the typical TMPRSS2-ERG fusion but also alternative rearrangements of the TMPRSS2 or ERG gene. We validated this assay on fresh, frozen, or formalin-fixed paraffin-embedded prostate cancer specimens, including cell lines, primary prostate cancer tissues, xenograft tissues derived from metastatic prostate cancer, and metastatic tissues from castration-resistant prostate cancer (CRPC) patients. When compared with either reverse transcription-polymerase chain reaction or the Gen-Probe method as the technical reference, analysis using the four-color FISH assay demonstrated an analytical sensitivity of 94.5% (95% confidence interval [CI] 0.80-0.99) and specificity of 100% (95% CI 0.89-1.00) for detecting the TMPRSS2-ERG fusion. The TMPRSS2-ERG fusion was detected in 41% and 43% of primary prostate cancer (n = 59) and CRPC tumors (n = 82), respectively. Rearrangements other than the typical TMPRSS2-ERG fusion were confirmed by karyotype analysis and found in 7% of primary cancer and 13% of CRPC tumors. Successful karyotype analyses are reported for the first time on four of the xenograft samples, complementing the FISH results. Analysis using the four-color FISH assay provides sensitive detection of TMPRSS2 and ERG gene rearrangements in prostate cancer.

  11. Key comparison BIPM.RI(I)-K6 of the standards for absorbed dose to water at 10 g cm-2 of the NMIJ, Japan and the BIPM in accelerator photon beams

    NASA Astrophysics Data System (ADS)

    Picard, S.; Burns, D. T.; Roger, P.; Shimizu, M.; Morishita, Y.; Kato, M.; Tanaka, T.; Kurosawa, T.; Saito, N.

    2016-01-01

    A comparison of the dosimetry for accelerator photon beams was carried out between the National Metrology Institute of Japan (NMIJ) and the Bureau International des Poids et Mesures (BIPM) from 9 to 23 April 2015. The comparison was based on the determination of absorbed dose to water at 10 g cm-2 for three radiation qualities at the NMIJ. The results, reported as ratios of the NMIJ and the BIPM evaluations (and with the combined standard uncertainties given in parentheses), are 0.9966 (47) at 6 MV, 0.9965 (60) at 10 MV and 0.9953 (50) at 15 MV. This result is the eighth in the on-going BIPM.RI(I)-K6 series of comparisons. Main text To reach the main text of this paper, click on Final Report. Note that this text is that which appears in Appendix B of the BIPM key comparison database kcdb.bipm.org/. The final report has been peer-reviewed and approved for publication by the CCRI, according to the provisions of the CIPM Mutual Recognition Arrangement (CIPM MRA).

  12. Enhanced therapeutic anti-inflammatory effect of betamethasone upon topical administration with low frequency, low intensity (20 kHz, 100 mW/cm2) ultrasound exposure on carrageenan-induced arthritis in mice model

    PubMed Central

    Cohen, Gadi; Natsheh, Hiba; Sunny, Youhan; Bawiec, Christopher R.; Touitou, Elka; Lerman, Melissa A.; Lazarovici, Philip; Lewin, Peter A.

    2015-01-01

    The purpose of this work was to investigate whether low frequency, low intensity (LFLI, 20 kHz, <100 mW/cm2, spatial-peak, temporal-peak) ultrasound (US), delivered by a light-weight (<100g), tether-free, fully wearable, battery powered applicator is capable of reducing inflammation in a mouse model of Rheumatoid Arthritis (RA). The therapeutic, acute, anti-inflammatory effect was estimated by the relative swelling induced in mice hind limb paws. In an independent, indirect approach, the inflammation was bio-imaged by measuring glycolytic activity with near infrared labeled 2-deoxy-glucose (2DG). The outcome of the experiments indicated that the combination of US exposure with topical application of 0.1% w/w betamethasone gel, exhibited statistically significant (p<0.05) enhanced anti-inflammatory properties in comparison with the drug or US treatment alone. The present study underscores the potential benefits of LFLI US assisted drug delivery. However, the proof of concept presented indicates the need for additional experiments to systematically evaluate and optimize the potential of, and the conditions for, safe, LFLI ultrasound promoted non-invasive drug delivery. PMID:26003010

  13. hERGAPDbase: a database documenting hERG channel inhibitory potentials and APD-prolongation activities of chemical compounds.

    PubMed

    Hishigaki, Haretsugu; Kuhara, Satoru

    2011-01-01

    Drug-induced QT interval prolongation is one of the most common reasons for the withdrawal of drugs from the market. In the past decade, at least nine drugs, i.e. terfenadine, astemizole, grepafloxacin, terodiline, droperidol, lidoflazine, sertindole, levomethadyl and cisapride, have been removed from the market or their use has been severely restricted because of drug-induced QT interval prolongation. Therefore, this irregularity is a major safety concern in the case of drugs submitted for regulatory approval. The most common mechanism of drug-induced QT interval prolongation may be drug-related inhibition of the human ether-á-go-go-related gene (hERG) channel, which subsequently results in prolongation of the cardiac action potential duration (APD). hERGAPDbase is a database of electrophysiological experimental data documenting potential hERG channel inhibitory actions and the APD-prolongation activities of chemical compounds. All data entries are manually collected from scientific papers and curated by a person. With hERGAPDbase, we aim to provide useful information for chemical and pharmacological scientists and enable easy access to electrophysiological experimental data on chemical compounds. Database URL: http://www.grt.kyushu-u.ac.jp/hergapdbase/.

  14. hERGAPDbase: a database documenting hERG channel inhibitory potentials and APD-prolongation activities of chemical compounds.

    PubMed

    Hishigaki, Haretsugu; Kuhara, Satoru

    2011-01-01

    Drug-induced QT interval prolongation is one of the most common reasons for the withdrawal of drugs from the market. In the past decade, at least nine drugs, i.e. terfenadine, astemizole, grepafloxacin, terodiline, droperidol, lidoflazine, sertindole, levomethadyl and cisapride, have been removed from the market or their use has been severely restricted because of drug-induced QT interval prolongation. Therefore, this irregularity is a major safety concern in the case of drugs submitted for regulatory approval. The most common mechanism of drug-induced QT interval prolongation may be drug-related inhibition of the human ether-á-go-go-related gene (hERG) channel, which subsequently results in prolongation of the cardiac action potential duration (APD). hERGAPDbase is a database of electrophysiological experimental data documenting potential hERG channel inhibitory actions and the APD-prolongation activities of chemical compounds. All data entries are manually collected from scientific papers and curated by a person. With hERGAPDbase, we aim to provide useful information for chemical and pharmacological scientists and enable easy access to electrophysiological experimental data on chemical compounds. Database URL: http://www.grt.kyushu-u.ac.jp/hergapdbase/. PMID:21586548

  15. Histopathological changes in retinas and F-ERG features of streptozotocin-induced diabetic rats treated with ozone

    PubMed Central

    Xie, Ting-Yu; Li, Qin; Chen, Xue-Yi

    2016-01-01

    AIM To study the histopathological changes in the retina and flash electroretinogram (F-ERG) features of ozone-treated streptozotocin (STZ)-induced diabetic rats. METHODS Seventy male Sprague Dawley rats were grouped as follows: blank group (GB, n=10), model control group (GM, n=18), ozone group (GO3, n=19), and oxygen group (GO2, n=18). The model was induced by single intraperitoneal injection of STZ. Ozone or oxygen enteroclysm was given twice per week for 4wk. F-ERG and histopathological examinations were performed one month after treatment. RESULTS Under dark adaption, as compared to GB, the other groups each had differential decreases in the a-wave amplitudes (P<0.05); the latencies were delayed in GM, GO2, and GO3 rats (P<0.05). Similar results were observed under light adaption, with the exception that the a-wave of the amplitudes (F=0.28, P>0.05). There were significant differences in the apoptosis index among the groups (P<0.05). Under ozone treatment, apoptosis was decreased in GO3 as compared to GM and GO2. CONCLUSION Ozone administration alleviates nerve damage and reduces pathology and apoptosis in the retinas of diabetic rats. PMID:27366680

  16. Rapid detection of ERG11 gene mutations in clinical Candida albicans isolates with reduced susceptibility to fluconazole by rolling circle amplification and DNA sequencing

    PubMed Central

    2009-01-01

    Background Amino acid substitutions in the target enzyme Erg11p of azole antifungals contribute to clinically-relevant azole resistance in Candida albicans. A simple molecular method for rapid detection of ERG11 gene mutations would be an advantage as a screening tool to identify potentially-resistant strains and to track their movement. To complement DNA sequencing, we developed a padlock probe and rolling circle amplification (RCA)-based method to detect a series of mutations in the C. albicans ERG11 gene using "reference" azole-resistant isolates with known mutations. The method was then used to estimate the frequency of ERG11 mutations and their type in 25 Australian clinical C. albicans isolates with reduced susceptibility to fluconazole and in 23 fluconazole-susceptible isolates. RCA results were compared DNA sequencing. Results The RCA assay correctly identified all ERG11 mutations in eight "reference" C. albicans isolates. When applied to 48 test strains, the RCA method showed 100% agreement with DNA sequencing where an ERG11 mutation-specific probe was used. Of 20 different missense mutations detected by sequencing in 24 of 25 (96%) isolates with reduced fluconazole susceptibility, 16 were detected by RCA. Five missense mutations were detected by both methods in 18 of 23 (78%) fluconazole-susceptible strains. DNA sequencing revealed that mutations in non-susceptible isolates were all due to homozygous nucleotide changes. With the exception of the mutations leading to amino acid substitution E266D, those in fluconazole-susceptible strains were heterozygous. Amino acid substitutions common to both sets of isolates were D116E, E266D, K128T, V437I and V488I. Substitutions unique to isolates with reduced fluconazole susceptibility were G464 S (n = 4 isolates), G448E (n = 3), G307S (n = 3), K143R (n = 3) and Y123H, S405F and R467K (each n = 1). DNA sequencing revealed a novel substitution, G450V, in one isolate. Conclusion The sensitive RCA assay described here

  17. Structure of the Cyclic Nucleotide-Binding Homology Domain of the hERG Channel and Its Insight into Type 2 Long QT Syndrome

    PubMed Central

    Li, Yan; Ng, Hui Qi; Li, Qingxin; Kang, CongBao

    2016-01-01

    The human ether-à-go-go related gene (hERG) channel is crucial for the cardiac action potential by contributing to the fast delayed-rectifier potassium current. Mutations in the hERG channel result in type 2 long QT syndrome (LQT2). The hERG channel contains a cyclic nucleotide-binding homology domain (CNBHD) and this domain is required for the channel gating though molecular interactions with the eag domain. Here we present solution structure of the CNBHD of the hERG channel. The structural study reveals that the CNBHD adopts a similar fold to other KCNH channels. It is self-liganded and it contains a short β-strand that blocks the nucleotide-binding pocket in the β-roll. Folding of LQT2-related mutations in this domain was shown to be affected by point mutation. Mutations in this domain can cause protein aggregation in E. coli cells or induce conformational changes. One mutant-R752W showed obvious chemical shift perturbation compared with the wild-type, but it still binds to the eag domain. The helix region from the N-terminal cap domain of the hERG channel showed unspecific interactions with the CNBHD. PMID:27025590

  18. The Completion Agenda: A Call to Action. Summary Report from the November 10-11, 2010, Meeting of the American Association of Community Colleges Commissions and Board of Directors

    ERIC Educational Resources Information Center

    McPhail, Christine Johnson

    2011-01-01

    At its annual joint board and commission meeting (Washington, DC, November 10-11, 2010), American Association of Community Colleges (AACC) focused attention on college completion by presenting two panel discussions on the completion agenda, followed by breakout sessions in which participants were assigned to focus groups tasked with providing…

  19. Adult and Higher Education in the Contemporary World: Its Role in Cultural Literacy. Conference Proceedings of the Adult Higher Education Alliance Annual Conference (35th, Orlando, Florida, March 10-11, 2015)

    ERIC Educational Resources Information Center

    Elufiede, Oluwakemi, Ed.; Flynn, Bonnie, Ed.

    2015-01-01

    This document is Conference Proceedings Of The Adult Higher Education Alliance, 35th Annual Conference. The theme of the conference was Adult And Higher Education In The Contemporary World: Its Role In Cultural Literacy. Conference was March 10-11, 2015. The event was hosted by and held at the College Of Education And Human Performance, Morgridge…

  20. U.S. Regional Agricultural Production in 2030 and 2095: Response to CO2 Fertilization and Hadley Climate Model (HadCM2) Projections of Greenhouse-Forced Climatic Change

    SciTech Connect

    NJ Rosenberg; RC Izaurralde: RA Brown

    1999-11-19

    Research activities underway to evaluate potential consequences of climate change and variability on the agriculture, water resources, and other U.S. sectors were mandated by the Global Change Research Act of 1990. These activities are being carried out in a public-private partnership under the guidance of the U.S. Global Change Research Program. Researchers at Pacific Northwest National Laboratory (PNNL) have been using integrated assessment methodologies to appraise the possible impacts of global warming and climatic variability on the behavior of managed and natural systems. This interim PNNL report contributes to the U.S. National Assessment process with an analysis of the modeled impacts of climatic changes projected by the Hadley/UKMO (HadCM2) general circulation model on agricultural productivity and selected environmental variables. The construction of climatic data for the simulation runs followed general guidelines established by the U.S. National Assessment Synthesis Team. The baseline climate data were obtained from national records for the period 1961 - 1990. The scenario runs for two future periods (2025 - 2030 and 2090 - 2099) were extracted from results of a HadCM2 run distributed at a half-degree spatial resolution. The Erosion Productivity Impact Calculator (EPIC) was used to simulate the behavior of 204 "representative farms" (i.e., soil-climate-management combinations) under baseline climate, the two future periods and their combinations with two levels of atmospheric C02 concentrations (365 and 560 ppm). Analysis of simulation results identified areas in Texas, New Mexico, Colorado, Utah, Arizona, and California that would experience large temperature increases by 2030. Slight cooling is expected by 2030 in parts of Alabama, Florida, Maine, Montana, Idaho, and Utah. Larger areas will experience increased warming by 2095. Uniform precipitation increases are expected by 2030 in the north eastern quarter of the country. These uniform precipitation

  1. Low-voltage back-gated atmospheric pressure chemical vapor deposition based graphene-striped channel transistor with high-κ dielectric showing room-temperature mobility > 11,000 cm(2)/V·s.

    PubMed

    Smith, Casey; Qaisi, Ramy; Liu, Zhihong; Yu, Qingkai; Hussain, Muhammad Mustafa

    2013-07-23

    Utilization of graphene may help realize innovative low-power replacements for III-V materials based high electron mobility transistors while extending operational frequencies closer to the THz regime for superior wireless communications, imaging, and other novel applications. Device architectures explored to date suffer a fundamental performance roadblock due to lack of compatible deposition techniques for nanometer-scale dielectrics required to efficiently modulate graphene transconductance (gm) while maintaining low gate capacitance-voltage product (CgsVgs). Here we show integration of a scaled (10 nm) high-κ gate dielectric aluminum oxide (Al2O3) with an atmospheric pressure chemical vapor deposition (APCVD)-derived graphene channel composed of multiple 0.25 μm stripes to repeatedly realize room-temperature mobility of 11,000 cm(2)/V·s or higher. This high performance is attributed to the APCVD graphene growth quality, excellent interfacial properties of the gate dielectric, conductivity enhancement in the graphene stripes due to low tox/Wgraphene ratio, and scaled high-κ dielectric gate modulation of carrier density allowing full actuation of the device with only ±1 V applied bias. The superior drive current and conductance at Vdd = 1 V compared to other top-gated devices requiring undesirable seed (such as aluminum and poly vinyl alcohol)-assisted dielectric deposition, bottom gate devices requiring excessive gate voltage for actuation, or monolithic (nonstriped) channels suggest that this facile transistor structure provides critical insight toward future device design and process integration to maximize CVD-based graphene transistor performance.

  2. Particle-size fractionation of aeolian sand along a climatic and geomorphic gradient of the Sinai-Negev erg

    NASA Astrophysics Data System (ADS)

    Roskin, Joel; Katra, Itzhak; Blumberg, Dan G.

    2015-04-01

    This study examines changes in the aeolian sand fractions along the west-east aeolian transport path of the northern Sinai Peninsula - northwestern (NW) Negev erg of Egypt and Israel. This erg originates from the Nile Delta and is composed of currently active linear (seif) dunes in northern Sinai (its western part), and currently stabilized vegetated linear dunes (VLDs) in the NW Negev dunefield (its eastern part). Sand samples from the Nile Delta, northern Sinai and NW Negev were analyzed for particle-size distribution and sand grain morphology in accordance to their Eastern Mediterranean INQUA Dunes Atlas luminescence and radiocarbon chronologies. Linear seif dunes differ from VLDs in their vegetation cover, linearity, and dynamics. Although both are continuous landforms with similar orientations and sand-grain roundness values, the linear dunes of Sinai are coarser-grained than the Negev VLDs. The VLDs have a significantly higher proportion of very fine sand (125-50 μm) content and a varying but lower sand fining ratio defined as the ratio of fine sand percentage to very fine sand percentage. Very fine sands are suggested to have been winnowed by saltation and low suspension from source deposits and sand sheets. Detailed semi-quantitative examinations of sand grains by a SEM of a Negev VLD shows that most grains do not exhibit features that can be attributed to aeolian abrasion by sand grain-grain collisions. From these observations we infer that fractionation of sand was a major process leading to downwind fining along the studied aeolian transport path. We suggest that the very fine sand fraction of Nile Delta and Sinai sands has been transported downwind since the late middle Pleistocene. In the late Pleistocene, sand reached the NW Negev in the form of VLDs due to last-glacial period windiness of intensities unprecedented today and probably larger sediment supply. Generally current and inferred past decreasing wind velocities and increasing precipitation

  3. High-performance beating pattern function of human induced pluripotent stem cell-derived cardiomyocyte-based biosensors for hERG inhibition recognition.

    PubMed

    Hu, Ning; Wang, Tianxing; Wang, Qin; Zhou, Jie; Zou, Ling; Su, Kaiqi; Wu, Jieying; Wang, Ping

    2015-05-15

    High-throughput and high clinical relevance methods are demanded to predict the drug-induced cardiotoxicity in pharmaceutical and biotechnology industries to effectively decrease late-stage drug attrition. In this study, human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) were integrated into an interdigital impedance sensor array to fabricate a high performance iPSC-CM-based biosensor array with high-throughput and high-consistency beating pattern. Typical withdrawal approved drugs (astemizole, sertindole, cisapride, and droperidol) with hERG inhibition and positive control E-4031 were employed to determine the beating pattern function. From the results, it can be concluded that this iPSC-CM-based biosensor array can specifically differentiate the hERG inhibitors from the non-hERG inhibition compounds through beating pattern function. PMID:25153933

  4. hERG1 positivity and Glut-1 negativity identifies high-risk TNM stage I and II colorectal cancer patients, regardless of adjuvant chemotherapy

    PubMed Central

    Muratori, Leonardo; Petroni, Giulia; Antonuzzo, Lorenzo; Boni, Luca; Iorio, Jessica; Lastraioli, Elena; Bartoli, Gianluca; Messerini, Luca; Di Costanzo, Francesco; Arcangeli, Annarosa

    2016-01-01

    Background The identification of early-stage colorectal cancer (CRC) with high risk of progression is one major clinical challenge, mainly due to lack of validated biomarkers. The aims of the present study were to analyze the prognostic impact of three molecular markers belonging to the ion channels and transporters family: the ether-à-go-go-related gene 1 (hERG1) and the calcium-activated KCa3.1 potassium channels, as well as the glucose transporter 1 (Glut-1); and to define the impact of adjuvant chemotherapy in conjunction with the abovementioned biomarkers, in a cohort of radically resected stage I–III CRC patients. Patients and methods The expressions of hERG1, KCa3.1, and Glut-1 were tested by immunohistochemistry on 162 surgical samples of nonmetastatic, stage I–III CRC patients. The median follow-up was 32 months. The association between biological markers, clinicopathological features, and survival outcomes was investigated by evaluating both disease-free survival and overall survival. Results Although no prognostic valence emerged for KCa3.1, evidence of a negative impact of hERG1 expression on survival outcomes was provided. On the contrary, Glut-1 expression had a positive impact. According to the results of the multivariate analysis, patients were stratified in four risk groups, based on TNM stage and hERG1/Glut-1 expression. After adjusting for adjuvant therapy, stage I and II, Glut-1-negative, and hERG1-positive patients showed the worst survival experience. Conclusion This study strongly indicates that the combination of hERG1 positivity and Glut-1 negativity behaves as a prognostic biomarker in radically resected CRC patients. This combination identifies a group of stage I and II CRC patients with a bad prognosis, even worse than that of stage III patients, regardless of adjuvant therapy accomplishment.

  5. Performance of a Single Assay for Both Type III and Type VI TMPRSS2:ERG Fusions in Noninvasive Prediction of Prostate Biopsy Outcome

    PubMed Central

    Clark, Jarrod P.; Munson, Kristofer W.; Gu, Jessie W.; Lamparska-Kupsik, Katarzyna; Chan, Kevin G.; Yoshida, Jeffrey S.; Kawachi, Mark H.; Crocitto, Laura E.; Wilson, Timothy G.; Feng, Ziding; Smith, Steven S.

    2010-01-01

    BACKGROUND TMPRSS2:ERG fusions are promising prostate cancer biomarkers. Because they can occur in multiple forms in a single cancer specimen, we developed a quantitative PCR test that detects both type III and type VI TMPRSS2:ERG fusions. The assay is quantified from a standard curve determined with a plasmid-cloned type III TMPRSS2:ERG fusion target. METHODS We collected expressed prostatic secretion (EPS) under an institutional review board–approved, blinded, prospective study from 74 patients undergoing transrectal ultrasound-guided biopsy for prostate cancer. We compared the characteristic performance of the test for type III and type VI TMPRSS2:ERG fusions in predicting biopsy outcome and distinguishing between high and low Gleason scores with similar tests for the expression of PCA3 and DNA methylation levels of the APC, RARB, RASSF1, and GSTP1 genes. We used logistic regression to analyze the effects of multiple biomarkers in linear combinations. RESULTS Each test provided a significant improvement in characteristic performance over baseline digital rectal examination (DRE) plus serum prostate-specific antigen (PSA); however, the test for type III and type VI TMPRSS2:ERG fusions yielded the best performance in predicting biopsy outcome [area under the curve (AUC) 0.823, 95% CI 0.728–0.919, P < 0.001] and Gleason grade >7 (AUC 0.844, 95% CI 0.740–0.948, P < 0.001). CONCLUSIONS Although each test appears to have diagnostic value, PSA plus DRE plus type III and type VI TMPRSS2:ERG provided the best diagnostic performance in EPS specimens. PMID:18948370

  6. Interactions between hERG and KCNQ1 α-subunits are mediated by their COOH termini and modulated by cAMP.

    PubMed

    Organ-Darling, Louise E; Vernon, Amanda N; Giovanniello, Jacqueline R; Lu, Yichun; Moshal, Karni; Roder, Karim; Li, Weiyan; Koren, Gideon

    2013-02-15

    KCNQ1 and hERG encode the voltage-gated potassium channel α-subunits of the cardiac repolarizing currents I(Ks) and I(Kr), respectively. These currents function in vivo with some redundancy to maintain appropriate action potential durations (APDs), and loss-of-function mutations in these channels manifest clinically as long QT syndrome, characterized by the prolongation of the QT interval, polymorphic ventricular tachycardia, and sudden cardiac death. Previous cellular electrophysiology experiments in transgenic rabbit cardiomyocytes and heterologous cell lines demonstrated functional downregulation of complementary repolarizing currents. Biochemical assays indicated direct, protein-protein interactions between KCNQ1 and hERG may underlie the interplay between I(Ks) and I(Kr). Our objective was to investigate hERG-KCNQ1 interactions in the intact cellular environment primarily through acceptor photobleach FRET (apFRET) experiments. We quantitatively assessed the extent of interactions based on fluorophore location and the potential regulation of interactions by physiologically relevant signals. apFRET experiments established specific hERG-KCNQ1 associations in both heterologous and primary cardiomyocytes. The largest FRET efficiency (E(f); 12.0 ± 5.2%) was seen between ion channels with GFP variants fused to the COOH termini. Acute treatment with forskolin + IBMX or a membrane-permeable cAMP analog significantly and specifically reduced the extent of hERG-KCNQ1 interactions (by 41 and 38%, respectively). Our results demonstrate direct interactions between KCNQ1 and hERG occur in both intact heterologous cells and primary cardiomyocytes and are mediated by their COOH termini. Furthermore, this interplay between channel proteins is regulated by intracellular cAMP.

  7. Normal photoresponses and altered b-wave responses to APB in the mdxCv3 mouse isolated retina ERG supports role for dystrophin in synaptic transmission

    PubMed Central

    GREEN, DANIEL G.; GUO, HAO

    2005-01-01

    The mdxCv3 mouse is a model for Duchenne muscular dystrophy (DMD). DMD is an X-linked disorder with defective expression of the protein dystrophin, and which is associated with a reduced b-wave and has other electroretinogram (ERG) abnormalities. To assess potential causes for the abnormalities, we recorded ERGs from pieces of isolated C57BL/6J and mdxCv3 mouse retinas, including measurements of transretinal and intraretinal potentials. The ERGs from the isolated mdxCv3 retina differ from those of control retinas in that they show reduced b-wave amplitudes and increased b-wave implicit times. Photovoltages obtained by recording across the photoreceptor outer segments of the retinas did not differ from normal, suggesting that the likely causes of the reduced b-wave are localized to the photoreceptor to ON-bipolar synapse. At a concentration of 50 μM, the glutamate analog DL-2-amino-4-phosphonobutyric acid (APB) blocks the b-wave component of the ERG, by binding to sites on the postsynaptic membrane. The On-bipolar cell contribution to the ERG was inferred by extracting the component that was blocked by APB. We found that this component was smaller in amplitude and had longer response latencies in the mdxCv3 mice, but was of similar overall time course. To assess the sensitivity of sites on the postsynaptic membrane to glutamate, the concentration of APB in the media was systematically varied, and the magnitude of blockage of the light response was quantified. We found that the mdxCv3 retina was 5-fold more sensitive to APB than control retinas. The ability of lower concentrations of APB to block the b-wave in mdxCv3 suggests that the ERG abnormalities may reflect alterations in either glutamate release, the glutamate postsynaptic binding sites, or in other proteins that modulate glutamate function in ON-bipolar cells. PMID:15683561

  8. Synthesis and biological evaluation of negative allosteric modulators of the Kv11.1(hERG) channel.

    PubMed

    Yu, Zhiyi; van Veldhoven, Jacobus P D; 't Hart, Ingrid M E; Kopf, Adrian H; Heitman, Laura H; IJzerman, Adriaan P

    2015-12-01

    We synthesized and evaluated a series of compounds for their allosteric modulation at the Kv11.1 (hERG) channel. Most compounds were negative allosteric modulators of [(3)H]dofetilide binding to the channel, in particular 7f, 7h-j and 7p. Compounds 7f and 7p were the most potent negative allosteric modulators amongst all ligands, significantly increasing the dissociation rate of dofetilide in the radioligand kinetic binding assay, while remarkably reducing the affinities of dofetilide and astemizole in a competitive displacement assay. Additionally, both 7f and 7p displayed peculiar displacement characteristics with Hill coefficients significantly distinct from unity as shown by e.g., dofetilide, further indicative of their allosteric effects on dofetilide binding. Our findings in this investigation yielded several promising negative allosteric modulators for future functional and clinical research with respect to their antiarrhythmic propensities, either alone or in combination with known Kv11.1 blockers. PMID:26519929

  9. tert-Butyl hydroperoxide-induced differing plasma membrane and oxidative stress processes in yeast strains BY4741 and erg5Δ.

    PubMed

    Gazdag, Zoltán; Máté, Gábor; Certik, Milan; Türmer, Katalin; Virág, Eszter; Pócsi, István; Pesti, Miklós

    2014-07-01

    The molecular mechanism of tert-butyl hydroperoxide (t-BuOOH) elicited cytotoxicity and the background of t-BuOOH sensitivity were studied in the Saccharomyces cerevisiae ergosterol-less gene deletion mutant erg5Δ and its parental strain BY4741. In comparison to BY4741, untreated erg5Δ cells exhibited alterations in sterol and fatty acid compositions of the plasma membrane, as reflected by the inherent amphotericin B resistance, an elevated level (31%) of plasma membrane rigidity and a decreased uptake of glycerol. Surprisingly, the untreated erg5Δ cells exhibited an unbalanced intracellular redox state, accompanied by the continuous upregulation of the antioxidant enzymes Mn superoxide dismutase, catalase, and glutathione S-transferase, which resulted in decreased specific concentrations of superoxide and peroxides and elevated levels of the hydroxyl radical and thiols. The 2.5-fold sensitivity of erg5Δ to t-BuOOH suggested that the oxidative stress adaptation processes of the mutant could not restore the redox homeostasis of the cells and there is an overlap between sterol and redox homeostases. t-BuOOH treatment of both strains induced adaptive modification of the sterol and fatty acid compositions, increased the plasma membrane fluidity and elevated the specific activities of most antioxidant enzymes through specific regulation processes in a strain-dependent manner. PMID:24687861

  10. The neutral, hydrophobic isoleucine at position I521 in the extracellular S4 domain of hERG contributes to channel gating equilibrium.

    PubMed

    Dou, Ying; Goodchild, Samuel J; Velde, Robert Vander; Wu, Yue; Fedida, David

    2013-08-15

    The human ether-a-go-go related (hERG) potassium channel has unusual functional characteristics in that the rates of channel activation and deactivation are much slower than inactivation, which is attributed to specific structural elements within the NH2 terminus and the S1-S4 voltage-sensing domains (VSD). Although the charged residues in the VSD have been extensively modified and mutated as a result, the role and importance of specific hydrophobic residues in the S4 has been much less explored in studies of hERG gating. We found that charged, but not neutral or hydrophobic, amino acid substitution of isoleucine 521 at the outer end of the S4 transmembrane domain resulted in channels activating at much more negative voltages associated with a marked hyperpolarization of the conductance-voltage (G-V) relationship. The contributions of different physicochemical properties to this effect were probed by chemical modification of channels substituted with cysteine at position I521. When positively charged reagents including tetramethyl-rhodamine-5-maleimide (TMRM), 1-(2-maleimidylethyl)-4-[5-(4-methoxyphenyl)oxazol-2-yl] pyridinium methane-sulfonate (PyMPO), [2-(trimethylammonium)ethyl] methanethiosulfonate chloride (MTSET), and 2-aminoethyl methanethiosulfonate hydrobromide (MTSEA) were bound to the cysteine, I521C channels activated at more negative membrane potentials. To examine the contributions to hERG gating of other residues at the outer end of S4 (520-528), we performed a cysteine scan combined with MTSET modification. Only L520C, along with I521C, shows a substantial hyperpolarizing shift of the G-V relationship upon MTSET modification. The data indicate that the neutral, hydrophobic residue I521 at the extracellular end of S4 is critical for stabilizing the closed conformation of the hERG channel relative to the open state and by comparison with Shaker supports the alignment of hERG I521 with Shaker L361.

  11. ERG deregulation induces IGF-1R expression in prostate cancer cells and affects sensitivity to anti-IGF-1R agents.

    PubMed

    Mancarella, Caterina; Casanova-Salas, Irene; Calatrava, Ana; Ventura, Selena; Garofalo, Cecilia; Rubio-Briones, José; Magistroni, Vera; Manara, Maria Cristina; López-Guerrero, José Antonio; Scotlandi, Katia

    2015-06-30

    Identifying patients who may benefit from targeted therapy is an urgent clinical issue in prostate cancer (PCa). We investigated the molecular relationship between TMPRSS2-ERG (T2E) fusion gene and insulin-like growth factor receptor (IGF-1R) to optimize the use of IGF-1R inhibitors.IGF-1R was analyzed in cell lines and in radical prostatectomy specimens in relation to T2E status. ERG binding to IGF-1R promoter was evaluated by chromatin immunoprecipitation (ChIP). Sensitivity to anti-IGF-1R agents was evaluated alone or in combination with anti-androgen abiraterone acetate in vitro at basal levels or upon ERG modulation.IGF-1R analysis performed in PCa cells or clinical samples showed that T2E expression correlated with higher IGF-1R expression at mRNA and protein levels. Genetic modulation of ERG directly affected IGF-1R protein levels in vitro. ChIP analysis showed that ERG binds IGF-1R promoter and that promoter occupancy is higher in T2E-positive cells. IGF-1R inhibition was more effective in cell lines expressing the fusion gene and combination of IGF-1R inhibitors with abiraterone acetate produced synergistic effects in T2E-expressing cells.Here, we provide the rationale for use of T2E fusion gene to select PCa patients for anti-IGF-1R treatments. The combination of anti-IGF-1R-HAbs with an anti-androgen therapy is strongly advocated for patients expressing T2E.

  12. ERG deregulation induces IGF-1R expression in prostate cancer cells and affects sensitivity to anti-IGF-1R agents

    PubMed Central

    Mancarella, Caterina; Casanova-Salas, Irene; Calatrava, Ana; Ventura, Selena; Garofalo, Cecilia; Rubio-Briones, José; Magistroni, Vera; Manara, Maria Cristina; López-Guerrero, José Antonio; Scotlandi, Katia

    2015-01-01

    Identifying patients who may benefit from targeted therapy is an urgent clinical issue in prostate cancer (PCa). We investigated the molecular relationship between TMPRSS2-ERG (T2E) fusion gene and insulin-like growth factor receptor (IGF-1R) to optimize the use of IGF-1R inhibitors. IGF-1R was analyzed in cell lines and in radical prostatectomy specimens in relation to T2E status. ERG binding to IGF-1R promoter was evaluated by chromatin immunoprecipitation (ChIP). Sensitivity to anti-IGF-1R agents was evaluated alone or in combination with anti-androgen abiraterone acetate in vitro at basal levels or upon ERG modulation. IGF-1R analysis performed in PCa cells or clinical samples showed that T2E expression correlated with higher IGF-1R expression at mRNA and protein levels. Genetic modulation of ERG directly affected IGF-1R protein levels in vitro. ChIP analysis showed that ERG binds IGF-1R promoter and that promoter occupancy is higher in T2E-positive cells. IGF-1R inhibition was more effective in cell lines expressing the fusion gene and combination of IGF-1R inhibitors with abiraterone acetate produced synergistic effects in T2E-expressing cells. Here, we provide the rationale for use of T2E fusion gene to select PCa patients for anti-IGF-1R treatments. The combination of anti-IGF-1R-HAbs with an anti-androgen therapy is strongly advocated for patients expressing T2E. PMID:25906745

  13. A complicated story of frost and wind: Present-day gully activity within the north polar erg, Mar

    NASA Astrophysics Data System (ADS)

    Diniega, Serina; Hansen, Candice; Allen, Amanda; Grisby, Nathan; Li, Zheyu Joey

    2016-10-01

    Analyses of high-resolution observations have shown that the dunes within the martian north polar erg (AKA Olympia Undae) are currently very active on seasonal and yearly timescales, with 20-60% of the dunes within five polar dune fields undergoing the formation of alcove-apron features each Mars year. Previous studies have hypothesized formation mechanisms, based on observations of when new alcove and alcove-apron features form within an individual field through one Mars year. However, results are ill-constrained (and thus different hypotheses have been proposed) as the polar hood and winter night mean very few images are taken during the actual period of activity. In this study, we mitigate this limitation by examining several fields over several Mars years -- thus bringing aggregated results as well as detailed correlation checks against environmental conditions and seasonal processes to bear on the problem. From this, we propose a new process that appears consistent with all observations: (1) small alcoves form along the dune brink in the autumn (under the polar hood) due to instabilities induced by the night-formation and morning-sublimation of frost. As autumn progresses, the seasonal frost layer builds over the altered dune slope. (2) In the early spring, sublimation activity is concentrated and/or enhanced over these alcoves, causing further erosion and the formation of larger alcove-apron features. From the planform dimensions of the newly formed alcoves, we can estimate the volume of sand moved down the dune slope during one period of activity and estimate the aeolian sediment flux by looking at how quickly the alcoves are erased. We find that, over a Mars year, the amount of material moved via alcove-apron activity and via the wind are both comparable to aeolian sand flux estimates over dunes within lower-latitude regions of Mars. Thus it appears that the formation of alcoves-aprons is a significant mechanism for dune advancement and evolution within the

  14. Effects of Spectral Characteristics of Ganzfeld Stimuli on the Photopic Negative Response (PhNR) of the ERG

    PubMed Central

    Rangaswamy, Nalini V.; Shirato, Suguru; Kaneko, Muneyoshi; Digby, Beth I.; Robson, John G.; Frishman, Laura J.

    2007-01-01

    Purpose To determine flash and background colors that best isolate the photopic negative response (PhNR) and maximize its amplitude in the primate ERG. Methods Photopic full-field flash ERGs were recorded from anesthetized macaque monkeys before and after pharmacologic blockade of Na+-dependent spiking activity with tetrodotoxin (TTX, 1 to 2 μM, n = 3), blockade of ionotropic glutamatergic transmission with cis-2,3 piperidine dicarboxylic acid (PDA, 3.3–3.8 mM, n = 3) or laser-induced monocular experimental glaucoma (n = 6), and from six normal human subjects. Photopically matched colored flashes of increasing stimulus strengths were presented on scotopically matched blue, white, or yellow backgrounds of 100 scot cd/m2 using an LED-based stimulator. Results PhNRs that could be eliminated by TTX or severe experimental glaucoma were present in responses to brief (<5 ms) and long-duration (200 ms) stimuli of all color combinations. In normal monkey and human eyes for brief low-energy flashes, PhNR amplitudes were highest for red flashes on blue backgrounds and blue flashes on yellow backgrounds. For high-energy flashes, amplitudes were more similar for all color combinations. For long-duration stimuli, the PhNRon at light onset in monkeys was larger for red and blue stimuli, regardless of background color, than for spectrally broader flashes, except for stimuli >17.7 cd/m2 when PhNRons were all of similar amplitude. For red flashes, eliminating the PhNRon pharmacologically or by glaucoma removed the slowly recovering negative wave that normally followed the transient b-wave and elevated the whole ON response close to the level of the b-wave peak. However, for white, blue, and green flashes, a lower-amplitude plateau that could be removed by PDA remained. Conclusions For weak to moderate flash strengths, the best stimulus for maximizing PhNR amplitude is one that primarily stimulates one cone type, on a background with minimal adaptive effect on cones. For stronger

  15. Combination of ERG9 Repression and Enzyme Fusion Technology for Improved Production of Amorphadiene in Saccharomyces cerevisiae

    PubMed Central

    Baadhe, Rama Raju; Mekala, Naveen Kumar; Parcha, Sreenivasa Rao; Prameela Devi, Yalavarthy

    2013-01-01

    The yeast strain (Saccharomyces cerevisiae) MTCC 3157 was selected for combinatorial biosynthesis of plant sesquiterpene amorpha-4,11-diene. Our main objective was to overproduce amorpha 4-11-diene, which is a key precursor molecule of artemisinin (antimalarial drug) produced naturally in plant Artemisia annua through mevalonate pathway. Farnesyl diphosphate (FPP) is a common intermediate metabolite of a variety of compounds in the mevalonate pathway of yeast and leads to the production of ergosterols, dolichol and ubiquinone, and so forth. In our studies, FPP converted to amorphadiene (AD) by expressing heterologous amorphadiene synthase (ADS) in yeast. First, ERG9 (squalane synthase) promoter of yeast was replaced with repressible methionine (MET3) promoter by using bipartite gene fusion method. Further to overcome the loss of the intermediate FPP through competitive pathways in yeast, fusion protein technology was adopted and farnesyldiphosphate synthase (FPPS) of yeast has been coupled with amorphadiene synthase (ADS) of plant origin (Artemisia annua L.) where amorphadiene production was improved by 2-fold (11.2 mg/L) and 4-fold (25.02 mg/L) in yeast strains YCF-002 and YCF-005 compared with control strain YCF-AD (5.5 mg/L), respectively. PMID:24282652

  16. Improved methodology for identifying the teratogenic potential in early drug development of hERG channel blocking drugs.

    PubMed

    Nilsson, M F; Danielsson, C; Sköld, A-C; Johansson, A; Blomgren, B; Wilson, J; Khan, K M; Bengtsson, E; Kultima, K; Webster, W S; Danielsson, B R

    2010-04-01

    Drugs blocking the potassium current IKr of the heart (via hERG channel-inhibition) have the potential to cause hypoxia-related teratogenic effects. However, this activity may be missed in conventional teratology studies because repeat dosing may cause resorptions. The aim of the present study was to investigate an alternative protocol to reveal the teratogenic potential of IKr-blocking drugs. The IKr blocker astemizole, given as a single dose (80 mg/kg) on gestation day (GD) 13 to pregnant rats caused digital defects. In whole rat embryo culture (2h) on GD 13, astemizole caused a decrease in embryonic heart rate at 20 nM, and arrhythmias at 200-400 nM. Cetirizine, without IKr-blocking properties, did not affect the rat embryonic heart in vitro. The present study shows that single dose testing on sensitive days of development, together with whole embryo culture, can be a useful methodology to better characterize the teratogenic potential of IKr-blocking drugs. PMID:20144703

  17. Jurassic giant erg deposits, flexure of the United States continental interior, and timing of the onset of Cordilleran shortening

    NASA Astrophysics Data System (ADS)

    Allen, Philip A.; Verlander, Jonathan E.; Burgess, Peter M.; Audet, D. Marc

    2000-02-01

    The requirement of long-term accommodation space for preservation in the geological record is particularly acute in the case of thick wind-blown deposits that accumulate to heights well above the regional elevation. The Mesozoic of the western United States contains a number of well-developed erg systems. The clue to their formation and preservation is the combination of a positive sand budget and the generation of shortening events in the early Mesozoic continental margin arc of the U.S. Cordillera, which flexed the continental interior downward. The combination of the creation of a wide topographic depression representing a retro-foreland basin, sheltered behind a mountain belt exerting a rain shadow effect, and a background dynamic subsidence, produced optimum conditions for the preservation of thick eolian deposits during the Jurassic. The onset of flexural subsidence in Utah is thought to have been as early as Early Jurassic on the basis of the characteristic signature of the subsidence profiles, which is in agreement with the recent documentation of Early Jurassic igneous and structural activity west of the Luning-Fencemaker thrust belt in Nevada.

  18. 44 CFR 10.11 - Environmental information.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 44 Emergency Management and Assistance 1 2013-10-01 2013-10-01 false Environmental information. 10... Environmental information. Interested persons may contact the Environmental Officer or the Regional Administrator for information regarding FEMA's compliance with NEPA....

  19. 10 CFR 10.11 - Criteria.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... the commission of acts of force or violence to prevent others from exercising their rights under the... individual. (8) Has been convicted of crimes indicating habitual criminal tendencies. (9) Has been convicted of a crime, or has a background, where the facts, circumstances, or conduct are of a...

  20. Engineering Review Group (ERG) and Geologic Review Group (GRG) report on brine migration at the Deaf Smith County site salt repository horizon

    SciTech Connect

    Not Available

    1986-01-01

    In April 1986, ONWI requested the ERG and GRG to jointly address the status of current knowledge of, and ONWI approach to further characterization of, the geohydrology of the candidate repository horizon of the potential site in Deaf Smith County, Texas. Specifically, the ERG-GRG was asked to evaluate the status of understanding of the hydrogeology of the Lower San Andres Unit 4 (LSA-4) evaporite section and identify any major gaps in the data; evaluate the current understanding of the chemistry and movement of brines in the LSA-4 salt and associated interbeds; develop recommendations for estimating the upper limit quantity of brines, and modeling the brine movement, with respect to the emplaced HLW packages; and identify questions concerning the chemistry of the brines and recommend a technical approach to addressing these questions. 19 refs.

  1. Discovery of novel tetrahydroisoquinoline derivatives as orally active N-type calcium channel blockers with high selectivity for hERG potassium channels.

    PubMed

    Ogiyama, Takashi; Inoue, Makoto; Honda, Shugo; Yamada, Hiroyoshi; Watanabe, Toshihiro; Gotoh, Takayasu; Kiso, Tetsuo; Koakutsu, Akiko; Kakimoto, Shuichiro; Shishikura, Jun-ichi

    2014-12-15

    N-type calcium channels represent a promising target for the treatment of neuropathic pain. The selective N-type calcium channel blocker ziconotide ameliorates severe chronic pain but has a narrow therapeutic window and requires intrathecal administration. We identified tetrahydroisoquinoline derivative 1a as a novel potent N-type calcium channel blocker. However, this compound also exhibited potent inhibitory activity against hERG channels. Structural optimizations led to identification of (1S)-(1-cyclohexyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-{[(1-hydroxycyclohexyl)methyl]amino}ethanone ((S)-1h), which exhibited high selectivity for hERG channels while retaining potency for N-type calcium channel inhibition. (S)-1h went on to demonstrate in vivo efficacy as an orally available N-type calcium channel blocker in a rat spinal nerve ligation model of neuropathic pain.

  2. Toward a New Gold Standard for Early Safety: Automated Temperature-Controlled hERG Test on the PatchLiner®

    PubMed Central

    Polonchuk, Liudmila

    2012-01-01

    The Patchliner® temperature-controlled automated patch clamp system was evaluated for testing drug effects on potassium currents through human ether-à-go-go related gene (hERG) channels expressed in Chinese hamster ovary cells at 35–37°C. IC50 values for a set of reference drugs were compared with those obtained using the conventional voltage clamp technique. The results showed good correlation between the data obtained using automated and conventional electrophysiology. Based on these results, the Patchliner® represents an innovative automated electrophysiology platform for conducting the hERG assay that substantially increases throughput and has the advantage of operating at physiological temperature. It allows fast, accurate, and direct assessment of channel function to identify potential proarrhythmic side effects and sets a new standard in ion channel research for drug safety testing. PMID:22303293

  3. The sterol C-14 reductase encoded by the Neurospora crassa erg-3 gene: essential charged and polar residues identified by site-specific mutagenesis.

    PubMed

    Prakash, A; Kasbekar, D P

    2002-01-01

    Sterol C-14 reductase catalyses the reduction of the Delta(14,15) bond in intermediates in the sterol biosynthesis pathway using NADPH as a cofactor. We have undertaken a systematic site-directed mutational analysis of all the conserved charged and potentially proton-donating residues of the sterol C-14 reductase from Neurospora crassa. The effect of each mutation was determined using an in vivo assay based on the complementation of the corresponding N. crassa mutant ( erg-3). The non-complementing mutations were also tested in the erg24 mutant of Saccharomyces cervisiae. The results are discussed with reference to the predicted topology of the enzyme and to its proposed catalytic mechanism, which involves addition of a proton from an appropriately positioned charged or polar residue to the substrate double bond, followed by addition of hydride ion from NADPH. PMID:11810252

  4. Modulation of hERG potassium channel gating normalizes action potential duration prolonged by dysfunctional KCNQ1 potassium channel

    PubMed Central

    Zhang, Hongkang; Zou, Beiyan; Yu, Haibo; Moretti, Alessandra; Wang, Xiaoying; Yan, Wei; Babcock, Joseph J.; Bellin, Milena; McManus, Owen B.; Tomaselli, Gordon; Nan, Fajun; Laugwitz, Karl-Ludwig; Li, Min

    2012-01-01

    Long QT syndrome (LQTS) is a genetic disease characterized by a prolonged QT interval in an electrocardiogram (ECG), leading to higher risk of sudden cardiac death. Among the 12 identified genes causal to heritable LQTS, ∼90% of affected individuals harbor mutations in either KCNQ1 or human ether-a-go-go related genes (hERG), which encode two repolarizing potassium currents known as IKs and IKr. The ability to quantitatively assess contributions of different current components is therefore important for investigating disease phenotypes and testing effectiveness of pharmacological modulation. Here we report a quantitative analysis by simulating cardiac action potentials of cultured human cardiomyocytes to match the experimental waveforms of both healthy control and LQT syndrome type 1 (LQT1) action potentials. The quantitative evaluation suggests that elevation of IKr by reducing voltage sensitivity of inactivation, not via slowing of deactivation, could more effectively restore normal QT duration if IKs is reduced. Using a unique specific chemical activator for IKr that has a primary effect of causing a right shift of V1/2 for inactivation, we then examined the duration changes of autonomous action potentials from differentiated human cardiomyocytes. Indeed, this activator causes dose-dependent shortening of the action potential durations and is able to normalize action potentials of cells of patients with LQT1. In contrast, an IKr chemical activator of primary effects in slowing channel deactivation was not effective in modulating action potential durations. Our studies provide both the theoretical basis and experimental support for compensatory normalization of action potential duration by a pharmacological agent. PMID:22745159

  5. Complete genome sequence of Arthrobacter sp. ERGS1:01, a putative novel bacterium with prospective cold active industrial enzymes, isolated from East Rathong glacier in India.

    PubMed

    Kumar, Rakshak; Singh, Dharam; Swarnkar, Mohit Kumar; Singh, Anil Kumar; Kumar, Sanjay

    2015-11-20

    We report the complete genome sequence of Arthrobacter sp. ERGS1:01, a novel bacterium which produces industrial enzymes at low temperature. East Rathong glacier in Sikkim Himalayas is untouched and unexplored for microbial diversity though it has a rich source of glaciers, alpine and meadows. Genome sequence has provided the basis for understanding its adaptation under harsh condition of Himalayan glacier, its ability to produce cold active industrial enzymes and has unlocked opportunities for microbial bioprospection from East Rathong glacier.

  6. Cysteine- rich secretory protein 3 (CRISP3), ERG and PTEN define a molecular subtype of prostate cancer with implication to patients' prognosis.

    PubMed

    Al Bashir, Samir; Alshalalfa, Mohammed; Hegazy, Samar A; Dolph, Michael; Donnelly, Bryan; Bismar, Tarek A

    2014-01-01

    Cysteine- rich secretory protein 3 (CRISP3) prognostic significance in prostate cancer (PCA) has generated mixed result. Herein, we investigated and independently validated CRISP3 expression in relation to ERG and PTEN genomic aberrations and clinical outcome. CRISP3 protein expression was examined by immunohistochemistry using a cohort of patients with localized PCA (n = 215) and castration resistant PCA (CRPC) (n = 46). The Memorial Sloan Kettering (MSKCC) and Swedish cohorts were used for prognostic validation. Results showed, CRISP3 protein intensity to be significantly associated with neoplastic epithelium, being highest in CRPC vs. benign prostate tissue (p < 0.0001), but was not related to Gleason score (GS). CRISP3 mRNA was significantly associated with higher GS (p = 0.022 in MSKCC, p = 1.1e-4 in Swedish). Significant association between CRISP3 expression and clinical outcome was documented at the mRNA but not the protein expression levels. CRISP3 mRNA expression was related to biochemical recurrence in the MSKCC (p = 0.038) and lethal disease in the Swedish cohort (p = 0.0086) and retained its prognostic value in the subgroup of patients with GS 6 & 7. Furthermore, CRISP3 protein and mRNA expression was significantly associated with positive ERG status and with PTEN deletions. Functional biology analysis documented phenylalanine metabolism as the most significant pathway governing high CRISP3 and ERG expression in this subtype of PCA. In conclusion, the combined status of CRISP3, ERG and PTEN define a molecular subtype of PCA with poorest and lethal outcome. Assessing their combined value may be of added value in stratifying patients into different prognostic groups and identify those with poorest clinical outcome.

  7. The t(10;11)(p13;q14) in the U937 cell line results in the fusion of the AF10 gene and CALM, encoding a new member of the AP-3 clathrin assembly protein family.

    PubMed Central

    Dreyling, M H; Martinez-Climent, J A; Zheng, M; Mao, J; Rowley, J D; Bohlander, S K

    1996-01-01

    The translocation t(10;11)(p13;q14) is a recurring chromosomal abnormality that has been observed in patients with acute lymphoblastic leukemia as well as acute myeloid leukemia. We have recently reported that the monocytic cell line U937 has a t(10;11)(p13;q14) translocation. Using a combination of positional cloning and candidate gene approach, we cloned the breakpoint and were able to show that AF10 is fused to a novel gene that we named CALM (Clathrin Assembly Lymphoid Myeloid leukemia gene) located at 11q14. AF10, a putative transcription factor, had recently been cloned as one of the fusion partners of MLL. CALM has a very high homology in its N-terminal third to the murine ap-3 gene which is one of the clathrin assembly proteins. The N-terminal region of ap-3 has been shown to bind to clathrin and to have a high-affinity binding site for phosphoinositols. The identification of the CALM/AF10 fusion gene in the widely used U937 cell line will contribute to our understanding of the malignant phenotype of this line. Images Fig. 1 Fig. 3 PMID:8643484

  8. Analysis of the ergosterol biosynthesis pathway cloning, molecular characterization and phylogeny of lanosterol 14 α-demethylase (ERG11) gene of Moniliophthora perniciosa

    PubMed Central

    de Oliveira Ceita, Geruza; Vilas-Boas, Laurival Antônio; Castilho, Marcelo Santos; Carazzolle, Marcelo Falsarella; Pirovani, Carlos Priminho; Selbach-Schnadelbach, Alessandra; Gramacho, Karina Peres; Ramos, Pablo Ivan Pereira; Barbosa, Luciana Veiga; Pereira, Gonçalo Amarante Guimarães; Góes-Neto, Aristóteles

    2014-01-01

    The phytopathogenic fungus Moniliophthora perniciosa (Stahel) Aime & Philips-Mora, causal agent of witches’ broom disease of cocoa, causes countless damage to cocoa production in Brazil. Molecular studies have attempted to identify genes that play important roles in fungal survival and virulence. In this study, sequences deposited in the M. perniciosa Genome Sequencing Project database were analyzed to identify potential biological targets. For the first time, the ergosterol biosynthetic pathway in M. perniciosa was studied and the lanosterol 14α-demethylase gene (ERG11) that encodes the main enzyme of this pathway and is a target for fungicides was cloned, characterized molecularly and its phylogeny analyzed. ERG11 genomic DNA and cDNA were characterized and sequence analysis of the ERG11 protein identified highly conserved domains typical of this enzyme, such as SRS1, SRS4, EXXR and the heme-binding region (HBR). Comparison of the protein sequences and phylogenetic analysis revealed that the M. perniciosa enzyme was most closely related to that of Coprinopsis cinerea. PMID:25505843

  9. ERG (Engineering Review Group) and GRG (Geologic Review Group) review of the horizontal versus vertical modes of waste emplacement at the Deaf Smith County site, Texas

    SciTech Connect

    Chytrowski, B.R.

    1988-01-01

    The Engineering Review Group (ERG) and Geologic Review Group (GRG) were established by the Office of Nuclear Waste Isolation (ONWI) to help evaluate specific issues in the US Department of Energy's nuclear waste repository program. The December 1985 meeting and the February 1986 meeting dealt with the evaluation of the Fluor Technology, Inc., architect-engineer recommendation of the horizontal mode of waste package emplacement for the Site Characterization Plan Conceptual Design Report (SCP-CDR). The ONWI recommendation regarding horizontal and vertical modes of waste package emplacement and associated studies was reviewed. This report documents the ERG and GRG's comments and recommendations on this subject and ONWI responses to the specific points raised by these groups. The ERG and GRG joint review groups concurred with ONWI recommendations that additional studies are required in order to reach a decision on the method of emplacement to be used. In the opinion of these groups, both methods can be implemented; however, should the decision be reached today the vertical mode would be preferred.

  10. Eolian-fluvial interaction in the Page Sandstone (Middle Jurassic) in south-central Utah, USA — a case study of erg-margin processes

    NASA Astrophysics Data System (ADS)

    Jones, Lawrence S.; Blakey, Ronald C.

    1997-03-01

    Channel- and lens-shaped deposits of non-eolian red sandstone are enclosed within the eolian Leche-e Member of the Page Sandstone in south-central Utah. Detailed analysis of lithology and geometry, and regional correlation of the red sandstone deposits suggests that the channel-shaped scours and in-filling deposits were formed by ephemeral stream processes, in contrast to earlier interpretations that suggested a marine estuarine origin. We hypothesize that ephemeral streams transporting volcanic debris flowed toward the north and northeast along the western edge of the Page erg. Local avulsion, possibly caused by eolian damming of an adjacent drainage, led to stream flow into low areas of the Page erg. Entrainment of loose eolian sand, combined with fluid loss via infiltration, led to a rapid increase in sediment/fluid ratio during flow events, initially resulting in sandy debris flow deposition. Subsequent floods entrained less material from the underlying, more cohesive, debris flow deposits, had a lower sediment/water ratio, and hence left deposits containing some evidence of flow turbulence. Eventually, stream drainage avulsed again, probably back to a more northerly course into the Carmel sea, fluvial deposition within the erg ceased, and eolian deposits covered the now intercalated fluvial complex.

  11. Origin of the Sinai-Negev erg, Egypt and Israel: mineralogical and geochemical evidence for the importance of the Nile and sea level history

    USGS Publications Warehouse

    Muhs, Daniel R.; Roskin, Joel; Tsoar, Haim; Skipp, Gary; Budahn, James R.; Sneh, Amihai; Porat, Naomi; Stanley, Jean-Daniel; Katra, Itzhak; Blumberg, Dan G.

    2013-01-01

    The Sinai–Negev erg occupies an area of 13,000 km2 in the deserts of Egypt and Israel. Aeolian sand of this erg has been proposed to be derived from the Nile Delta, but empirical data supporting this view are lacking. An alternative source sediment is sand from the large Wadi El Arish drainage system in central and northern Sinai. Mineralogy of the Negev and Sinai dunes shows that they are high in quartz, with much smaller amounts of K-feldspar and plagioclase. Both Nile Delta sands and Sinai wadi sands, upstream of the dunes, also have high amounts of quartz relative to K-feldspar and plagioclase. However, Sinai wadi sands have abundant calcite, whereas Nile Delta sands have little or no calcite. Overall, the mineralogical data suggest that the dunes are derived dominantly from the Nile Delta, with Sinai wadi sands being a minor contributor. Geochemical data that proxy for both the light mineral fraction (SiO2/10–Al2O3 + Na2O + K2O–CaO) and heavy mineral fraction (Fe2O3–MgO–TiO2) also indicate a dominant Nile Delta source for the dunes. Thus, we report here the first empirical evidence that the Sinai–Negev dunes are derived dominantly from the Nile Delta. Linkage of the Sinai–Negev erg to the Nile Delta as a source is consistent with the distribution of OSL ages of Negev dunes in recent studies. Stratigraphic studies show that during the Last Glacial period, when dune incursions in the Sinai–Negev erg began, what is now the Nile Delta area was characterized by a broad, sandy, minimally vegetated plain, with seasonally dry anastomosing channels. Such conditions were ideal for providing a ready source of sand for aeolian transport under what were probably much stronger glacial-age winds. With the post-glacial rise in sea level, the Nile River began to aggrade. Post-glacial sedimentation has been dominated by fine-grained silts and clays. Thus, sea level, along with favorable climatic conditions, emerges as a major influence on the timing of dune

  12. Efficient Catalyst One-Pot Synthesis of 7-(Aryl)-10,10-dimethyl-10,11-dihydrochromeno[4,3-b]chromene-6,8(7H,9H)-dione Derivatives Complemented by Antibacterial Activity

    PubMed Central

    Al-Majedy, Yasameen K.; Kadhum, Abdul Amir H.; Mohamad, Abu Bakar

    2016-01-01

    The problem of bacteria resistance to many known agents has inspired scientists and researchers to discover novel efficient antibacterial drugs. Three rapid, clean, and highly efficient methods were developed for one-pot synthesis of 7-(aryl)-10,10-dimethyl-10,11-dihydrochromeno[4,3-b]chromene-6,8(7H,9H)-dione derivatives. Three components are condensed in the synthesis, 4-hydroxycoumarin, 5,5-dimethyl-1,3-cyclohexanedione, and aromatic aldehydes, using tetrabutylammonium bromide (TBAB), diammonium hydrogen phosphate (DAHP), or ferric chloride (FeCl3), respectively. Each method has different reaction mechanisms according to the catalyst. The present methods have advantages, including one-pot synthesis, excellent yields, short reaction times, and easy isolation of product. All catalysts utilized in our study could be reused several times without losing their catalytic efficiency. All synthesized compounds were fully characterized and evaluated for their antibacterial activity. PMID:27563671

  13. Measurements of developing teeth, and carpals and epiphyses of the ulna and radius for assessing new cut-offs at the age thresholds of 10, 11, 12, 13 and 14 years.

    PubMed

    Cameriere, R; De Luca, S; Cingolani, M; Ferrante, L

    2015-08-01

    The minimum age of criminal responsibility is the youngest age at which children may be held liable for infringements of penal laws. New cut-offs at the age thresholds of 10, 11, 12, 13 and 14 years were determined by applying three different methods: measurement of open apices in tooth roots (T); the ratio between the total area of carpal bones and epiphyses of the ulna and radius (HW); and the combined method (THW). The sample consisted of 291 Italian children (152 boys, 139 girls), aged between 5 and 15 years. The sensitivity and specificity were established. As regards THW, specificity reached the maximum of 95% in boys aged 10, and the minimum of 87% in boys aged 11. The best score of the Positive Predictive Value (PPV) was obtained in boys at 10 years with the THW method and the worst in girls of 12 with the HW method.

  14. Efficient Catalyst One-Pot Synthesis of 7-(Aryl)-10,10-dimethyl-10,11-dihydrochromeno[4,3-b]chromene-6,8(7H,9H)-dione Derivatives Complemented by Antibacterial Activity.

    PubMed

    Al-Majedy, Yasameen K; Al-Amiery, Ahmed A; Kadhum, Abdul Amir H; Mohamad, Abu Bakar

    2016-01-01

    The problem of bacteria resistance to many known agents has inspired scientists and researchers to discover novel efficient antibacterial drugs. Three rapid, clean, and highly efficient methods were developed for one-pot synthesis of 7-(aryl)-10,10-dimethyl-10,11-dihydrochromeno[4,3-b]chromene-6,8(7H,9H)-dione derivatives. Three components are condensed in the synthesis, 4-hydroxycoumarin, 5,5-dimethyl-1,3-cyclohexanedione, and aromatic aldehydes, using tetrabutylammonium bromide (TBAB), diammonium hydrogen phosphate (DAHP), or ferric chloride (FeCl3), respectively. Each method has different reaction mechanisms according to the catalyst. The present methods have advantages, including one-pot synthesis, excellent yields, short reaction times, and easy isolation of product. All catalysts utilized in our study could be reused several times without losing their catalytic efficiency. All synthesized compounds were fully characterized and evaluated for their antibacterial activity. PMID:27563671

  15. Ivabradine prolongs phase 3 of cardiac repolarization and blocks the hERG1 (KCNH2) current over a concentration-range overlapping with that required to block HCN4.

    PubMed

    Lees-Miller, James P; Guo, Jiqing; Wang, Yibo; Perissinotti, Laura L; Noskov, Sergei Y; Duff, Henry J

    2015-08-01

    In Europe, ivabradine has recently been approved to treat patients with angina who have intolerance to beta blockers and/or heart failure. Ivabradine is considered to act specifically on the sinoatrial node by inhibiting the If current (the funny current) to slow automaticity. However, in vitro studies show that ivabradine prolongs phase 3 repolarization in ventricular tissue. No episodes of Torsades de Pointes have been reported in randomized clinical studies. The objective of this study is to assess whether ivabradine blocked the hERG1 current. In the present study we discovered that ivabradine prolongs action potential and blocks the hERG current over a range of concentrations overlapping with those required to block HCN4. Ivabradine produced tonic, rather than use-dependent block. The mutation Y652A significantly suppressed pharmacologic block of hERG by ivabradine. Disruption of C-type inactivation also suppressed block of hERG1 by ivabradine. Molecular docking and molecular dynamics simulations indicate that ivabradine may access the inner cavity of the hERG1 via a lipophilic route and has a well-defined binding site in the closed state of the channel. Structural organization of the binding pockets for ivabradine is discussed. Ivabradine blocks hERG and prolongs action potential duration. Our study is potentially important because it indicates the need for active post marketing surveillance of ivabradine. Importantly, proarrhythmia of a number of other drugs has only been discovered during post marketing surveillance. PMID:25986146

  16. Amorphous nanostructuralization in HOPG by 1014 W cm-2 laser

    NASA Astrophysics Data System (ADS)

    NISHIMURA, Yasuhiko; KITAGAWA, Yoneyoshi; MORI, Yoshitaka; ISHII, Katsuhiro; HANAYAMA, Ryohei; AZUMA, Hirozumi; HIOKI, Tatsumi; NISHI, Teppei; MOTOHIRO, Tomoyoshi; KOMEDA, Osamu; SEKINE, Takashi; SATO, Nakahiro; KURITA, Takashi; KAWASHIMA, Toshiyuki; KAN, Hirofumi; SUNAHARA, Atsushi; SENTOKU, Yasuhiko; MIURA, Eisuke

    2016-05-01

    This reports provide an amorphous nanostructuralization technique on the surface modification in Highly Oriented Pyrolytic Graphite (HOPG) by using a femtosecond laser. We showed, for the first time, that the surface of HOPG is changed to the amorphous nanostructuralization graphite by using a femtosecond laser-driven compression technique. Our results also suggest that the HOPG surface is changed until the deeper area from the surface by the laser-driven shock wave. A single shot of a femtosecond laser beam (1.27 ∼ 1.33×1014 Wcm∼2 in intensity, with 2 mm-diameter, and 110 fs in pulse width) is irradiated under the vacuum ambience onto a 2 mm-thick of HOPG. The calculated impact pressures on a sample was 8.3 ∼ 8.7 GPa. Crystal structure in the HOPG were analyzed using a Raman spectroscopy and an X-ray diffraction, those analyzing depth from the surface were 50 nm and 350 μm, respectively.

  17. The multifocal electroretinogram (mfERG) and cone isolating stimuli: variation in L- and M-cone driven signals across the retina.

    PubMed

    Albrecht, Johannes; Jägle, Herbert; Hood, Donald C; Sharpe, Lindsay T

    2002-01-01

    Multifocal electroretinograms (mfERG) were recorded from 38 normal trichromats with a pattern-reversing display that modulated only their long-wavelength sensitive (L) or only their middle-wavelength sensitive (M) cones at equal cone contrasts and average quantal catches. The display consisted of scaled, 103 hexagonal elements, subtending 84 degrees x 75 degrees of visual angle. Typically, the amplitude of the L-cone driven signal was greater than that for the M-cone driven one at all retinal eccentricities, but large differences were found among observers. These values correlated with L- to M-cone ratios obtained psychophysically in the same observers using 2 degrees (dia.) heterochromatic flicker photometry. Interestingly, the L- to M-cone driven amplitude ratios differed between the central and peripheral retina. For the central fovea (5 degrees dia.), the mean ratio was 1.4 +/- 0.6 (for the N1P1 component), whereas for the annular ring centered at 40 degrees in the periphery, it was 2.3 +/- 2.0. The mean P1 latency of the summed M-cone driven mfERG (28.0 +/- 2.6 ms) was significantly advanced relative to the L-cone driven signal (29.0 +/- 1.9 ms), but the mean N1 latencies were similar (15.6 +/- 1.7 ms and 16.2 +/- 1.3 ms, respectively). The P1 latency difference between the L- and M-cone driven waveforms was not found in the central 5 degrees (dia.) of the retina. However, it increased with retinal eccentricity. The regional differences in the amplitudes and latencies of the L- and M-cone driven mfERG signals can be related to variations in the L- to M-cone ratios and/or the receptor to bipolar gain factors that depend on eccentricity.

  18. Overexpression of erg20 gene encoding farnesyl pyrophosphate synthase has contrasting effects on activity of enzymes of the dolichyl and sterol branches of mevalonate pathway in Trichoderma reesei.

    PubMed

    Piłsyk, Sebastian; Perlińska-Lenart, Urszula; Górka-Nieć, Wioletta; Graczyk, Sebastian; Antosiewicz, Beata; Zembek, Patrycja; Palamarczyk, Grażyna; Kruszewska, Joanna S

    2014-07-10

    The mevalonate pathway is the most diverse metabolic route resulting in the biosynthesis of at least 30,000 isoprenoid compounds, many of which, such as sterols or dolichols, are indispensable for living cells. In the filamentous fungus Trichoderma of major biotechnological interest isoprenoid metabolites are also involved in the biocontrol processes giving the mevalonate pathway an additional significance. On the other hand, little is known about genes coding for enzymes of the mevalonate pathway in Trichoderma. Here, we present cloning and functional analysis of the erg20 gene from Trichoderma reesei coding for farnesyl pyrophosphate (FPP) synthase (EC 2.5.1.10), an enzyme located at the branching point of the mevalonate pathway. Expression of the gene in a thermosensitive erg20-2 mutant of Saccharomyces cerevisiae impaired in the FPP synthase activity suppressed the thermosensitive phenotype. The same gene overexpressed in T. reesei significantly enhanced the FPP synthase activity and also stimulated the activity of cis-prenyltransferase, an enzyme of the dolichyl branch of the mevalonate pathway. Unexpectedly, the activity of squalene synthase from the other, sterol branch, was significantly decreased without, however, affecting ergosterol level.

  19. NMR solution structure of the N-terminal domain of hERG and its interaction with the S4-S5 linker

    SciTech Connect

    Li, Qingxin; Gayen, Shovanlal; Chen, Angela Shuyi; Huang, Qiwei; Raida, Manfred; Kang, CongBao

    2010-12-03

    Research highlights: {yields} The N-terminal domain (NTD, eag domain) containing 135 residues of hERG was expressed and purified from E. coli cells. {yields} Solution structure of NTD was determined with NMR spectroscopy. {yields} The alpha-helical region (residues 13-23) was demonstrated to possess the characteristics of an amphipathic helix. {yields} NMR titration confirmed the interaction between NTD and the peptide from the S4-S5 linker. -- Abstract: The human Ether-a-go-go Related Gene (hERG) potassium channel mediates the rapid delayed rectifier current (IKr) in the cardiac action potential. Mutations in the 135 amino acid residue N-terminal domain (NTD) cause channel dysfunction or mis-translocation. To study the structure of NTD, it was overexpressed and purified from Escherichia coli cells using affinity purification and gel filtration chromatography. The purified protein behaved as a monomer under purification conditions. Far- and near-UV, circular dichroism (CD) and solution nuclear magnetic resonance (NMR) studies showed that the purified protein was well-folded. The solution structure of NTD was obtained and the N-terminal residues 13-23 forming an amphipathic helix which may be important for the protein-protein or protein-membrane interactions. NMR titration experiment also demonstrated that residues from 88 to 94 in NTD are important for the molecular interaction with the peptide derived from the S4-S5 linker.

  20. Protein binding-dependent decreases in hERG channel blocker potency assessed by whole-cell voltage clamp in serum.

    PubMed

    Margulis, Michael; Sorota, Steve; Chu, Inhou; Soares, Anthony; Priestley, Tony; Nomeir, Amin A

    2010-04-01

    In vitro hERG blocking potency is measured in drug discovery as part of an integrated cardiovascular risk assessment. Typically, the concentrations producing 50% inhibition are measured in protein-free saline solutions and compared with calculated free therapeutic in vivo Cmax values to estimate a hERG safety multiple. The free/unbound fraction is believed responsible for activity. We tested the validity of this approach with 12 compounds by determining potencies in voltage clamp studies conducted in the absence and presence of 100% dialyzed fetal bovine serum (FBS). Bath drug concentrations in saline solutions were measured to account for loss of compounds due to solubility, stability, and/or adsorption. Protein binding in dialyzed FBS was measured to enable predictions of serum IC50s based on the unbound fraction and the saline IC50. For 11 of 12 compounds, the measured potency in the presence of dialyzed FBS was within 2-fold of the predicted potency. The predicted IC50 in dialyzed FBS for one highly bound compound, amiodarone, was 9-fold higher than the measured serum IC50. These data suggest that for highly bound compounds, direct measurement of IC50s in the presence of 100% serum may provide a more accurate estimate of in vivo potencies than the approach based on calculated serum shifts. PMID:20125032

  1. Hydrogeology and water quality of significant sand and gravel aquifers in parts of Androscoggin, Cumberland, Franklin, Kennebec, Lincoln, Oxford, Sagadahoc, and Somerset Counties, Maine: Sand and gravel aquifer maps 10, 11, 16, 17 and 32

    SciTech Connect

    Tepper, D.H.; Williams, J.S.; Tolman, A.L.; Prescott, G.C.

    1985-01-01

    A reconnaissance level geohydrologic study was made of 2,408 sq mi in Androscoggin, Cumberland, Franklin, Kennebec, Lincoln, Oxford, Sagadahoc and Somerset Counties in Maine. This area is included in Maps 10, 11, 16, 17, and 32 of the Sand and Gravel Aquifer Map Series published by the Maine Geological Survey. The significant sand and gravel aquifers, consist of glacial ice-contact and outwash deposits which occur primarily in the valleys of the major rivers and along their tributaries. Significant aquifers comprise almost 109 sq mi, but yields that exceed 50 gal/min are estimated to be available within only 21% of this area. Typically, the water table is within 20 ft of the land surface. Based on seismic data, the great known depth to bedrock is 340 ft. The regional groundwater quality has the following characteristics: It is slightly acidic to slightly basic; calcium and sodium are the most abundant cations; bicarbonate is the most abundant anion; and the water is soft. In some localities concentrations of iron and manganese are high enough to limit use of the water without treatment. Sixty-six sites, including 32 solid waste facilities and 18 salt-storage lots were identified as potential sources of groundwater contamination to the sand and gravel aquifers in the study area. 79 refs., 11 figs., 9 tabs.

  2. Study of the neutron and proton capture reactions 10,11B(n, γ), 11B(p, γ), 14C(p, γ), and 15N(p, γ) at thermal and astrophysical energies

    NASA Astrophysics Data System (ADS)

    Dubovichenko, Sergey; Dzhazairov-Kakhramanov, Albert

    2014-07-01

    We have studied the neutron-capture reactions 10,11B(n, γ) and the role of the 11B(n, γ) reaction in seeding r-process nucleosynthesis. The possibility of the description of the available experimental data for cross-sections of the neutron capture reaction on 10B at thermal and astrophysical energies, taking into account the resonance at 475 keV, was considered within the framework of the modified potential cluster model (MPCM) with forbidden states (FS) and accounting for the resonance behavior of the scattering phase shifts. In the framework of the same model, the possibility of describing the available experimental data for the total cross-sections of the neutron radiative capture on 11B at thermal and astrophysical energies were considered with taking into account the 21 and 430 keV resonances. Description of the available experimental data on the total cross-sections and astrophysical S-factor of the radiative proton capture on 11B to the GS of 12C was treated at astrophysical energies. The possibility of description of the experimental data for the astrophysical S-factor of the radiative proton capture on 14C to the GS of 15N at astrophysical energies, and the radiative proton capture on 15N at the energies from 50 to 1500 keV was considered in the framework of the MPCM with the classification of the orbital states according to Young tableaux. It was shown that, on the basis of the M1 and the E1 transitions from different states of the p15N scattering to the GS of 16O in the p15N channel, it is quite succeed to explain general behavior of the S-factor in the considered energy range in the presence of two resonances.

  3. Effect of azelastine on cardiac repolarization of guinea-pig cardiomyocytes, hERG K⁺ channel, and human L-type and T-type Ca²⁺ channel.

    PubMed

    Park, Mi-Hyeong; Lee, Seung Ho; Chu, Dae Hyun; Won, Kwang Hee; Choi, Bok Hee; Choe, Han; Jo, Su-Hyun

    2013-09-20

    Azelastine is a second generation histamine H₁-receptor antagonist used as an anti-asthmatic and anti-allergic drug that can induce QT prolongation and torsades de pointes. We investigated the acute effects of azelastine on human ether-a-go-go-related gene (hERG) channels, action potential duration (APD), and L-type (I(Ca,L)) and T-type Ca²⁺ current (I(Ca,T)) to determine the electrophysiological basis for its proarrhythmic potential. Azelastine increased the APD at 90% of repolarization concentration dependently, with an IC₅₀ of 1.08 nM in guinea-pig ventricular myocytes. We examined the effects of azelastine on the hERG channels expressed in Xenopus oocytes and HEK293 cells using two-microelectrode voltage-clamp and patch-clamp techniques. Azelastine induced a concentration-dependent decrease of the hERG current amplitude at the end of the voltage steps and tail currents. The IC₅₀ for the azelastine-induced block of the hERG currents expressed in HEK293 cells was 11.43 nM, while the drug inhibited I(Ca,L) and I(Ca,T) with IC₅₀ values of 7.60 and 26.21 μM, respectively. The S6 domain mutations, Y652A partially attenuated and F656A abolished hERG current block. These results suggest that azelastine is a potent blocker of hERG channels rather than I(Ca,L) or I(Ca,T), providing molecular mechanisms for the arrhythmogenic side effects during the clinical administration of azelastine. PMID:24005046

  4. High-resolution mapping of D16led-1, Gart, Gas-4, Cbr, Pcp-4, and Erg on distal mouse chromosome 16.

    PubMed

    Mjaatvedt, A E; Citron, M P; Reeves, R H

    1993-08-01

    More than 500 backcross progeny from four intersubspecific backcrosses were typed for six markers on distal mouse chromosome 16. Five of these represented genes that mapped within the Sod-1 to Ets-2 interval, which was shown previously to contain the weaver (wv) gene. The map order, including previously mapped reference markers, is (cen)-D16H21S16-D16Led-1-App-Sod-1-Gart-Gas-4-Cbr++ +-wv-Pcp-4-Erg-Ets-2. This gene order recapitulates the order of the genes on human chromosome 21 where known. Two of these markers further define the region containing the weaver gene to a 3.9-cM segment between Cbr and Pcp-4. In addition, Pcp-4 was localized to human chromosome 21 by the presence of a human-specific restriction fragment in WAV-17, a mouse-human somatic cell hybrid with human chromosome 21 as the only human contribution.

  5. ApoE4 induces synaptic and ERG impairments in the retina of young targeted replacement apoE4 mice.

    PubMed

    Antes, Ran; Ezra-Elia, Raaya; Weinberger, Dov; Solomon, Arie; Ofri, Ron; Michaelson, Daniel M

    2013-01-01

    The vertebrate retina, which is part of the central nervous system, is a window into the brain. The present study investigated the extent to which the retina can be used as a model for studying the pathological effects of apolipoprotein E4 (apoE4), the most prevalent genetic risk factor for Alzheimer's disease (AD). Immunohistochemical studies of retinas from young (4 months old) apoE4-targeted replacement mice and from corresponding mice which express the AD benign apoE3 allele, revealed that the density of the perikarya of the different classes of retinal neurons was not affected by apoE4. In contrast, the synaptic density of the retinal synaptic layers, which was assessed immunohistochemically and by immunoblot experiments, was significantly lower in the apoE4 than in the apoE3 mice. This was associated with reduced levels of the presynaptic vesicular glutamatergic transporter, VGluT1, but not of either the GABAergic vesicular transporter, VGaT, or the cholinergic vesicular transporter, VAChT, suggesting that the glutamatergic nerve terminals are preferentially affected by apoE4. In contrast, the post synaptic scaffold proteins PSD-95 and Gephyrin, which reside in excitatory and inhibitory synapses, respectively, were both elevated, and their ratio was not affected by apoE4. Electroretinogram (ERG) recordings revealed significant attenuation of mixed rod-cone responses in dark-adapted eyes of apoE4 mice. These findings suggest that the reduced ERG response in the apoE4 mice may be related to the observed decrease in the retinal nerve terminals and that the retina could be used as a novel model for non-invasive monitoring of the effects of apoE4 on the CNS.

  6. Why Can dl-Sotalol Prolong the QT Interval In Vivo Despite Its Weak Inhibitory Effect on hERG K(+) Channels In Vitro? Electrophysiological and Pharmacokinetic Analysis with the Halothane-Anesthetized Guinea Pig Model.

    PubMed

    Katagi, Jun; Nakamura, Yuji; Cao, Xin; Ohara, Hiroshi; Honda, Atsushi; Izumi-Nakaseko, Hiroko; Ando, Kentaro; Sugiyama, Atsushi

    2016-04-01

    In order to bridge the gap of action of dl-sotalol between the human ether-a-go-go-related gene (hERG) K(+) channel inhibition in vitro and QT-interval prolongation in vivo, its electropharmacological effect and pharmacokinetic property were simultaneously studied in comparison with those of 10 drugs having potential to prolong the QT interval (positive drugs: bepridil, haloperidol, dl-sotalol, terfenadine, thioridazine, moxifloxacin, pimozide, sparfloxacin, diphenhydramine, imipramine and ketoconazole) and four drugs lacking such property (negative drugs: enalapril, phenytoin, propranolol or verapamil) with the halothane-anesthetized guinea pig model. A dose of each drug that caused 10 % prolongation of Fridericia-corrected QT interval (QTcF) was calculated, which was compared with respective known hERG K(+) IC50 value and currently obtained heart/plasma concentration ratio. Each positive drug prolonged the QTcF in a dose-related manner, whereas such effect was not observed by the negative drugs. Drugs with more potent hERG K(+) channel inhibition showed higher heart/plasma concentration ratio, resulting in more potent QTcF prolongation in vivo. The potency of dl-sotalol for QTcF prolongation was flat middle, although its hERG K(+) channel inhibitory property as well as heart/plasma concentration ratio was the smallest among the positive drugs, which may be partly explained by its lack of binding to plasma protein.

  7. The pharmacological profile of 2-(8-methyl-10,11-dihydro-11-oxodibenz[b,f]oxepin-2-yl)propionic acid (AD-1590), a new non-steroidal anti-inflammatory agent with potent antipyretic activity.

    PubMed

    Nakamura, H; Yokoyama, Y; Motoyoshi, S; Ishii, K; Imazu, C; Seto, Y; Kadokawa, T; Shimizu, M

    1983-01-01

    Anti-inflammatory, analgesic, antipyretic and gastrointestinal ulcerogenic activities of 2-(8-methyl-10,11-dihydro-11-oxodibenz(b,f]oxepin-2-yl)propionic acid (AD-1590), a new non-steroidal anti-inflammatory drug, were compared with indomethacin (INN: indomethacin) and other non-steroidal anti-inflammatory drugs (NSAID) in experimental animals. AD-1590 showed the potent inhibitory activity on acute and subacute inflammation such as carrageenin hind paw edema (oral ED50 = 1.35 mg/kg), acetic acid-induced increased vascular permeability (0.205 mg/kg), UV-erythema (0.295 mg/kg) and felt pellet-induced granuloma formation (1.7 mg/kg), and its potency was on the whole 2 to 3 times that of indomethacin. Oral analgesic ED50-values of AD-1590 were 0.245, 8.32 and 13.9 mg/kg in the writhing tests, and 2.45 mg/kg in the silver nitrate-induced arthritic pain test. Analgesic potency of AD-1590 was on the whole comparable to that of indomethacin. Against the pyrexia caused by two kinds of pyrogens (yeast and adjuvant), AD-1590 exerted a strong antipyretic action at oral doses as low as 0.02 to 0.1 mg/kg, and its potency (ED50 equal 0.0210 and 0.0406 mg/kg) was 8.7 to 11 times that of indomethacin. , AD-1590 displayed the antipyretic activity at low doses which were widely different from its anti-inflammatory and analgesic effective dose. The body temperature was not affected by 20 mg/kg p.o. of AD-1590 in the afebrile animals. AD-1590 was the strongest antipyretic drug among 10 NSAID tested. In rats, AD-1590 produced gastrointestinal ulcer similar to indomethacin, and its gastric ulcerogenicity (SUD50 equal 13.8 mg/kg p.o.) was about one-half that of indomethacin. The activity of AD-1590 in the fecal occult bleeding test in beagle dogs was weaker than that of indomethacin. The potency of AD-1590 (IC50 equal 0.78 mumol/l) as a prostaglandin synthetase inhibitor was about 2.7 times that of indomethacin in the in vitro test. The safety index (SUD50/ED50) of AD-1590 was larger than

  8. Trichodiene Production in a Trichoderma harzianum erg1-Silenced Strain Provides Evidence of the Importance of the Sterol Biosynthetic Pathway in Inducing Plant Defense-Related Gene Expression.

    PubMed

    Malmierca, M G; McCormick, S P; Cardoza, R E; Monte, E; Alexander, N J; Gutiérrez, S

    2015-11-01

    Trichoderma species are often used as biocontrol agents against plant-pathogenic fungi. A complex molecular interaction occurs among the biocontrol agent, the antagonistic fungus, and the plant. Terpenes and sterols produced by the biocontrol fungus have been found to affect gene expression in both the antagonistic fungus and the plant. The terpene trichodiene (TD) elicits the expression of genes related to tomato defense and to Botrytis virulence. We show here that TD itself is able to induce the expression of Botrytis genes involved in the synthesis of botrydial (BOT) and also induces terpene gene expression in Trichoderma spp. The terpene ergosterol, in addition to its role as a structural component of the fungal cell membranes, acts as an elicitor of defense response in plants. In the present work, using a transformant of T. harzianum, which is silenced in the erg1 gene and accumulates high levels of squalene, we show that this ergosterol precursor also acts as an important elicitor molecule of tomato defense-related genes and induces Botrytis genes involved in BOT biosynthesis, in both cases, in a concentration-dependent manner. Our data emphasize the importance of a balance of squalene and ergosterol in fungal interactions as well as in the biocontrol activity of Trichoderma spp. PMID:26168138

  9. Acute and Chronic Toxicity, Cytochrome P450 Enzyme Inhibition, and hERG Channel Blockade Studies with a Polyherbal, Ayurvedic Formulation for Inflammation

    PubMed Central

    Dey, Debendranath; Chaskar, Sunetra; Athavale, Nitin; Chitre, Deepa

    2015-01-01

    Ayurvedic plants are known for thousands of years to have anti-inflammatory and antiarthritic effect. We have recently shown that BV-9238, a proprietary formulation of Withania somnifera, Boswellia serrata, Zingiber officinale, and Curcuma longa, inhibits LPS-induced TNF-alpha and nitric oxide production from mouse macrophage and reduces inflammation in different animal models. To evaluate the safety parameters of BV-9238, we conducted a cytotoxicity study in RAW 264.7 cells (0.005–1 mg/mL) by MTT/formazan method, an acute single dose (2–10 g/kg bodyweight) toxicity study and a 180-day chronic study with 1 g and 2 g/kg bodyweight in Sprague Dawley rats. Some sedation, ptosis, and ataxia were observed for first 15–20 min in very high acute doses and hence not used for further chronic studies. At the end of 180 days, gross and histopathology, blood cell counts, liver and renal functions were all at normal levels. Further, a modest attempt was made to assess the effects of BV-9238 (0.5 µg/mL) on six major human cytochrome P450 enzymes and 3H radioligand binding assay with human hERG receptors. BV-9238 did not show any significant inhibition of these enzymes at the tested dose. All these suggest that BV-9238 has potential as a safe and well tolerated anti-inflammatory formulation for future use. PMID:25893199

  10. Trichodiene Production in a Trichoderma harzianum erg1-Silenced Strain Provides Evidence of the Importance of the Sterol Biosynthetic Pathway in Inducing Plant Defense-Related Gene Expression.

    PubMed

    Malmierca, M G; McCormick, S P; Cardoza, R E; Monte, E; Alexander, N J; Gutiérrez, S

    2015-11-01

    Trichoderma species are often used as biocontrol agents against plant-pathogenic fungi. A complex molecular interaction occurs among the biocontrol agent, the antagonistic fungus, and the plant. Terpenes and sterols produced by the biocontrol fungus have been found to affect gene expression in both the antagonistic fungus and the plant. The terpene trichodiene (TD) elicits the expression of genes related to tomato defense and to Botrytis virulence. We show here that TD itself is able to induce the expression of Botrytis genes involved in the synthesis of botrydial (BOT) and also induces terpene gene expression in Trichoderma spp. The terpene ergosterol, in addition to its role as a structural component of the fungal cell membranes, acts as an elicitor of defense response in plants. In the present work, using a transformant of T. harzianum, which is silenced in the erg1 gene and accumulates high levels of squalene, we show that this ergosterol precursor also acts as an important elicitor molecule of tomato defense-related genes and induces Botrytis genes involved in BOT biosynthesis, in both cases, in a concentration-dependent manner. Our data emphasize the importance of a balance of squalene and ergosterol in fungal interactions as well as in the biocontrol activity of Trichoderma spp.

  11. Violent Star Formation in NGC 2363: Erratum

    NASA Astrophysics Data System (ADS)

    Gonzalez-Delgado, Rosa M.; Perez, Enrique; Tenorio-Tagle, Guillermo; Vilchez, Jose M.; Terlevich, Elena; Terlevich, Roberto; Telles, Eduardo; Rodríguez Espinosa, Jose M.; Mas-Hesse, Miguel; Garcia-Vargas, Maria Luisa; Diaz, Angeles I.; Cepa, Jordi; Castaneda, Hector

    1996-12-01

    In the paper "Violent Star Formation in NGC 2363" by Rosa M. Gonzalez- Delgado, Enrique Perez, Guillermo Tenorio-Tagle, Jose M. Vilchez, Elena Terlevich, Roberto Terlevich, Eduardo Telles, Jose M. Rodriguez-Espinosa, Miguel Mas-Hesse, Maria Luisa Garcia-Vargas, Angeles I. Diaz, Jordi Cepa, and Hector Castaneda (ApJ, 437,239 [1994)), there are three errors in Section 5.4. The Paschen discontinuity in knot A is (0.82 +/- 0.19) x 10^-16^ ergs s^-1^ cm^-2^ A^-1^, the coefficient in the formula in page 258 is 2.445 x 10^11^, and the units in the ordinate axis of Figure 16 are 10^-15^ ergs cm^-2^ s^-1^ A^-1^. These are typographical errors, and they do not affect the determination of the electron temperature using the Paschen jump and the discussion and conclusions in this paper.

  12. [Methods of recording local ERG].

    PubMed

    Shamshinova, A M; Govardovskiĭ, V I; Golubtsov, K V

    1989-01-01

    Two methods for recording the retinal local biopotential with the gaze fixation control and without this control are described, to be used for the assessment of the status of any retinal or macular site, among other things. A ring-shaped sucker electrode is employed in both methods; this electrode is supplied with a transparent anterior window and infrared-illuminated mirror in one method and in the other the electrode incorporates a light-emitting diode and an optic system that helps create a 6-20 degrees stimulus. Theoretical analysis and experimental findings evidence that the minimal area on the retina from which a local response may be obtained, fit for clinical purposes, conforms to 10-15 degrees with a stimulus 5 times brighter than semisaturating brightness. The local response share in this case is 70% and the number of possible blendings 50. The results explaining the choice of the conditions for the retinal local biopotential recording are presented. The suggested methods help assess the function of the macular area, distinguish between the functions of the cone and rod systems, record the total and Hanz-Feld electroretinograms without electrode substitution, record the macular biopotential in babies and in patients with nystagmus or with cataracts of various origins. PMID:2617751

  13. Human phosphodiesterase 4D7 (PDE4D7) expression is increased in TMPRSS2-ERG-positive primary prostate cancer and independently adds to a reduced risk of post-surgical disease progression

    PubMed Central

    Böttcher, R; Henderson, D J P; Dulla, K; van Strijp, D; Waanders, L F; Tevz, G; Lehman, M L; Merkle, D; van Leenders, G J L H; Baillie, G S; Jenster, G; Houslay, M D; Hoffmann, R

    2015-01-01

    Background: There is an acute need to uncover biomarkers that reflect the molecular pathologies, underpinning prostate cancer progression and poor patient outcome. We have previously demonstrated that in prostate cancer cell lines PDE4D7 is downregulated in advanced cases of the disease. To investigate further the prognostic power of PDE4D7 expression during prostate cancer progression and assess how downregulation of this PDE isoform may affect disease outcome, we have examined PDE4D7 expression in physiologically relevant primary human samples. Methods: About 1405 patient samples across 8 publically available qPCR, Affymetrix Exon 1.0 ST arrays and RNA sequencing data sets were screened for PDE4D7 expression. The TMPRSS2-ERG gene rearrangement status of patient samples was determined by transformation of the exon array and RNA seq expression data to robust z-scores followed by the application of a threshold >3 to define a positive TMPRSS2-ERG gene fusion event in a tumour sample. Results: We demonstrate that PDE4D7 expression positively correlates with primary tumour development. We also show a positive association with the highly prostate cancer-specific gene rearrangement between TMPRSS2 and the ETS transcription factor family member ERG. In addition, we find that in primary TMPRSS2-ERG-positive tumours PDE4D7 expression is significantly positively correlated with low-grade disease and a reduced likelihood of progression after primary treatment. Conversely, PDE4D7 transcript levels become significantly decreased in castration resistant prostate cancer (CRPC). Conclusions: We further characterise and add physiological relevance to PDE4D7 as a novel marker that is associated with the development and progression of prostate tumours. We propose that the assessment of PDE4D7 levels may provide a novel, independent predictor of post-surgical disease progression. PMID:26575822

  14. Demonstration of physical proximity between the N terminus and the S4-S5 linker of the human ether-a-go-go-related gene (hERG) potassium channel.

    PubMed

    de la Peña, Pilar; Alonso-Ron, Carlos; Machín, Angeles; Fernández-Trillo, Jorge; Carretero, Luis; Domínguez, Pedro; Barros, Francisco

    2011-05-27

    Potassium channels encoded by the human ether-à-go-go-related gene (hERG) contribute to cardiac repolarization as a result of their characteristic gating properties. The hERG channel N terminus acts as a crucial determinant in gating. It is also known that the S4-S5 linker couples the voltage-sensing machinery to the channel gate. Moreover, this linker has been repeatedly proposed as an interaction site for the distal portion of the N terminus controlling channel gating, but direct evidence for such an interaction is still lacking. In this study, we used disulfide bond formation between pairs of engineered cysteines to demonstrate the close proximity between the beginning of the N terminus and the S4-S5 linker. Currents from channels with introduced cysteines were rapidly and strongly attenuated by an oxidizing agent, this effect being maximal for cysteine pairs located around amino acids 3 and 542 of the hERG sequence. The state-dependent modification of the double-mutant channels, but not the single-cysteine mutants, and the ability to readily reverse modification with the reducing agent dithiothreitol indicate that a disulfide bond is formed under oxidizing conditions, locking the channels in a non-conducting state. We conclude that physical interactions between the N-terminal-most segment of the N terminus and the S4-S5 linker constitute an essential component of the hERG gating machinery, thus providing a molecular basis for previous data and indicating an important contribution of these cytoplasmic domains in controlling its unusual gating and hence determining its physiological role in setting the electrical behavior of cardiac and other cell types.

  15. Total petroleum systems of the Grand Erg/Ahnet Province, Algeria and Morocco; the Tanezzuft-Timimoun, Tanezzuft-Ahnet, Tanezzuft-Sbaa, Tanezzuft Mouydir, Tanezzuft-Benoud, and Tanezzuft-Bechar/Abadla

    USGS Publications Warehouse

    Klett, T.R.

    2000-01-01

    Undiscovered, conventional oil and gas resources were assessed within total petroleum systems of the Grand Erg/Ahnet Province (2058) as part of the U.S. Geological Survey World Petroleum Assessment 2000. The majority of the Grand Erg/ Ahnet Province is in western Algeria; a very small portion extends into Morocco. The province includes the Timimoun Basin, Ahnet Basin, Sbaa Basin, Mouydir Basin, Benoud Trough, Bechar/Abadla Basin(s), and part of the Oued Mya Basin. Although several petroleum systems may exist within each of these basins, only seven ?composite? total petroleum systems were identified. Each total petroleum system occurs in a separate basin, and each comprises a single assessment unit. The main source rocks are the Silurian Tanezzuft Formation (or lateral equivalents) and Middle to Upper Devonian mudstone. Maturation history and the major migration pathways from source to reservoir are unique to each basin. The total petroleum systems were named after the oldest major source rock and the basin in which it resides. The estimated means of the undiscovered conventional petroleum volumes in total petroleum systems of the Grand Erg/ Ahnet Province are as follows: [MMBO, million barrels of oil; BCFG, billion cubic feet of gas; MMBNGL, million barrels of natural gas liquids] Total Petroleum System MMBO BCFG MMBNGL Tanezzuft-Timimoun 31 1,128 56 Tanezzuft-Ahnet 34 2,973 149 Tanezzuft-Sbaa 162 645 11 Tanezzuft-Mouydir 12 292 14 Tanezzuft-Benoud 72 2,541 125 Tanezzuft-Bechar/Abadla 16 441 22

  16. 27 CFR 10.11 - Meaning of terms.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ..., Delegation of the Administrator's Authorities in 27 CFR Part 10, Commercial Bribery. Industry member. Any person engaged in business as a distiller, brewer, recitifier, blender, or other producer, or as...

  17. 27 CFR 10.11 - Meaning of terms.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ..., Delegation of the Administrator's Authorities in 27 CFR Part 10, Commercial Bribery. Industry member. Any person engaged in business as a distiller, brewer, recitifier, blender, or other producer, or as...

  18. Boletin de Informacion Educativa, Ano VI, No. 10/11 (Educational Information Bulletin, Volume VI, No. 10/11).

    ERIC Educational Resources Information Center

    Ministerio de Educacion y Cultura, Santa Fe (Argentina). Centro de Documentacion e Informacion Educativa de la Provincia de Santa Fe.

    This information bulletin is published by the Documentation and Educational Information Center in the Argentine province of Santa Fe. The bulletin reports on educational developments in the province and abroad, educational problems, statistics, legislation, documentation and information techniques, and information from international organizations.…

  19. VizieR Online Data Catalog: XMM-Newton Slew Survey in 2-10keV (Warwick+, 2012)

    NASA Astrophysics Data System (ADS)

    Warwick, R. S.; Saxton, R. D.; Read, A. M.

    2012-10-01

    Details of the sources which comprise the hard-band selected XSS extragalactic sample are given in the Table. The table provides the following information for each source: the XSS name; whether the source was also detected in the XSS soft band (1=yes, 0=no); the XSS hard band (2-10keV) flux and error on the flux (in units of 10-11ergs/cm2/s) ; the RA and Dec of the proposed counterpart; the name of the counterpart; the type of the counterpart; the redshift (if known). (1 data file).

  20. Acute alteration of cardiac ECG, action potential, I{sub Kr} and the human ether-a-go-go-related gene (hERG) K{sup +} channel by PCB 126 and PCB 77

    SciTech Connect

    Park, Mi-Hyeong; Park, Won Sun; Jo, Su-Hyun

    2012-07-01

    Polychlorinated biphenyls (PCBs) have been known as serious persistent organic pollutants (POPs), causing developmental delays and motor dysfunction. We have investigated the effects of two PCB congeners, 3,3′,4,4′-tetrachlorobiphenyl (PCB 77) and 3,3′,4,4′,5-pentachlorobiphenyl (PCB 126) on ECG, action potential, and the rapidly activating delayed rectifier K{sup +} current (I{sub Kr}) of guinea pigs' hearts, and hERG K{sup +} current expressed in Xenopus oocytes. PCB 126 shortened the corrected QT interval (QTc) of ECG and decreased the action potential duration at 90% (APD{sub 90}), and 50% of repolarization (APD{sub 50}) (P < 0.05) without changing the action potential duration at 20% (APD{sub 20}). PCB 77 decreased APD{sub 20} (P < 0.05) without affecting QTc, APD{sub 90}, and APD{sub 50}. The PCB 126 increased the I{sub Kr} in guinea-pig ventricular myocytes held at 36 °C and hERG K{sup +} current amplitude at the end of the voltage steps in voltage-dependent mode (P < 0.05); however, PCB 77 did not change the hERG K{sup +} current amplitude. The PCB 77 increased the diastolic Ca{sup 2+} and decreased Ca{sup 2+} transient amplitude (P < 0.05), however PCB 126 did not change. The results suggest that PCB 126 shortened the QTc and decreased the APD{sub 90} possibly by increasing I{sub Kr}, while PCB 77 decreased the APD{sub 20} possibly by other modulation related with intracellular Ca{sup 2+}. The present data indicate that the environmental toxicants, PCBs, can acutely affect cardiac electrophysiology including ECG, action potential, intracellular Ca{sup 2+}, and channel activity, resulting in toxic effects on the cardiac function in view of the possible accumulation of the PCBs in human body. -- Highlights: ► PCBs are known as serious environmental pollutants and developmental disruptors. ► PCB 126 shortened QT interval of ECG and action potential duration. ► PCB 126 increased human ether-a-go-go-related K{sup +} current and I{sub Kr}. ► PCB

  1. The S4-S5 linker directly couples voltage sensor movement to the activation gate in the human ether-a'-go-go-related gene (hERG) K+ channel.

    PubMed

    Ferrer, Tania; Rupp, Jason; Piper, David R; Tristani-Firouzi, Martin

    2006-05-01

    A key unresolved question regarding the basic function of voltage-gated ion channels is how movement of the voltage sensor is coupled to channel opening. We previously proposed that the S4-S5 linker couples voltage sensor movement to the S6 domain in the human ether-a'-go-go-related gene (hERG) K+ channel. The recently solved crystal structure of the voltage-gated Kv1.2 channel reveals that the S4-S5 linker is the structural link between the voltage sensing and pore domains. In this study, we used chimeras constructed from hERG and ether-a'-go-go (EAG) channels to identify interactions between residues in the S4-S5 linker and S6 domain that were critical for stabilizing the channel in a closed state. To verify the spatial proximity of these regions, we introduced cysteines in the S4-S5 linker and at the C-terminal end of the S6 domain and then probed for the effect of oxidation. The D540C-L666C channel current decreased in an oxidizing environment in a state-dependent manner consistent with formation of a disulfide bond that locked the channel in a closed state. Disulfide bond formation also restricted movement of the voltage sensor, as measured by gating currents. Taken together, these data confirm that the S4-S5 linker directly couples voltage sensor movement to the activation gate. Moreover, rather than functioning simply as a mechanical lever, these findings imply that specific interactions between the S4-S5 linker and the activation gate stabilize the closed channel conformation.

  2. Benchmarking the ERG valve tip and MRI Interventions Smart Flow neurocatheter convection-enhanced delivery system's performance in a gel model of the brain: employing infusion protocols proposed for gene therapy for Parkinson's disease

    NASA Astrophysics Data System (ADS)

    Sillay, Karl; Schomberg, Dominic; Hinchman, Angelica; Kumbier, Lauren; Ross, Chris; Kubota, Ken; Brodsky, Ethan; Miranpuri, Gurwattan

    2012-04-01

    Convection-enhanced delivery (CED) is an advanced infusion technique used to deliver therapeutic agents into the brain. CED has shown promise in recent clinical trials. Independent verification of published parameters is warranted with benchmark testing of published parameters in applicable models such as gel phantoms, ex vivo tissue and in vivo non-human animal models to effectively inform planned and future clinical therapies. In the current study, specific performance characteristics of two CED infusion catheter systems, such as backflow, infusion cloud morphology, volume of distribution (mm3) versus the infused volume (mm3) (Vd/Vi) ratios, rate of infusion (µl min-1) and pressure (mmHg), were examined to ensure published performance standards for the ERG valve-tip (VT) catheter. We tested the hypothesis that the ERG VT catheter with an infusion protocol of a steady 1 µl min-1 functionality is comparable to the newly FDA approved MRI Interventions Smart Flow (SF) catheter with the UCSF infusion protocol in an agarose gel model. In the gel phantom models, no significant difference was found in performance parameters between the VT and SF catheter. We report, for the first time, such benchmark characteristics in CED between these two otherwise similar single-end port VT with stylet and end-port non-stylet infusion systems. Results of the current study in agarose gel models suggest that the performance of the VT catheter is comparable to the SF catheter and warrants further investigation as a tool in the armamentarium of CED techniques for eventual clinical use and application.

  3. Synthesis, biological assessment, and molecular modeling of racemic 7-aryl-9,10,11,12-tetrahydro-7H-benzo[7,8]chromeno[2,3-b]quinolin-8-amines as potential drugs for the treatment of Alzheimer's disease.

    PubMed

    Maalej, Emna; Chabchoub, Fakher; Oset-Gasque, María Jesús; Esquivias-Pérez, Mario; González, María P; Monjas, Leticia; Pérez, Concepción; de los Ríos, Cristóbal; Rodríguez-Franco, María Isabel; Iriepa, Isabel; Moraleda, Ignacio; Chioua, Mourad; Romero, Alejandro; Marco-Contelles, José; Samadi, Abdelouahid

    2012-08-01

    The synthesis, pharmacological analysis and molecular modeling of the readily available racemic tacrine analogs 21-30, bearing the 7-aryl-9,10,11,12-tetrahydro-7H-benzo[7,8]chromeno[2,3-b]quinolin-8-amine heterocyclic ring system (II), prepared by Friedländer reaction of 2-amino-4-aryl-4H-benzo[h]chromene-3-carbonitriles (11-20) with cyclohexanone, are described in this paper. Molecules 21-30 are potent and selective inhibitors of hAChE, in the low micromolar range, one of the most potent inhibitors, 4-(8-amino-9,10,11,12-tetrahydro-7H-benzo[7,8]chromeno[2,3-b]quinolin-7-yl)-2-methoxyphenol (25), showing a IC(50) (hAChE) = 0.33 ± 0.04 μM. Kinetic studies of compound 25 proved that this compound is a mixed type inhibitor for EeAChE (K(i) = 81 nM). Accordingly, molecular modeling of inhibitor 25 showed that both enantiomers have two major predicted binding modes at the active and at the peripheral anionic sites of AChE. Inhibitor 25 has an excellent antioxidant profile as determined in the ORAC experiment (1.47 ± 0.10 Trolox equiv). Inhibitors 26-28 and 30 are permeable to BBB as determined in the PAMPA assay. Compared to tacrine, selected compounds 26-28 and 30 showed less hepatic toxicity in HepG2 cells. Moreover, cell viability-related studies in cortical neurons in primary cultures show that compounds 26-28 and 30 (0.1-50 μM) have significant neuroprotective effects against mitochondrial chain blockers-induced cell death, and, unlike tacrine, are not neurotoxic at concentrations lower than 50 μM. It is worth highlighting that compound 27 has the best neuroprotective properties out of all assayed compounds and shows no neurotoxicity. To sum up, these tacrine analogs can be considered as attractive multipotent therapeutic molecules on pharmacological receptors playing key roles in the progress of Alzheimer's disease. PMID:22795665

  4. Ion Irradiation Experiments on the Murchison CM2 Carbonaceous Chondrite: Simulating Space Weathering of Primitive Asteroids

    NASA Technical Reports Server (NTRS)

    Keller, L. P.; Christoffersen, R.; Dukes, C. A.; Baragiola, R. A.; Rahman, Z.

    2015-01-01

    Remote sensing observations show that space weathering processes affect all airless bodies in the Solar System to some degree. Sample analyses and lab experiments provide insights into the chemical, spectroscopic and mineralogic effects of space weathering and aid in the interpretation of remote- sensing data. For example, analyses of particles returned from the S-type asteroid Itokawa by the Hayabusa mission revealed that space-weathering on that body was dominated by interactions with the solar wind acting on LL ordinary chondrite-like materials [1, 2]. Understanding and predicting how the surface regoliths of primitive carbonaceous asteroids respond to space weathering processes is important for future sample return missions (Hayabusa 2 and OSIRIS-REx) that are targeting objects of this type. Here, we report the results of our preliminary ion irradiation experiments on a hydrated carbonaceous chondrite with emphasis on microstructural and infrared spectral changes.

  5. Stable dense plasma jets produced at laser power densities around 1014 W/cm2

    NASA Astrophysics Data System (ADS)

    Kasperczuk, A.; Pisarczyk, T.; Borodziuk, S.; Ullschmied, J.; Krousky, E.; Masek, K.; Rohlena, K.; Skala, J.; Hora, H.

    2006-06-01

    The results of investigations are presented that are connected with defocused laser beam-planar target interaction. Following the very large focus laser-plasma interaction experiments on the Nova [H. T. Powell, J. A. Caird, J. E. Murray, and C. E. Thompson, 1991 ICF Annual Report UCRL-LR-105820-91, p. 163 (1991)] and GEKKO-XII [C. Yamanaka, Y. Kato, Y. Izawa, K. Yoshida, T. Yamanaka, T. Sasaki, T. Nakatsuka, J. Kuroda, and S. Nakai, IEEE J. Quantum Electron. QE-17, 1639 (1981)] lasers, as well as on the National Ignition Facility (NIF) laser [W. J. Hogan, E. I. Moses, B. E. Warner, M. S. Sorem, and J. M. Soures, Nucl. Fusion 41, 567 (2001)] with generation of high Mach number jets, this paper is devoted to similar jet generation with very detailed measurements of density profiles by using high-power lasers at large focus conditions. The experiment was carried out with target materials of different mass densities (Al, Cu, Ag, Ta, and Pb) using the Prague Asterix Laser System (PALS) iodine laser [K. Jungwirth, A. Cejnarova, L. Juha, B. Kralikowa, J. Krasa, E. Krousky, P. Krupickova, L. Laska, K. Masek, A. Prag, O. Renner, K. Rohlena, B. Rus, J. Skala, P. Straka, and J. Ullschmied, Phys. Plasmas 8, 2495 (2001)]. The investigations were conducted for the laser radiation energy of 100J at two wavelengths of 1.315 and 0.438μm (the first and third harmonics of laser radiation), pulse duration of 0.4ns, and a focal spot radius of 300μm. Most of the experimental data were obtained by means of a three-frame laser interferometer and an x-ray streak camera; the crater parameters were obtained by using the crater replica technique. These investigations have shown that stable dense plasma jets can be produced in a simple configuration of laser beam-planar target interaction, provided that a proper target material is used.

  6. Coordinated Chemical and Isotopic Imaging of Bells (CM2) Meteorite Matrix

    NASA Technical Reports Server (NTRS)

    Clemett, S. J.; Messenger, S.; Naklamura-Messenger, K.; Thomas-Keprta, K. L.

    2014-01-01

    Meteoritic organic matter is a complex conglomeration of species formed in distinct environments and processes in circumstellar space, the interstellar medium, the Solar Nebula and asteroids. Consequently meteorites constitute a unique record of primordial organic chemical evolution. While bulk chemical analysis has provided a detailed description of the range and diversity of organic species present in carbonaceous chondrites, there is little information as to how these species are spatially distributed and their relationship to the host mineral matrix. The distribution of organic phases is nevertheless critical to understanding parent body processes. The CM and CI chondrites all display evidence of low temperature (< 350K) aqueous alteration that may have led to aqueous geochromatographic separation of organics and synthesis of new organics coupled to aqueous mineral alteration. Here we present the results of the first coordinated in situ isotopic and chemical mapping study of the Bells meteorite using a newly developed two-step laser mass spectrometer (mu-L(sup 2)MS) capable of measuring a broad range of organic compounds.

  7. Design of a 10**36 CM-2 S-1 Super-B Factory

    SciTech Connect

    Biagini, M.E.; Boni, R.; Boscolo, M.; Demma, T.; Drago, A.; Guiducci, S.; Raimondi, P.; Tomassini, S.; Zobov, M.; Bertsche, Kirk J.; Novokhatski, A.; Seeman, J.; Sullivan, M.; Wienands, U.; Wittmer, W.; Bettoni, S.; Paoloni, E.; Marchiori, G.; Bogomyagkov, A.; Koop, I.; Levichev, E.; /Novosibirsk, IYF

    2011-10-24

    Parameters have been studied for a high luminosity e{sup +}e{sup -} collider operating at the Upsilon 4S that would deliver a luminosity of 1 to 4 x 10{sup 36}/cm{sup 2}/s. This collider, called a Super-B Factory, would use a combination of linear collider and storage ring techniques. In this scheme an electron beam and a positron beam are stored in low-emittance damping rings similar to those designed for a Linear Collider (LC) or the next generation light source. A LC style interaction region is included in the ring to produce sub-millimeter vertical beta functions at the collision point. A large crossing angle (+/- 24 mrad) is used at the collision point to allow beam separation. A crab-waist scheme is used to reduce the hourglass effect and restore peak luminosity. Beam currents of 1.8 A at 4 x 7 GeV in 1251 bunches can produce a luminosity of 10{sup 36}/cm{sup 2}/s with upgrade possibilities. Such a collider would produce an integrated luminosity of about 10,000 fb{sup -1} (10 ab{sup -1}) in a running year (10{sup 7} sec) at the {gamma}(4S) resonance. Further possibilities include having longitudinally polarized e- at the IR and operating at the J/Psi and Psi beam energies.

  8. W/Z production cross sections and asymmetries at E(CM) = 2-TeV

    SciTech Connect

    Bellavance, Angela M.; /Nebraska U.

    2005-06-01

    The most recent results for W and Z boson production cross sections and asymmetries are presented from the CDF and D0 collaborations using Run II data taken at the Fermi National Accelerator Laboratory (FNAL) Tevatron. Data set sizes range from 72 pb{sup -1} to 226 pb{sup -1}, and results range from published to preliminary. Results presented agree with the Standard Model and world averages within errors.

  9. A t(16;21)(p11;q22) in Acute Myeloid Leukemia (AML) Resulting in Fusion of the FUS/TLS and ERG Genes: A Review of the Literature.

    PubMed

    Buchanan, Justin; Tirado, Carlos A

    2016-01-01

    The t(16;21)(p11;q22) is a rare chromosomal abnormality that appears in approximately 1% of acute myeloid leukemia (AML) cases. Previously, between 50 and 60 cases have been reported. In this review, we will discuss the literature regarding t(16;21) as well as cases published. We compiled 68 cases from the Mitelman Database of Chromosome Aberrations and Gene Fusions in Cancer as well as 10 additional cases in the literature, for a total of 78 cases. The t(16;21) results in the TLS(FUS)-ERG fusion protein, which is believed to function as a transcriptional activator in leukemogenesis and has been demonstrated to interfere in normal pre-mRNA splicing functions of FUS/TLS. Reverse-transcriptase polymerase chain reaction of fusion transcripts in patients, has been demonstrated to have diagnostic significance in monitoring for minimal residual disease. Cytogenetically, about half of the cases had secondary chromosomal abnormalities; we found that trisomy 8 and 10 were the most common abnormalities, occurring in 9.1% of the otal cases for each. t(16;21) in AML has been described with various morphological features, such as phagocytosis and vacuolation, and is present in multiple FAB types. Immunophenotypic characteristics such as CD33 and CD34 expression have also been noted, and several studies have examined the relation between CD56 receptor expression and t(16;21) AML. In general, t(16;21) in AML is associated with a poor prognosis and this abnormality could serve as cytogenetic indicator in determining diagnosis and prognosis. Herein, we summarize the cytogenetic features found in the the Mitelman Database of Chromosome Aberrations and Gene Fusions in Cancer for t(16;21) in AML, as well as review the current literature associated with t(16;21), AML and its features. PMID:27183148

  10. Discovery of 5-Chloro-1-(5-chloro-2-(methylsulfonyl)benzyl)-2-imino-1,2-dihydropyridine-3-carboxamide (TAK-259) as a Novel, Selective, and Orally Active α1D Adrenoceptor Antagonist with Antiurinary Frequency Effects: Reducing Human Ether-a-go-go-Related Gene (hERG) Liabilities.

    PubMed

    Sakauchi, Nobuki; Kohara, Yasuhisa; Sato, Ayumu; Suzaki, Tomohiko; Imai, Yumi; Okabe, Yuichi; Imai, Shigemitsu; Saikawa, Reiko; Nagabukuro, Hiroshi; Kuno, Haruhiko; Fujita, Hisashi; Kamo, Izumi; Yoshida, Masato

    2016-04-14

    A novel structural class of iminopyridine derivative 1 was identified as a potent and selective human α1D adrenoceptor (α1D adrenergic receptor; α1D-AR) antagonist against α1A- and α1B-AR through screening of an in-house compound library. From initial structure-activity relationship studies, we found lead compound 9m with hERG K(+) channel liability. To develop analogues with reduced hERG K(+) channel inhibition, a combination of site-directed mutagenesis and docking studies was employed. Further optimization led to the discovery of (R)-9s and 9u, which showed antagonistic activity by a bladder strip test in rats with bladder outlet obstruction, as well as ameliorated cystitis-induced urinary frequency in rats. Ultimately, 9u was selected as a clinical candidate. This is the first study to show the utility of iminopyridine derivatives as selective α1D-AR antagonists and evaluate their effects in vivo.

  11. Discovery of 5-Chloro-1-(5-chloro-2-(methylsulfonyl)benzyl)-2-imino-1,2-dihydropyridine-3-carboxamide (TAK-259) as a Novel, Selective, and Orally Active α1D Adrenoceptor Antagonist with Antiurinary Frequency Effects: Reducing Human Ether-a-go-go-Related Gene (hERG) Liabilities.

    PubMed

    Sakauchi, Nobuki; Kohara, Yasuhisa; Sato, Ayumu; Suzaki, Tomohiko; Imai, Yumi; Okabe, Yuichi; Imai, Shigemitsu; Saikawa, Reiko; Nagabukuro, Hiroshi; Kuno, Haruhiko; Fujita, Hisashi; Kamo, Izumi; Yoshida, Masato

    2016-04-14

    A novel structural class of iminopyridine derivative 1 was identified as a potent and selective human α1D adrenoceptor (α1D adrenergic receptor; α1D-AR) antagonist against α1A- and α1B-AR through screening of an in-house compound library. From initial structure-activity relationship studies, we found lead compound 9m with hERG K(+) channel liability. To develop analogues with reduced hERG K(+) channel inhibition, a combination of site-directed mutagenesis and docking studies was employed. Further optimization led to the discovery of (R)-9s and 9u, which showed antagonistic activity by a bladder strip test in rats with bladder outlet obstruction, as well as ameliorated cystitis-induced urinary frequency in rats. Ultimately, 9u was selected as a clinical candidate. This is the first study to show the utility of iminopyridine derivatives as selective α1D-AR antagonists and evaluate their effects in vivo. PMID:26954848

  12. Development of an Orally Available and Central Nervous System (CNS) Penetrant Toxoplasma gondii Calcium-Dependent Protein Kinase 1 (TgCDPK1) Inhibitor with Minimal Human Ether-a-go-go-Related Gene (hERG) Activity for the Treatment of Toxoplasmosis.

    PubMed

    Vidadala, Rama Subba Rao; Rivas, Kasey L; Ojo, Kayode K; Hulverson, Matthew A; Zambriski, Jennifer A; Bruzual, Igor; Schultz, Tracey L; Huang, Wenlin; Zhang, Zhongsheng; Scheele, Suzanne; DeRocher, Amy E; Choi, Ryan; Barrett, Lynn K; Siddaramaiah, Latha Kallur; Hol, Wim G J; Fan, Erkang; Merritt, Ethan A; Parsons, Marilyn; Freiberg, Gail; Marsh, Kennan; Kempf, Dale J; Carruthers, Vern B; Isoherranen, Nina; Doggett, J Stone; Van Voorhis, Wesley C; Maly, Dustin J

    2016-07-14

    New therapies are needed for the treatment of toxoplasmosis, which is a disease caused by the protozoan parasite Toxoplasma gondii. To this end, we previously developed a potent and selective inhibitor (compound 1) of Toxoplasma gondii calcium-dependent protein kinase 1 (TgCDPK1) that possesses antitoxoplasmosis activity in vitro and in vivo. Unfortunately, 1 has potent human ether-a-go-go-related gene (hERG) inhibitory activity, associated with long Q-T syndrome, and consequently presents a cardiotoxicity risk. Here, we describe the identification of an optimized TgCDPK1 inhibitor 32, which does not have a hERG liability and possesses a favorable pharmacokinetic profile in small and large animals. 32 is CNS-penetrant and highly effective in acute and latent mouse models of T. gondii infection, significantly reducing the amount of parasite in the brain, spleen, and peritoneal fluid and reducing brain cysts by >85%. These properties make 32 a promising lead for the development of a new antitoxoplasmosis therapy. PMID:27309760

  13. ISS-Lobster: a low-cost wide-field X-ray transient detector on the ISS

    NASA Astrophysics Data System (ADS)

    Petre, Robert; Camp, Jordan; Barthelmy, Scott; Gehrels, Neil; Racusin, Judith; Marshall, Frank; Ptak, Andrew

    2015-04-01

    ISS-Lobster is a wide-field X-ray transient detector proposed to be deployed on the International Space Station. Through its unique imaging X-ray optics that allow a 30 deg by 30 deg FoV, a 1 arc min position resolution and a 10-11 erg/(sec cm2) sensitivity in 2000 sec, ISS-Lobster will observe numerous events per year of X-ray transients related to compact objects, including: tidal disruptions of stars, supernova shock breakouts, neutron star bursts and superbursts, high redshift Gamma-Ray Bursts, and perhaps most exciting, X-ray counterparts of gravitational wave detections involving stellar mass and possibly supermassive black holes. The mission includes a 3-axis gimbal system that allows fast Target of Opportunity pointing, and a small gamma-ray burst monitor to be contributed by the Technion (Israel Institute of Technology).

  14. Chasing the Identification of ASCA Galactic Objects (ChIcAGO): An X-Ray Survey of Unidentified Sources in the Galactic Plane. I. Source Sample and Initial Results

    NASA Astrophysics Data System (ADS)

    Anderson, Gemma E.; Gaensler, B. M.; Kaplan, David L.; Slane, Patrick O.; Muno, Michael P.; Posselt, Bettina; Hong, Jaesub; Murray, Stephen S.; Steeghs, Danny T. H.; Brogan, Crystal L.; Drake, Jeremy J.; Farrell, Sean A.; Benjamin, Robert A.; Chakrabarty, Deepto; Drew, Janet E.; Finley, John P.; Grindlay, Jonathan E.; Lazio, T. Joseph W.; Lee, Julia C.; Mauerhan, Jon C.; van Kerkwijk, Marten H.

    2014-05-01

    We present the Chasing the Identification of ASCA Galactic Objects (ChIcAGO) survey, which is designed to identify the unknown X-ray sources discovered during the ASCA Galactic Plane Survey (AGPS). Little is known about most of the AGPS sources, especially those that emit primarily in hard X-rays (2-10 keV) within the Fx ~ 10-13 to 10-11 erg cm-2 s-1 X-ray flux range. In ChIcAGO, the subarcsecond localization capabilities of Chandra have been combined with a detailed multiwavelength follow-up program, with the ultimate goal of classifying the >100 unidentified sources in the AGPS. Overall to date, 93 unidentified AGPS sources have been observed with Chandra as part of the ChIcAGO survey. A total of 253 X-ray point sources have been detected in these Chandra observations within 3' of the original ASCA positions. We have identified infrared and optical counterparts to the majority of these sources, using both new observations and catalogs from existing Galactic plane surveys. X-ray and infrared population statistics for the X-ray point sources detected in the Chandra observations reveal that the primary populations of Galactic plane X-ray sources that emit in the Fx ~ 10-13 to 10-11 erg cm-2 s-1 flux range are active stellar coronae, massive stars with strong stellar winds that are possibly in colliding wind binaries, X-ray binaries, and magnetars. There is also another primary population that is still unidentified but, on the basis of its X-ray and infrared properties, likely comprises partly Galactic sources and partly active galactic nuclei.

  15. Polymer-based solar cells having an active area of 1.6 cm2 fabricated via spray coating

    NASA Astrophysics Data System (ADS)

    Scarratt, N. W.; Griffin, J.; Wang, T.; Zhang, Y.; Yi, H.; Iraqi, A.; Lidzey, D. G.

    2015-12-01

    We demonstrate the fabrication of polymer solar cells in which both a PEDOT:PSS hole transport and a PCDTBT:PC71BM photoactive layer are deposited by spray-casting. Two device geometries are explored, with devices having a pixel area of 165 mm2 attaining a power conversion efficiency of 3.7%. Surface metrology indicates that the PEDOT:PSS and PCDTBT:PC71BM layers have a roughness of 2.57 nm and 1.18 nm over an area of 100 μm2. Light beam induced current mapping reveals fluctuations in current generation efficiency over length-scales of ˜2 mm, with the average photocurrent being 75% of its maximum value.

  16. Spectral characteristics of iron-bearing phyllosilicates: Comparison to Orgueil (CI1), Murchison and Murray (CM2)

    USGS Publications Warehouse

    Calvin, W.M.; King, T.V.V.

    1997-01-01

    Phyllosilicate alteration minerals are commonly found in low petrologic types of carbonaceous chondrites. Previous spectral studies have examined Mg-bearing phyllosilicates with limited success in matching the spectral properties of CM and CI chondrites. Transmission electron microscope and other analytical techniques suggest that Fe-bearing clays are more abundant in CI and CM chondrites than magnesian varieties. Here, we present the results of an examination of the reflectance spectra of Fe-phyllosilicates, including serpentines and berthierines, of which the latter were formerly known as septechlorites. We have measured the diffuse reflectance spectra of powdered samples from 0.3 to 25 ??m. We find that these minerals provide a better spectral match to many of the features seen in CI and CM chondrites, and simple linear combinations of the spectra of both Fe- and Mg-phyllosilicates closely approximate the spectra of CM and CI chondrites.

  17. 53Mn-53Cr dating of aqueously formed carbonates in the CM2 lithology of the Sutter's Mill carbonaceous chondrite

    NASA Astrophysics Data System (ADS)

    Jilly, Christine E.; Huss, Gary R.; Krot, Alexander N.; Nagashima, Kazuhide; Yin, Qing-Zhu; Sugiura, Naoji

    2014-11-01

    Radiometric dating of secondary minerals can be used to constrain the timing of aqueous alteration on meteoritic parent bodies. Dolomite is a well-documented secondary mineral in CM chondrites, and is thought to have formed by precipitation from an aqueous fluid on the CM parent body within several million years of accretion. The petrographic context of crosscutting dolomite veins indicates that aqueous alteration occurred in situ, rather than in the nebular setting. Here, we present 53Mn-53Cr systematics for dolomite grains in Sutter's Mill section SM51-1. The Mn-Cr isotope data show well-resolved excesses of 53Cr correlated with 55Mn/52Cr ratio, which we interpret as evidence for the in situ decay of radioactive 53Mn. After correcting for the relative sensitivities of Mn and Cr using a synthetic Mn- and Cr-bearing calcite standard, the data yield an isochron with slope corresponding to an initial 53Mn/55Mn ratio of 3.42 ± 0.86 × 10-6. The reported error includes systematic uncertainty from the relative sensitivity factor. When calculated relative to the U-corrected Pb-Pb absolute age of the D'Orbigny angrite, Sutter's Mill dolomites give a formation age between 4564.8 and 4562.2 Ma (2.4-5.0 Myr after the birth of the solar system). This age is contemporaneous with previously reported ages for secondary carbonates in CM and CI chondrites. Consistent carbonate precipitation ages between the carbonaceous chondrite groups suggest that aqueous alteration was a common process during the early stages of parent body formation, probably occurring via heating from internal 26Al decay. The high-precision isochron for Sutter's Mill dolomite indicates that late-stage processing did not reach temperatures that were high enough to further disturb the Mn-Cr isochron.

  18. Compositional Zoning and Mn-Cr Systematics in Carbonates from the Y791198 CM2 Carbonaceous Chondrite

    NASA Technical Reports Server (NTRS)

    Brearley, Adrian J.; Hutcheon, Ian D.; Browning, Lauren

    2001-01-01

    Cathodoluminescence and microprobe analyses show that carbonates in Y791198 exhibit complex zoning. Cr-Mn dating suggests formation of carbonates 10 Ma after CAI formation Additional information is contained in the original extended abstract..

  19. Fine-Grained Rims in the Allan Hills 81002 and Lewis Cliff 90500 CM2 Meteorites: Their Origin and Modification

    NASA Technical Reports Server (NTRS)

    Hua, X.; Wang, J.; Buseck, P. R.

    2002-01-01

    Antarctic CM meteorites Allan Hills (ALH) 8 1002 and Lewis Cliff (LEW) 90500 contain abundant fine-grained rims (FGRs) that surround a variety of coarse-grained objects. FGRs from both meteorites have similar compositions and petrographic features, independent of their enclosed objects. The FGRs are chemically homogeneous at the 10 m scale for major and minor elements and at the 25 m scale for trace elements. They display accretionary features and contain large amounts of volatiles, presumably water. They are depleted in Ca, Mn, and S but enriched in P. All FGRs show a slightly fractionated rare earth element (REE) pattern, with enrichments of Gd and Yb and depletion of Er. Gd is twice as abundant as Er. Our results indicate that those FGRs are not genetically related to their enclosed cores. They were sampled from a reservoir of homogeneously mixed dust, prior to accretion to their parent body. The rim materials subsequently experienced aqueous alteration under identical conditions. Based on their mineral, textural, and especially chemical similarities, we conclude that ALH 8 1002 and LEW 90500 likely have a similar or identical source.

  20. CO2 laser devices and applications; Proceedings of the Seminar, Washington, DC, April 10, 11, 1980

    NASA Astrophysics Data System (ADS)

    Hartwick, T. S.

    1980-01-01

    Studies contained in this volume provide an overview of the recent advances in CO2 lasers and CO2 laser systems and their commercial and military applications. Papers are presented on the development of a flyable CO2 laser beacon, a frequency-stabilized hybrid CO2 lasers, compact CO2 lasers, and pulsed CO2 lasers. Other papers include: carbon dioxide lasers in rangefinding, scanning laser Doppler anemometry system, wide-bandwidth CO2 laser photomixers, infrared fiber optics for CO2 laser applications, and industrial applications of far-infrared lasers.

  1. Ultraviolet technology III; Proceedings of the Meeting, San Diego, CA, Aug. 10, 11, 1989

    SciTech Connect

    Huffman, R.E.

    1989-01-01

    The present conference discusses topics in atmospheric UV radiance, UV detectors, and UV airborne sensors. Attention is given to a UV limb imaging experiment, UV ionospheric remote sensing with the Polar BEAR satellite, photon counting by means of microchannel plate (MCP) intensified electrographic cameras, the use of electron-bombarded virtual-phase CCDs and UV imaging detectors, results of dynamic range measurements on multianode microchannel-array detectors, and confined quantum state photomultiplier design. Also discussed are linear array-based UV spectrographs, a multianode MCP for plasma diagnostics, neutral-density UV filters obeying Beer's law, calibration and performance of the UV plume instrument, a magnetic-focus MCP image tube's evaluation, large CCD arrays with enhanced UV performance, images from a UV solar-blind photon-counting camera, and the design of high power laser polarizers.

  2. Regional School Design Workshop. (11th, Windsor, Ontario, March 10-11, 1970).

    ERIC Educational Resources Information Center

    Ontario Dept. of Education, Toronto. School Planning and Building Research Section.

    This report contains speeches and notes of workshop participants meeting to discuss school planning. Participants included educators, architects, engineers, and contractors. Twenty-two selections cover such topics as open plan schools, instructional materials centers, site selection, fire protection, environmental control, the school as a…

  3. French Curriculum Guide-Level III and IV; Grades 10, 11, 12.

    ERIC Educational Resources Information Center

    Kennedy, Dora F.; And Others

    This is a sequel to the French guide for Levels 1 and 2 (grades 7 and above). Materials for Level 3 center around: (1) the teaching of grammar using two different texts, (2) reading, (3) cultural education, and (4) supplementary lesson plans, quizzes, exercises, and tests. Other chapters discuss coverage of basic materials, differences among the…

  4. Pioneer 10/11 data analysis of the trapped radiation experiment

    NASA Technical Reports Server (NTRS)

    Fillius, W.

    1982-01-01

    The data handling operations and the database produced by the Trapped Radiation Experiment on the NASA Pioneer 10 and 11 spacecraft are outlined. In situ measurements of trapped radiation at both Jupiter and Saturn, the extension of cosmic ray observations to the outer heliosphere, the presence of Jovian electrons in interplanetary space, analyses of the interaction between planetary satellites and the trapped radiation that engulfs them, and further investigations of the radiation enviroments of both planets are reported.

  5. PROCEEDINGS: 1989 INTERNATIONAL CONFERENCE ON MUNICIPAL WASTE COMBUSTION - VOLUME 4: SESSIONS 9, 10, 11, AND 12

    EPA Science Inventory

    The proceedings document presentations at the International Conference on Municipal Waste Combustion (MWC), held on April 11-14, 1989, in Hollywood, Florida. The objective of the Conference was to provide an effective international forum for the exchange and transfer of informati...

  6. REPORT OF NATIONAL ADVISORY COMMITTEE ON HEALTH OCCUPATIONS EDUCATION (MARCH 10-11, 1966).

    ERIC Educational Resources Information Center

    Office of Education (DHEW), Washington, DC.

    COMMITTEE MEMBERS AND OFFICE OF EDUCATION STAFF MET WITH RESOURCE PERSONS IN HEALTH OCCUPATIONS AREA. HIGHLIGHTS OF THE SPECIALISTS REPORTS ARE--BY 1970, 60 TO 70 THOUSAND MEDICAL TECHNOLOGISTS WILL BE NEEDED. PROGRAMS DEVELOPED IN TECHNICAL AND HIGH SCHOOLS AND COMMUNITY COLLEGES ARE ALL NEEDED TO REACH THIS GOAL. SHORTAGES OF QUALIFIED TEACHERS…

  7. Shuttle cryogenic supply system optimization study. Volume 3: Technical report, section 10, 11 and 12

    NASA Technical Reports Server (NTRS)

    1973-01-01

    The evaluation of candidate cryogenic fuel systems for space shuttle vehicles is discussed. A set of guidelines was used to establish a matrix of possible combinations for the integration of potential cryogenic systems. The various concepts and combinations which resulted from the integration efforts are described. The parameters which were considered in developing the matrix are: (1) storage of cryogenic materials, (2) fuel lines, (3) tank pressure control, (4) thermal control, (5) fluid control, and (6) fluid conditioning. Block diagrams and drawings of the candidate systems are provided. Performance predictions for the systems are outlined in tables of data.

  8. Advanced Simulation and Computing FY10-11 Implementation Plan Volume 2, Rev. 0

    SciTech Connect

    Carnes, B

    2009-06-08

    The Stockpile Stewardship Program (SSP) is a single, highly integrated technical program for maintaining the surety and reliability of the U.S. nuclear stockpile. The SSP uses past nuclear test data along with current and future non-nuclear test data, computational modeling and simulation, and experimental facilities to advance understanding of nuclear weapons. It includes stockpile surveillance, experimental research, development and engineering programs, and an appropriately scaled production capability to support stockpile requirements. This integrated national program requires the continued use of current facilities and programs along with new experimental facilities and computational enhancements to support these programs. The Advanced Simulation and Computing Program (ASC) is a cornerstone of the SSP, providing simulation capabilities and computational resources to support the annual stockpile assessment and certification, to study advanced nuclear weapons design and manufacturing processes, to analyze accident scenarios and weapons aging, and to provide the tools to enable stockpile Life Extension Programs (LEPs) and the resolution of Significant Finding Investigations (SFIs). This requires a balanced resource, including technical staff, hardware, simulation software, and computer science solutions. In its first decade, the ASC strategy focused on demonstrating simulation capabilities of unprecedented scale in three spatial dimensions. In its second decade, ASC is focused on increasing its predictive capabilities in a three-dimensional simulation environment while maintaining support to the SSP. The program continues to improve its unique tools for solving progressively more difficult stockpile problems (focused on sufficient resolution, dimensionality and scientific details); to quantify critical margins and uncertainties (QMU); and to resolve increasingly difficult analyses needed for the SSP. Moreover, ASC has restructured its business model from one that was very successful in delivering an initial capability to one that is integrated and focused on requirements-driven products that address long-standing technical questions related to enhanced predictive capability in the simulation tools. ASC must continue to meet three objectives: Objective 1 Robust Tools--Develop robust models, codes, and computational techniques to support stockpile needs such as refurbishments, SFIs, LEPs, annual assessments, and evolving future requirements. Objective 2 Prediction through Simulation--Deliver validated physics and engineering tools to enable simulations of nuclear weapons performance in a variety of operational environments and physical regimes and to enable risk-informed decisions about the performance, safety, and reliability of the stockpile. Objective 3 Balanced Operational Infrastructure--Implement a balanced computing platform acquisition strategy and operational infrastructure to meet Directed Stockpile Work (DSW) and SSP needs for capacity and high-end simulation capabilities.

  9. CWEX-10/11: Overview of Results From the First Two Crop/Wind-Energy Experiments

    NASA Astrophysics Data System (ADS)

    Takle, E. S.; Rajewski, D. A.; Prueger, J. H.; Oncley, S.; Lundquist, J. K.; Horst, T. W.; Rhodes, M. E.; Pfeiffer, R.; Hatfield, J.; Spoth, K. K.; Doorenbos, R.

    2012-12-01

    We have conducted experiments in a 200-turbine operating wind farm in Iowa to measure aerodynamic and microclimate properties of the environment in and around turbines in an area of intensely managed agricultural crops. Surface measurements at multiple locations were made of temperature, humidity, wind speed, wind direction, turbulence, and fluxes of heat, momentum, moisture and CO2. These together with remotely sensed wind speed, wind direction and turbulence at hub height accumulated over the growing seasons of 2010 and 2011 enable us to begin understanding of how turbines influence microclimate conditions in a wind-farm. SCADA data from 13 turbines enable studies of wakes and their interactions with each other and with the surface. Our studies corroborate published results that report reduction in wind speed, increased night-time temperature and decreased the daytime temperature in regions leeward of leading turbines in a wind farm. Our microclimate measurements enable us to go beyond previous reports to investigate spatial structures of mean wind, turbulence kinetic energy, thermal stability, and fluxes of heat, moisture and CO2 at the surface. Control cases are provided by evaluating surface conditions under a wide variety of wind directions and evaluating surface conditions at times when turbines were turned off or abrupt wind shifts were documented. Careful delineation of wind directions from the SCADA data reveal lateral characteristics of wakes and allow comparisons of power reduction for multiple interacting turbines with comparable results reported for off-shore wind farms. Our studies suggest that near-surface conditions are influenced by the presence of overlying wakes, wakes that impinge on the surface, and an irregular standing wave pressure field created by lines of turbines presenting an obstacle to the flow. Surface stability observed concurrently with wake interactions provides some insights on diurnal variability of wind farm performance.

  10. Structure of 10,11Li and the reaction 11Li (p , d)10Li

    NASA Astrophysics Data System (ADS)

    Fortune, H. T.

    2016-09-01

    I examine the properties of 11Li and the low-lying resonances in 10Li, as they relate to neutron removal from 11Li. Comparison with results from a recent 11Li (p , d) reaction strongly suggests that that experiment observed only the 2+ resonance, and not the 1+.

  11. Newton's Apple Teachers Guides. Seasons 9-10-11-12: A Collection of Lessons and Activities.

    ERIC Educational Resources Information Center

    Twin Cities Public Television, St. Paul, MN.

    Newton's Apple is a PBS family science program that explores basic science through high-energy, hands-on demonstrations. This volume is a collection of the teacher's guides from four seasons of Newton's Apple which were originally broadcast from 1991 through 1994. Each of the four seasons in the volume contains 26 lessons and a combination of…

  12. 20 CFR 10.11 - Who maintains custody and control of FECA records?

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... Employees' Compensation Act File). This system of records is maintained by and under the control of OWCP... 20 Employees' Benefits 1 2012-04-01 2012-04-01 false Who maintains custody and control of FECA... and control of FECA records? All records relating to claims for benefits filed under the...

  13. 20 CFR 10.11 - Who maintains custody and control of FECA records?

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... Employees' Compensation Act File). This system of records is maintained by and under the control of OWCP... 20 Employees' Benefits 1 2011-04-01 2011-04-01 false Who maintains custody and control of FECA... and control of FECA records? All records relating to claims for benefits filed under the...

  14. 20 CFR 10.11 - Who maintains custody and control of FECA records?

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... Employees' Compensation Act File). This system of records is maintained by and under the control of OWCP... 20 Employees' Benefits 1 2013-04-01 2012-04-01 true Who maintains custody and control of FECA... and control of FECA records? All records relating to claims for benefits filed under the...

  15. Career Education: Some Essential Learner Outcomes. Senior High Grades 10, 11, 12.

    ERIC Educational Resources Information Center

    Tennyson, W. Wesley; And Others

    This guide, one of a series for various grade levels, contains Some Essential Learner Ouctomes (SELOs) for career education in high schools in Minnesota. (The SELOs are selected samples of knowledge statements considered as essential learning outcomes for students in each of the subject areas taught in schools.) These SELOs for the senior high…

  16. Aerodynamic measurements: normative data for children ages 6:0 to 10:11 years.

    PubMed

    Weinrich, Barbara; Salz, Beth; Hughes, Michael

    2005-09-01

    Normative measures of open quotient, speed quotient, maximum flow declination rate (MFDR), and subglottal pressure were determined for 75 children between the ages of 6 years 0 months and 10 years 11 months. The participants produced a sustained /a/ at low, comfort, and high pitches for a minimum of 5 seconds, and five to seven repetitions of /pa/ at low, comfort, and high pitches. No statistically significant differences were found in the mean measures of any aerodynamic variables (open quotient, speed quotient, maximum flow declination rate, subglottal pressure) between the frequency levels (low, comfort, high pitches). Also, no strong evidence (P > .05) exists that age or sex effect differed between the frequency levels (low, comfort, high) for any of the aerodynamic measures. For /a/ response tasks, mean open quotient measures increased slightly from low to comfort frequency and from comfort to high frequency. Mean speed quotient measures showed minimal differences between low and comfort frequency, with decreased mean measures for high frequency. Mean MFDR measures increased from low to comfort frequency and from comfort to high frequency. Mean subglottal pressure measures increased slightly from low to comfort frequency and from comfort to high frequency.

  17. Theory and modeling in nanoscience: Report of the May 10-11, 2002Workshop

    SciTech Connect

    McCurdy, C. William; Stechel, Ellen; Cummings, Peter; Hendrickson, Bruce; Keyes, David

    2002-06-28

    On May 10 and 11, 2002, a workshop entitled ''Theory and Modeling in Nanoscience'' was held in San Francisco, California, sponsored by the offices of Basic Energy Science and Advanced Scientific Computing Research of the Department of Energy. The Basic Energy Sciences Advisory Committee and the Advanced Scientific Computing Advisory Committee convened the workshop to identify challenges and opportunities for theory, modeling, and simulation in nanoscience and nanotechnology, and additionally to investigate the growing and promising role of applied mathematics and computer science in meeting those challenges. This report is the result of those contributions and the discussions at the workshop.

  18. Imaging spectroscopy; Proceedings of the Seminar, Los Angeles, CA, February 10, 11, 1981

    NASA Technical Reports Server (NTRS)

    Norris, D. D.

    1981-01-01

    The seminar concentrated on the science applications of spectral imaging, multispectral imaging sensors, and spectral filtering. Papers are presented on spectroscopic remote sensing for geological applications, spectral mapping of Jupiter, system design of an interferometer imaging sounder and a common module imaging spectral radiometer. Other topics discussed include the performance and application of an intensified linear self-scanned array instrument, tunable optical filtering using an interferometer for selective modulation, design studies for a spectrally agile staring sensor system, and acousto-optic tunable filters for high-resolution spectral analysis.

  19. Environmental I.D.E.A.S. Clusters 10, 11, 12, Physical Sciences. Preliminary Edition.

    ERIC Educational Resources Information Center

    Helmick, Robert; And Others

    Approximately 30 experiments related to environmental problems comprise this manual. The three conceptual themes under which these lessons are organized deal with: (1) change; (2) the interaction of custom, rule, and law in society; and (3) economy, life style, and individual attitudes. Provided are materials for both students and teachers.…

  20. Strand IV Environmental and Community Health, World Health, Grades 10, 11, and 12.

    ERIC Educational Resources Information Center

    New York State Education Dept., Albany. Bureau of Secondary Curriculum Development.

    Special attention to the implications of world health problems and the effectiveness of international understanding and cooperation in alleviating harmful health conditions is given in this prototype curriculum for grades 10-12. The importance of student participation and ultimate involvement and commitment to world health problems is reflected.…

  1. Optical space communication II; Proceedings of the Meeting, Munich, Germany, June 10, 11, 1991

    NASA Astrophysics Data System (ADS)

    Franz, Juergen

    1991-05-01

    The present conference discusses the European SILEX project for optical space communications (OSP), Japanese activities in OSPs, deep-space OSP, a high data-rate interorbit link based on diode-pumped Nd:YAG laser technology, an electrooptic modulator for high-speed Nd:YAG laser communications, an unobscured mirror telescope for telecommunications, and optical carrier modulation by integrated optical devices in lithium niobate. Also discussed are micromachined scanning mirrors for laser-beam deflection, coherent optical fiber communications, a 90-deg optical hybrid for coherent receivers, economic factors relevant to an OSP, the effect of microaccelerations on an OSP terminal, and a novel fiber-optics-based conical scan-tracking device.

  2. Surface characterization and testing II; Proceedings of the Meeting, San Diego, CA, Aug. 10, 11, 1989

    NASA Technical Reports Server (NTRS)

    Greivenkamp, John E. (Editor); Young, Matt (Editor)

    1989-01-01

    Various papers on surface characterization and testing are presented. Individual topics addressed include: simple Hartmann test data interpretation, optimum configuration of the Offner null corrector, system for phase-shifting interferometry in the presence of vibration, fringe variation and visibility in speckle-shearing interferometry, functional integral representation of rough surfaces, calibration of surface heights in an interferometric optical profiler, image formation in common path differential profilometers, SEM of optical surfaces, measuring surface profiles with scanning tunneling microscopes, surface profile measurements of curved parts, high-resolution optical profiler, scanning heterodyne interferometer with immunity from microphonics, real-time crystal axis measurements of semiconductor materials, radial metrology with a panoramic annular lens, surface analysis for the characterization of defects in thin-film processes, Spacelab Optical Viewport glass assembly optical test program for the Starlab mission, scanning differential intensity and phase system for optical metrology.

  3. Health Education: Cancer Prevention and Control. Curriculum Guides, Grades 10, 11, and 12.

    ERIC Educational Resources Information Center

    New York State Education Dept., Albany. Curriculum Development Center.

    These curriculum guidelines for tenth-, eleventh-, and twelfth-grade students discuss the prevention, early detection and treatment, and control of cancer. The nature of cancer, the epidemiological factors related to it, the types of treatments available, and rehabilitation of cancer victims are discussed. Finally, the unit discusses personal and…

  4. 15 CFR 10.11 - Revision or amendment of a standard.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... established public policy; or (3) The standard or any part of it is being used to mislead users or consumers or is determined to be against the interest of users, consumers, or the public in general. (b) A... to the standard with appropriate dissemination and public notice of the addendum; and (iii) If...

  5. 15 CFR 10.11 - Revision or amendment of a standard.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... established public policy; or (3) The standard or any part of it is being used to mislead users or consumers or is determined to be against the interest of users, consumers, or the public in general. (b) A... to the standard with appropriate dissemination and public notice of the addendum; and (iii) If...

  6. 15 CFR 10.11 - Revision or amendment of a standard.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... established public policy; or (3) The standard or any part of it is being used to mislead users or consumers or is determined to be against the interest of users, consumers, or the public in general. (b) A... to the standard with appropriate dissemination and public notice of the addendum; and (iii) If...

  7. 15 CFR 10.11 - Revision or amendment of a standard.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... established public policy; or (3) The standard or any part of it is being used to mislead users or consumers or is determined to be against the interest of users, consumers, or the public in general. (b) A... to the standard with appropriate dissemination and public notice of the addendum; and (iii) If...

  8. Strand IV Environmental and Community Health, Ecology and Epidemiology of Health, Grades 10, 11, and 12.

    ERIC Educational Resources Information Center

    New York State Education Dept., Albany. Bureau of Secondary Curriculum Development.

    A frame of reference concerning health implications, based on the interaction of numerous factors in the physical, social, and biological environments, is provided in this prototype curriculum for grades 10-12. Development of sound techniques in problem solving is encouraged, resulting from the need to understand the nature and complexities of…

  9. Can Direct Collapse Black Holes Launch Gamma-Ray Bursts and Grow to Supermassive Black Holes?

    NASA Astrophysics Data System (ADS)

    Matsumoto, Tatsuya; Nakauchi, Daisuke; Ioka, Kunihito; Heger, Alexander; Nakamura, Takashi

    2015-09-01

    The existence of black holes (BHs) of mass ˜ {10}9 {M}⊙ at z≳ 6 is a big puzzle in astrophysics because even optimistic estimates of the accretion time are insufficient for stellar-mass BHs of ˜ 10 {M}⊙ to grow into such supermassive BHs. A resolution of this puzzle might be the direct collapse of supermassive stars with mass M˜ {10}5 {M}⊙ into massive seed BHs. We find that if a jet is launched from the accretion disk around the central BH, the jet can break out of the star because of the structure of the radiation-pressure-dominated envelope. Such ultralong gamma-ray bursts with duration of ˜ {10}4-106 s and flux of 10-11-10-8 erg s-1 cm-2 could be detectable by Swift. We estimate an event rate of ≲ 1 {{yr}}-1. The total explosion energy is ≳1055-{10}56 {erg}. The resulting negative feedback delays the growth of the remnant BH by about 70 {Myr} or evacuates the host galaxy completely.

  10. Reproducibility of ERG responses obtained with the DTL electrode.

    PubMed

    Hébert, M; Vaegan; Lachapelle, P

    1999-03-01

    Previous investigators have suggested that the DTL fibre electrode might not be suitable for the recording of replicable electroretinograms. We present experimental evidence that when used adequately, this electrode does permit the recording of highly reproducible retinal potentials.

  11. Meeresalgen von Helgoland: Zweite Ergänzung

    NASA Astrophysics Data System (ADS)

    Kornmann, P.; Sahling, P.-H.

    1994-12-01

    This investigation complements two previous publications by Kornmann & Sahling [1977, 1983]. The paper summarizes floristic changes that have taken place in the marine macroalgal flora of Helgoland, North Sea, over the past 100 years. Moreover, taxonomical and, partly, life history data are given on 5 genera of green algae, e.g. Ulva, including the description of a new species, Ulva tenera; 5 genera of brown algae, e.g. Fucus ceranoides, Sargassum muticum, both species being new records for Helgoland; and 6 genera of red algae, e.g. Porphyra; Mastocarpus stellatus, which is also a new record for Helgoland.)

  12. Recommendations for a toxicological screening ERG procedure in laboratory animals.

    PubMed

    Rosolen, Serge G; Rigaudière, Florence; Le Gargasson, Jean-François; Brigell, Mitchell G

    2005-01-01

    Electroretinography, using laboratory animals, is a commonly used technique for determining the retinal toxicity of chemical agents. In this paper, guidelines for performing this test are provided. The physiologic basis for visual testing is presented with attention to inter-species differences. Technical aspects of animal recordings are reviewed, including animal preparation, stimulation, signal conditioning, recording and data analysis. Finally, suggested protocols for recording in diurnal and nocturnal species are presented. PMID:16249957

  13. Suzaku Observation of the Unidentified Very High Energy Gamma-Ray Source HESS J1702-420

    NASA Astrophysics Data System (ADS)

    Fujinaga, Takahisa; Bamba, Aya; Dotani, Tadayasu; Ozaki, Masanobu; Pü:Hlhofer, Gerd; Wagner, Stefan; Reimer, Olaf; Funk, Stefan; Hinton, Jim

    2011-11-01

    A deep X-ray observation of the unidentified very high energy (VHE) gamma-ray source HESS J1702-420, for the first time, was carried out by Suzaku. No bright sources were detected in the XIS field of view (FOV), except for two faint point-like sources. The two sources, however, are considered not to be related to HESS J1702-420, because their fluxes in the 2-10 keV band (˜10-14 erg s-1 cm-2) are ˜3 orders of magnitude smaller than the VHE gamma-ray flux in the 1-10 TeV band (FTeV = 3.1 × 10-11 erg s-1 cm-2). We compared the energy spectrum of diffuse emission, extracted from the entire XIS FOV with those from nearby observations. If we consider the systematic error of background subtraction, no significant diffuse emission was detected with an upper limit of FX < 2.7 × 10-12 erg s-1 cm-2 in the 2-10 keV band for an assumed power-law spectrum of Γ = 2.1 and a source size same as that in the VHE band. The upper limit of the X-ray flux is twelve-times as small as the VHE gamma-ray flux. The large flux ratio (FTeV/FX) indicates that HESS J1702-420 is another example of a ``dark'' particle accelerator. If we use a simple one-zone leptonic model, in which VHE gamma-rays are produced through inverse Compton scattering of the cosmic microwave background and interstellar far-infrared emission, and the X-rays via the synchrotron mechanism, an upper limit of the magnetic field (1.7μG), is obtained from the flux ratio. Because the magnetic field is weaker than the typical value in the galactic plane (3-10 νG), the simple one-zone model may not work for HESS J1702-420 and a significant fraction of the VHE gamma-rays may originate from protons.

  14. Fermi-LAT constraints on the pulsar wind nebula nature of HESS J1857+026

    NASA Astrophysics Data System (ADS)

    Rousseau, R.; Grondin, M.-H.; Van Etten, A.; Lemoine-Goumard, M.; Bogdanov, S.; Hessels, J. W. T.; Kaspi, V. M.; Arzoumanian, Z.; Camilo, F.; Casandjian, J. M.; Espinoza, C. M.; Johnston, S.; Lyne, A. G.; Smith, D. A.; Stappers, B. W.; Caliandro, G. A.

    2012-08-01

    Context. Since its launch, the Fermi satellite has firmly identified 5 pulsar wind nebulae plus a large number of candidates, all powered by young and energetic pulsars. HESS J1857 + 026 is a spatially extended γ-ray source detected by H.E.S.S. and classified as a possible pulsar wind nebula candidate powered by PSR J1856 + 0245. Aims: We search for γ-ray pulsations from PSR J1856+0245 and explore the characteristics of its associated pulsar wind nebula. Methods: Using a rotational ephemeris obtained from the Lovell telescope at Jodrell Bank Observatory at 1.5 GHz, we phase-fold 36 months of γ-ray data acquired by the Large Area Telescope (LAT) aboard Fermi. We also perform a complete γ-ray spectral and morphological analysis. Results: No γ-ray pulsations were detected from PSR J1856+0245. However, significant emission is detected at a position coincident with the TeV source HESS J1857 + 026. The γ-ray spectrum is well described by a simple power-law with a spectral index of Γ = 1.53 ± 0.11stat ± 0.55syst and an energy flux of G(0.1-100 GeV) = (2.71 ± 0.52stat ± 1.51syst) × 10-11 erg cm-2 s-1. The γ-ray luminosity is LPWNγ (0.1-100 GeV)=(2.5 ± 0.5stat ± 1.5syst) × 1035 (d/9 kpc)2 erg s-1, assuming a distance of 9 kpc. This implies a γ-ray efficiency of ~5% for Ė = 4.6 × 1036 erg s-1, in the range expected for pulsar wind nebulae. Detailed multi-wavelength modeling provides new constraints on its pulsar wind nebula nature.

  15. Multiwavelength Observations of the Very High Energy Blazar 1ES 2344+514

    NASA Astrophysics Data System (ADS)

    Acciari, V. A.; Aliu, E.; Arlen, T.; Aune, T.; Beilicke, M.; Benbow, W.; Boltuch, D.; Bugaev, V.; Cannon, A.; Ciupik, L.; Cogan, P.; Colin, P.; Dickherber, R.; Falcone, A.; Fegan, S. J.; Finley, J. P.; Fortin, P.; Fortson, L. F.; Furniss, A.; Gall, D.; Gillanders, G. H.; Grube, J.; Guenette, R.; Gyuk, G.; Hanna, D.; Holder, J.; Horan, D.; Hui, C. M.; Humensky, T. B.; Imran, A.; Kaaret, P.; Karlsson, N.; Kertzman, M.; Kieda, D.; Kildea, J.; Konopelko, A.; Krawczynski, H.; Krennrich, F.; Lang, M. J.; LeBohec, S.; Maier, G.; Moriarty, P.; Mukherjee, R.; Ong, R. A.; Otte, A. N.; Pandel, D.; Perkins, J. S.; Pichel, A.; Pohl, M.; Quinn, J.; Ragan, K.; Reynolds, P. T.; Rose, H. J.; Schroedter, M.; Sembroski, G. H.; Smith, A. W.; Steele, D.; Swordy, S. P.; Theiling, M.; Toner, J. A.; Varlotta, A.; Vassiliev, V. V.; Vincent, S.; Wagner, R.; Wakely, S. P.; Ward, J. E.; Weekes, T. C.; Weinstein, A.; Weisgarber, T.; Williams, D. A.; Wissel, S.; Wood, M.; Zitzer, B.

    2011-09-01

    Multiwavelength observations of the high-frequency-peaked blazar 1ES 2344+514 were performed from 2007 October to 2008 January. The campaign represents the first contemporaneous data on the object at very high energy (VHE, E >100 GeV) γ-ray, X-ray, and UV energies. Observations with VERITAS in VHE γ-rays yield a strong detection of 20σ with 633 excess events in a total exposure of 18.1 hr live time. A strong VHE γ-ray flare on 2007 December 7 is measured at F(>300 GeV) = (6.76 ± 0.62) × 10-11 photons cm-2 s-1, corresponding to 48% of the Crab Nebula flux. Excluding this flaring episode, nightly variability at lower fluxes is observed with a time-averaged mean of F(>300 GeV) = (1.06 ± 0.09) × 10-11 photons cm-2 s-1 (7.6% of the Crab Nebula flux). The differential photon spectrum between 390 GeV and 8.3 TeV for the time-averaged observations excluding 2007 December 7 is well described by a power law with a photon index of Γ = 2.78 ± 0.09stat ± 0.15syst. On the flaring night of 2007 December 7 the measured VHE γ-ray photon index was Γ = 2.43 ± 0.22stat ± 0.15syst. Over the full period of VERITAS observations contemporaneous X-ray and UV data were taken with Swift and RXTE. The measured 2-10 keV flux ranged by a factor of ~7 during the campaign. On 2007 December 8 the highest ever observed X-ray flux from 1ES 2344+514 was measured by Swift X-ray Telescope at a flux of F(2-10 keV) = (6.28 ± 0.31) × 10-11 erg cm-2 s-1. Evidence for a correlation between the X-ray flux and VHE γ-ray flux on nightly timescales is indicated with a Pearson correlation coefficient of r = 0.60 ± 0.11. Contemporaneous spectral energy distributions (SEDs) of 1ES 2344+514 are presented for two distinct flux states. A one-zone synchrotron self-Compton (SSC) model describes both SEDs using parameters consistent with previous SSC modeling of 1ES 2344+514 from non-contemporaneous observations.

  16. Tropic Responses of Funaria Spores to Red Light

    PubMed Central

    Jaffe, Lionel; Etzold, Helmut

    1965-01-01

    The tropic responses of Funaria hygrometrica spores to continuous illumination with red light (610 to 690 mμ) have been studied over the intensity range from 10-5 through 10+6 erg/cm2 second, using both plane polarized light and partial illumination with unpolarized light. From the relative frequency of outgrowth origin in different directions, the following is inferred. (1). The germination direction of chloronemal filaments is directly influenced by red light over this whole intensity range, while that of rhizoids tends to be opposite the chloronema. (2) Three photoreceptor systems direct chloronemal primordia: (a) A low intensity system acting from 10-5 to 10-0.5 erg/cm2 second. It favors their growth from a cell's brightest part(s). Its photoreceptors are disoriented, excited by the electric vector, and probably are dispersed phytochrome molecules. (b) A medium intensity system which acts largely alone only at 100.5 erg/cm2 second but is influential from 100 to 105 erg/cm2 second. It likewise favors growth from a cell's brightest part(s); its receptor molecules are also excited electrically, but they are tangentially oriented. (c) A high intensity system which acts alone from 105 to 106 erg/cm2 second and is influential down to 101 erg/cm2 second. It favors growth of the chloronemas from a cell's darkest part. Its receptors probably are magnetically excited and tangentially oriented. The polarotropic responses of the chloronemas resemble those directing their origins. One new feature is that under intense (106 erg/cm2 second) plane polarized and vertically directed light, many soon grow to form tight helices. ImagesFigure 1Figure 2Figure 14Figure 15 PMID:5863438

  17. Strand I - Physical Health; Disease Prevention and Control for Grades 10, 11, and 12. Special Edition for Evaluation and Discussion.

    ERIC Educational Resources Information Center

    New York State Education Dept., Albany. Bureau of Secondary Curriculum Development.

    This health curriculum guide, intended for use in grades ten through twelve, addresses itself to disease prevention and control concepts which are particularly relevant to the adolescent's physical health needs. The contents of the guide are presented in outline form and cover source of injection, preventing the spread of communicable diseases,…

  18. Proceedings of the Eastern Region Annual Research Conference in Agricultural Education (Easton, Maryland, May 10-11, 1985).

    ERIC Educational Resources Information Center

    1985

    Twelve major papers delivered during this conference on agricultural education in the Northeastern states are included in this volume: (1) "Status of Pennsylvania Special Needs Students in Vocational Agriculture: Phase IV--Job Performance Follow-Up," by Dennis C. Scanlon and Connie D. Baggett; (2) "Education, Age and Experience: Their Correlation…

  19. Interdisciplinary Student/Teacher Materials in Energy, the Environment, and the Economy: Agriculture, Energy, and Society, Grades 10, 11, 12.

    ERIC Educational Resources Information Center

    Brock, Phyllis; And Others

    This interdisciplinary instructional unit contains eleven lessons for grades 10-12 which focus on the energy component of food production. There are lessons which contrast food production systems in various cultures and also lessons which look at different systems and techniques in use in this country. There are lessons dealing with organic…

  20. Real-time signal processing XII; Proceedings of the Meeting, San Diego, CA, Aug. 10, 11, 1989

    SciTech Connect

    Letellier, J.P.

    1989-01-01

    The conference addresses trends in electronic implementations, algorithms and architectures for signal processing, optical processors, and trends in optical processing. Papers on optical point-to-point interconnections and their use in neural nets are included, along with works dealing with both the general use of neural nets and the specific use of specialized neural nets in system applications. A series of papers on the computation of two-dimensional Fourier transforms is found in the proceedings, as well as works on programing methods for crystallography, fast mapping of gravity equations on a linear array, adaptive signal processing using a liquid-crystal television, and hybrid digital-optical processors. Focus is placed on electrooptical implementations for two-dimensional array neural nets, radar imaging using the Wigner-Ville distribution, a recursive optical notching filter, and parallel algorithms for automatic target identification using CO{sub 2}-laser radar imagery.