Aviation Logistics Support in the United States Coast Guard: An Assessment of Management and Cost-Effectiveness

DTIC Science & Technology

1993-01-01

34 with air stations, with DoD support sources, with AR&SC, with other USCG Headquarters elements, with commercial vendors, and with research and...STRATEGY FOR THE FUTURE Based on our research , knowledge of other aviation logistics support programs, and analysis of the USCG’s program, we believe that...concerted effort to develop and refine the maintenance and supply data the model uses. That effort should include ditermining the basic Ao requirement and

Operation DOMINIC I-1962.

DTIC Science & Technology

1983-02-01

ISLAND DANGER AREA IS A CIRCLE WITH RADII" JOHNSTON ISLAND (1) 470 nm- ( 871 km) 30 APRIL-12 JUNE 1962 AND DANGER AREA 22 SEPTEMBER-1S OCTOBER 1962 (21...AFCRL. Prolect Report: Reference C. 2018 . .I Project 6.4 -- E- and F-Region Physical Chemistry Agencies: Air Force Cambtidge Research Laboratory (AFCRL...1076) USS RECLAIMER (ARS-42) LISSTO LOVANA (AO- 64) 0USS GURKE (00-783) 2 - USS HALSEY POWELL (DO-686) aJ H I TM SI L N SURFACE ZERO S10- 0 30 60 Go

Dynamic Characteristics of Human Motor Performance in Control Systems.

DTIC Science & Technology

1979-01-01

h drynontrol system . Several lines of inves ___ igaion avebee use inaddiionto nputoutut sudis wth hmansubets LI.- 7 Th (nulreycmriigifrainfosusl...TAB Untjc. ao un c ’ n TTci St rLi b DYNAMIC CHARACTERISTICS OF HUMAN MOTOR PERFORMANCE IN CONTROL SYSTEMS %iOSRTR. 8-0 76 0 Ar3) -O75 -8’O’f FINAL...whereby motor patterns are represented in the nervous system . Findings include a detailing of linear and non-linear features of motor activity in

Iran-Regional Country Study.

DTIC Science & Technology

1982-04-16

AO-A116 226 ARMY WAR COLL CARLISLE BARRACKS PA F/6 5/4 IRAN-REGIONAL C OUNTRY STUDY.IUI UNCLASSIFIED AR8 AE I m I I..h EE f ii111112.0...ORGANIZATION NAME AND ADDRESS 10. PROGRAM ELEMENT, PROJECT. TASK AREA & WORK UNIT NUMBERS US Army War College Carlisle Barracks, PA 17013 11. CONTROLLING...PAGE(WIFhIf Date REmfot)J Bi9 US ARMY WAR COLLEGE INDIVIDUAL RESEARCH BASED ESSAY The views xpressed in this paper are those of the author and do not

Flame-ion chemistry of the lanthanide metals Ce, Pr and Nd

NASA Astrophysics Data System (ADS)

Patterson, Patricia M.; Goodings, John M.

1996-01-01

A pair of premixed, H2---O2---Ar flames of fuel-rich (FR) and fuel-lean (FL) composition, both at atmospheric pressure and 2425 K, were doped with about 10-6 mol fraction of the lanthanide metals La, Ce, Pr and Nd; from a previous study, La was used as a benchmark. The metals produce solid particles in the flames and gaseous metallic species. The latter include metallic atoms A near the flame reaction zone, but only the monoxide AO, the oxide hydroxide OAOH and, in some cases, the dioxide AO2 further downstream at equilibrium. Metallic ions (< 1% of the total metal) were observed by sampling the flames through a nozzle into a mass spectrometer. All of the observed ions can be represented by four hydrate series: (a) major signals of AO+·nH2O (n = 0-3) for La, Ce, Pr and Nd; (b) small signals of AO2H+·nH2O (n = 0-2) for Ce, Pr and Nd; (c) still smaller signals of AO2+·nH2O (n = 0, 1) for Ce, Pr and Nd in the FL flame only; and (d) tiny signals of AOH+·nH2O (n = 0, 1) for Pr and Nd in the FR flame only. The actual structures of some of these ions may not correspond to simple hydrates: e.g. AO+·H2O = A(OH)2+ = protonated OAOH; AO2H+·H2O = A(OH)3+, etc. Since hydrogen flames contain essentially no natural ionization, a major objective was to consider probable ionization mechanisms for the metals. The primary reactions include both chemi-ionization, and thermal (collisional) ionization of AO whose ionization energy is low (about 5 eV). Some of the ions are formed by secondary ion/molecule reactions including three-body hydration, proton transfer, electron (charge) transfer, H atom abstraction by radicals and oxidation. In addition, the chemical ionization of the metallic species by H3O+ was investigated. The flame-ion chemistry of these metals is discussed in detail.

Batch and column studies on biosorption of acid dyes on fresh water macro alga Azolla filiculoides.

PubMed

Padmesh, T V N; Vijayaraghavan, K; Sekaran, G; Velan, M

2005-10-17

The biosorption of Acid red 88 (AR88), Acid green 3 (AG3) and Acid orange 7 (AO7) by deactivated fresh water macro alga Azolla filiculoides was investigated in batch mode. Langmuir and Freundlich adsorption models were used for the mathematical description of the batch biosorption equilibrium data and model constants were evaluated. The adsorption capacity was pH dependent with a maximum value of 109.0 mg/g at pH 7 for AR88, 133.5 mg/g at pH 3 for AG3 and 109.6 mg/g at pH 3 for AO7, respectively, was obtained. The pseudo first and second order kinetic models were also applied to the experimental kinetic data and high correlation coefficients favor pseudo second order model for the present systems. The ability of A. filiculoides to biosorb AG3 in packed column was also investigated. The column experiments were conducted to study the effect of important design parameters such as initial dye concentration (50-100 mg/L), bed height (15-25 cm) and flow rate (5-15 mL/min) to the well-adsorbed dye. At optimum bed height (25 cm), flow rate (5 mL/min) and initial dye concentration (100 mg/L), A. filiculoides exhibited 28.1mg/g for AG3. The Bed Depth Service Time model and the Thomas model were used to analyze the experimental data and the model parameters were evaluated.

Principles of Organization in Intuitive and Analytical Cognition.

DTIC Science & Technology

1981-02-15

t al., 1980, for comment). These strategies are organizing principles , or heuristics, that are "good enough." Such organizing principles are to Le ...AD-AO% 570 COLOADO UNIV AT BOULDER CENTER FOR RESEARCH ON JUD -ETC F/6 5/10 PRINCIPLES OF ORGANIZATION IN INTUITIVE AND ANALYTICAL COGNITIO-ETC(U...X’i 2k7 I S 3 U A CENTRFO RE&AR LEVEL 7 PRINCIPLES OF 6RGANIZATION IN INTUITIVE AND ANAL.2ICAL COGNITION Kenneth R./Hammond j Acession For I’IT GRA&I

Light Emitting Diodes for Fiber Optic Communications.

DTIC Science & Technology

1981-03-31

asC.3~~ in.(c)- above and do- (1) pcait by volu.3 of dicst.iLle =zto.- Pazo 10 .61Edd, tcxcopt colvonts used cha-l bo: * ( a ) Methyl. alcohbl I7or 04...AD £101 480 LASER DIODE LABS INC NEW BRUNSWICK NJ / 1 / L I GT EMITTING DIODES FOR FIBER OPTIC COWMICATIONS.Cul AR, at A GENNARO DAARO-76-C-813 NA 1...PRArrcmA. P . 1"UNISPE-D TO DDC CONTAINE A II&~-’llryBE v., R OF :AO , MflG DO 9W CORADCOM U S ARMY COMMUNICATIONS RESEARCH 9 DEVELOPMENT COMMAND

Long-Term Valve Performance of TAVR and SAVR: A Report From the PARTNER I Trial.

PubMed

Daubert, Melissa A; Weissman, Neil J; Hahn, Rebecca T; Pibarot, Philippe; Parvataneni, Rupa; Mack, Michael J; Svensson, Lars G; Gopal, Deepika; Kapadia, Samir; Siegel, Robert J; Kodali, Susheel K; Szeto, Wilson Y; Makkar, Raj; Leon, Martin B; Douglas, Pamela S

2016-12-08

The aim of this study was to evaluate the long-term performance of transcatheter aortic valve replacement (TAVR) and surgical aortic valve replacement (SAVR) through longitudinal echocardiographic analysis. The long-term performance of the SAPIEN TAVR is not well-described. Therefore, we examined the hemodynamic and valvular profile of the SAPIEN TAVR over 5 years. All patients receiving TAVR or SAVR with first post-implant (FPI) and 5-year echoes were analyzed for aortic valve (AV) peak velocity, AV mean gradient, AV area, peak left ventricular (LV) outflow tract and in-stent velocities, Doppler velocity index, aortic regurgitation (AR), LV mass index, stroke volume index, and cardiac index. The FPI and 5-year data were compared using a paired t test or McNemar's analyses. There were 86 TAVR and 48 SAVR patients with paired FPI and 5-year echocardiograms. Baseline characteristics were similar between groups. The AV area did not change significantly 5 years after TAVR (p = 0.35). The AV mean gradient also remained stable: 11.5 ± 5.4 mm Hg at FPI to 11.0 ± 6.3 mm Hg at 5 years (p = 0.41). In contrast, the peak AV and LV outflow tract velocities decreased (p = 0.03 and p = 0.008, respectively), as did in-stent velocity (p = 0.015). Correspondingly, the TAVR Doppler velocity index was unchanged (p = 0.07). Among TAVR patients, there was no change in total AR (p = 0.40), transvalvular AR (p = 0.37), or paravalvular AR (p = 0.26). Stroke volume index and cardiac index remained stable (p = 0.16 and p = 0.25, respectively). However, there was a significant regression of LV mass index (p < 0.0001). The longitudinal evaluation among SAVR patients revealed similar trends. There was a low rate of adverse events among TAVR and SAVR patients alive at 5 years. Longitudinal assessment of the PARTNER I trial (THE PARTNER TRIAL: Placement of AoRTic TraNscathetER Valve Trial) demonstrates that valve performance and cardiac hemodynamics are stable after implantation in both SAPIEN TAVR and SAVR in patients alive at 5 years. (THE PARTNER TRIAL: Placement of AoRTic TraNscathetER Valve Trial; NCT00530894). Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Computer Programs for Producing Single-Event Aircraft Noise Data for Specific Engine Power and Meteorological Conditions for Use with USAF (United States Air Force) Community Noise Model (NOISEMAP).

DTIC Science & Technology

1983-04-01

containing the atmospheric ab- sorption coefficients in dB per 1000 for standard day temperature and relative humidity. ATN8(24) Atmospheric...t L% Ias0% ar.. r- N0%aO CD -F PFa -N CaN.F F-S I-.6 0CP-. NF O3rIl DN X C CP.4 (a.,MJ-Nft In0 0N M66 %L 0% P- .FK..4 N t-4 DC2 a OAa*A e Sn U fU 4 0

Prime Contract Awards Alphabetically by Contractor, by State or Country, and Place, Fiscal Year 1987. Part 6. Donnegan Systems, Incorporated-Fairfield Machine Company, Incorporated.

DTIC Science & Technology

1987-01-01

go- 0 00 0C0 C 00 000 00 0 10 CC I M .COCO Z- - - r-F P- -- rI , zt zt ,r - z - z - - I-- Zol I MOOC I,4-~- CON-00N <C 0-4 00- 4 00 <o C4-4-- 00040-4...InI 1 - In I- P. - --f- 1( ar - -r 1 P rf- -QvQv0vf- - - 0L I W I (AO MOOC Ll 70 CAC co V)00 0 n 0 0120000CO0 (10000 V) 00 0 (.12 00 0 0000

Estudo comparativo entre estrelas centrais de nebulosas planetárias deficientes em hidrogênio

NASA Astrophysics Data System (ADS)

Marcolino, W. L. F.; de Araújo, F. X.

2003-08-01

Apresentamos neste trabalho o resultado de um estudo das principais características espectrais das estrelas centrais de nebulosas planetárias (ECNP) deficientes em hidrogênio. A origem e a evolução dessas estrelas ainda constitui um problema em aberto na evolução estelar. Geralmente esses objetos são divididos em [WCE], [WCL] e [WELS]. Os tipos [WCE] e [WCL] apresentam um espectro típico de uma estrela Wolf-Rayet carbonada de população I e as [WELS] apresentam linhas fracas de carbono e oxigênio em emissão. Existem evidências que apontam a seguinte sequência evolutiva : [WCL] = > [WCE] = > [WELS] = > PG 1159 (pré anã-branca). No entanto, tal cenário apresenta falhas como por exemplo a falta de ECNP entre os tipos [WCL] e [WCE]. Baseados em uma amostra de 24 objetos obtida no telescópio de 1.52m em La Silla, Chile (acordo ESO/ON), ao longo do ano 2000, apresentamos os resultados da comparação das larguras equivalentes de diversas linhas relevantes entre os tipos [WCL], [WCE] e [WELS]. Verificamos que nossos dados estão de acordo com a sequência evolutiva. Baseado nas linhas de C IV, conseguimos dividir pela primeira vez as [WELS] em dois grupos principais. Além disso, os dados reforçam a afirmação de que as [WCE] são as estrelas que possuem a maior temperatura entre as ECNP deficientes em hidrogênio. Discutimos ainda, a escassez de dados disponíveis na literatura e a necessidade da obtenção de parametros físicos para estes objetos.

Compendium of Shock Wave Data. Volume 2, Revision 1. Section A2. Inorganic Compounds Section B. Hydrocarbons

DTIC Science & Technology

1977-06-01

5K9AR uret 14’T17 TABLE I TUNGSTEN CARBIDE 53-23--- 1 B i 5 4fL 3 2 0 int IU aF n PAGE 4011.1 ś-1---I RUtILFr. CRYSTAL AND NATURAL (TIIANIUM OXIDCl...COtMIENTS : I I SOURCE: KOIR1ER. 5. B .. SINITSYN. M, V., ruNIIKOV. A, I., UR1. IN. V, a. AND BLINOV . A. V. SOVIET PHYS-.JIEP. VOL. 20. P. 911 119651...AO Uii Coaapendiux of* ýIoek Wave Daa.3otion A2. Inorganuic Compounds. Oection B , "r~iooarbona. ______________ I. Ca"TRACT 09GOAMY wmuimea Lawrt

A teoria da percolação aplicada às galáxias aneladas peculiares

NASA Astrophysics Data System (ADS)

Poppe, P. C. R.; Martin, V. A. F.; de Medeiros, N. G. F.; Faúndez-Abans, M.; Oliveira-Abans, M.

2003-08-01

Formulado no final da década de 50, o modelo de percolação concentra-se em descrever o meio poroso, que será visto neste trabalho como uma rede de canais aleatórios, por onde escoa um fluido determinístico. Se o número de canais for suficientemente grande, então eles estarão ligados e o meio se tornará permeável à passagem do fluido. Neste caso, dizemos que houve a percolação do fluido. Reformulando o modelo acima, podemos escrever um código particularmente adaptado para simulações em Galáxias, onde iremos supor que os canais formam um reticulado, e que cada sítio da rede representa um poro que será interpretado como uma região ativa de formação estelar. Para cada elo teremos um pequeno canal ligando dois sítios vizinhos, que poderá, após um tempo "t", induzir ou não a formação de uma região ativa no poro vizinho. Para simular a passagem desta região ativa através dos poros, diremos que um elo está aberto com probabilidade p e fechado com probabilidade 1-p. Dessa forma, passamos a imaginar configurações de elos abertos e fechados, onde cada configuração ocorre com uma certa probabilidade, dada por p|A|(1-p)|F|, onde |A| é o número de elos abertos e |F| o número de elos fechados da configuração. A expressão anterior só tem importância física se |A| e |F| forem ambos finitos, pois, caso contrário, a probabilidade de ocorrência de uma dada configuração será sempre nula. Neste trabalho, foram considerados dados cinemáticos publicados na literatura bem como aqueles obtidos pelos autores a partir de observações fotométricas realizadas no Observatório de Las Campanãs, em 1994, para a Galáxia Anelada Peculiar HRG 03401. Mostraremos que para certos valores de p, situados entre 0,5 e 0,6, os clusters assim formados irão simular, de maneira coerente, o referido objeto.

Prime Contractors with Awards Over $25,000 by Name, Location, and Contract Number, Fiscal Year 1992 (Daubert Industries, Inc.-Gaylord Industries, Inc.)

DTIC Science & Technology

1993-01-01

a0 m~ ar (0 - a 0 a4 04 H50 4 a 4 C-1 am a C3 L) 0ý an 0 a n c Za4 00 C.ým 4Lo j I N O Nol 0IS)0 cl r- m - anNe t"I ý ý Ll2 an N -z Do~ acca -fN- 0a’J...c to aQ Coo," I "o o) " ’ mC, ,I e nnI to a) ammc)oc Il I I L) o c wo x I Ca u m2 a. U r-7f cc ~ nl.< C0C) -*4~-0na-ao " 0 ELI ao (v acCa ’’ a~al~ nal...Fw IE~ 1. E F1 F4 o F. c4I F 4 F OF. F7 )I - F ~-4 .F 4 F 41) w 10 A F F W)( o4 v7- m ’mo7 l T =444 45 o o .7 c> S . o Lc4 mo - 04 NNr a)0 lo 7 1 7 o

IAU South West Asian ROAD

NASA Astrophysics Data System (ADS)

Mickaelian, Areg; Azatyan, Naira; Farmanyan, Sona; Mikayelyan, Gor

2016-10-01

Armenia is hosting the IAU South West Asian (SWA) Regional Office of Astronomy for Development (ROAD). It is a county of ancient astronomy and is also rich in modern astronomical facilities and infrastructures, hence may successfully serve as a regional center for various activities. Byurakan Astrophysical Observatory (BAO) has 2.6m and 1m Schmidt, as well as a number of smaller telescopes that are an observational basis for joint projects and collaborations. Armenian Virtual Observatory (ArVO) is hosting astronomical databases, such as the Digitized First Byurakan Survey (DFBS) and may also serve as a basis for development of VO structures in this region. Recently we have conducted a number of new activities; a meeting on ``Relation of Astronomy to other Sciences, Culture and Society" (RASCS) was organized by BAO and Armenian Astronomical Society (ArAS) in Oct 2014 in Byurakan. Activities related to Archaeoastronomy and Astronomy in Culture (AAC) were initiated as well. Discussions on future Armenian-Iranian collaboration in astronomy were carried out, including an Armenian-Iranian Astronomical Workshop held in Oct 2015 in Byurakan. Similar workshops have been carried out between BAO and Abastumani Astronomical Observatory (AbAO, Georgia) since 1974.

On the Origins of the Recent Greenland Melt in the US 2012 Heat Wave

NASA Astrophysics Data System (ADS)

Neff, W. D.; Shupe, M.; Ralph, F. M.; Compo, G.; Turner, D. D.

2012-12-01

Recent reports had the majority of the Greenland ice sheet surface melting on 8-12 July 2012 (http://www.nasa.gov/topics/earth/features/greenland-melt.html). Even at Summit Station, the temperature reached 1Co above freezing. A companion paper (Miller et al., AGU) describes the cloud and radiation properties at Summit during this episode that affected boundary layer exchange processes. Here we describe the likely synoptic processes, coupling mid-latitudes with the polar regions, at work leading to this unusual event. These include back trajectories that originated ten days earlier in the US Midwest where 8oC surface temperature anomalies were present on 1 July and then exited over the Atlantic Ocean gaining substantial moisture in the process. Over the ocean, a thin filament of moisture transport formed at the boundary of a trough of low pressure (extending from the high Arctic) with a subtropical ridge. Such filaments are often referred to as atmospheric rivers (ARs) and account for a substantial portion of the northward transport of moisture from the tropics and extratropics (Zhu and Newell 1998 Mon. Wea. Rev.). Examination of SSMIS imagery from this event shows the evolution of this AR over several days and oriented along the path of the back-trajectory from Summit Station on 11 July. In its final stage, the AR impinged and spread along the southern coast of Greenland. Moisture content in this AR was exceptionally high for this latitude, exceeding 6 cm of vertically integrated water vapor. This event was also characterized by a distortion of the polar vortex corresponding to negative 2-sigma anomaly in the Arctic Oscillation (AO). Such melting episodes are rare over Greenland with ice-core evidence suggesting a return period averaging about 150 years with the last such episode reportedly in 1889 (http://dartmouthigert.wordpress.com/2012/07/21/new-summit-melt-layer/). Using the 20th Century Reanalysis (Compo et al., 2012), we have examined synoptic patterns present in June and July 1889 during positive anomalies in surface temperatures over this two-month period. During one such event on 30 July 1889, a strong trough-ridge pattern had set up, potentially bringing warm southerly flow from the eastern US to Greenland. One of the unique features of the most recent event was prolonged drought and high temperatures over North America during the spring and summer of 2012 - an implication being that having a persistent source of unusually warm air over North America, coupled with a relatively rare, and short-lived negative anomaly in the AO created almost perfect conditions for the warming of Greenland above the freezing point. This is one example of how an extreme event that appears to be part of the general picture of a warming Arctic may in fact have its origins in the mid-latitudes.

Hierarchical Neural Network (HNN) for Closed Loop Decision Making: Designing the Architecture of a Hierarchical Neural Network to Model Attention, Learning and Goal Oriented Behavior

DTIC Science & Technology

1990-12-01

030(M aau fr e~ re u’. ~oil(eIOE, form a::o n lit Send c f"ent lt ar nq this Ourde" "tii tor ay otther a .e n Of p, amid". to W4Vsntinlln...etadnuaeters ief’ice. 0 i 0reor Iformat.a;tio n ax; d 1 21 ;eQo Q offait of IA4naqe-m.t and Sudget. P01osoer t m edltoru Prole (07044 ,l81.’Nairil m O C NMI. I...I Application of Neural Networks to Robotics I Ziaudin Ahmnad John Selizuky Allm Gun Dmeel University, Depwunent of Electrical miCapue Engineeing

Symposium on Commercial Aviation Energy Conservation Strategies, April 2-3, 1981. Papers and Presentations

DTIC Science & Technology

1981-04-03

rfofci"ř C*;sn:a»ion *«9c" ** = ! 9 . Ptf’iofming Ofge^’ic’io1- Nj->« are Add’«»» j Department of Energy and Federal Aviation 1... 9 . These data are for a typical CAL DC-10-10 flight profile, which was determined from the data of Reference 8 to be a stage length of 1150 nm, with...I Ml a « 9 a?)i 0640 OC a») am 0 91 04) am ans a«) OM 0*5 an4 0 7M 046 a MI az« an 047 a»* ao» a is (Ml aiM o.ars am Oft 0 791 & IM a«» M0 a

Profile of thoracic trauma victims submitted to chest drainage.

PubMed

Broska, Cesar Augusto; Botelho, Adriane Barbosa; Linhares, André DE Castro; DE-Oliveria, Mariana Santos; Veronese, Gabriela; Naufel, Carlos Roberto; Batista, Lislaine Cruz; Diogo, Maria Angélica Kurpel

2017-01-01

to describe and compare the variables involved in trauma victims undergoing thoracic drainage. we conducted a retrospective, analytical, descriptive, cross-sectional study, with medical records of patients attended at the Trauma Service of the Curitiba Evangelical University Hospital between February 2011 and January 2014. there were 488 patients undergoing chest drainage, 84.7% men and 15.3% women, with an average age of 38.2 years. Attendances usually occurred at night, without predominance between open or closed mechanism, gender or age group. The majority of patients with thoracic trauma requiring drainage were diagnosed by anamnesis and physical examination (41.1%) and drained in the emergency room (80.8%). Most of the patients (66.2%) had another associated lesion, mostly some abdominal viscera. Complications were present in 16.6% (81 patients), most of them due to drainage positioning error (9.2%). The mean hospital stay was 15 days and drainage lasted for an average of 8.1 days, with no statistical difference between open and closed trauma. The clinical outcome was discharge in most cases. the profile of patients with thoracic trauma is that of young men, attended at night, with some other associated lesion. Although diagnosis and treatment were rapid and most often without the need for complex examinations, the time of drainage, hospitalization and complications were higher than in the literature, which can be explained by the drainage being made at the Emergency Room and the presence of associated injuries. descrever e comparar as variáveis envolvidas nos pacientes vítimas de trauma torácico submetidos à drenagem de tórax. estudo transversal descritivo analítico retrospectivo realizado com prontuários de pacientes atendidos no Serviço de Trauma do Hospital Universitário Evangélico de Curitiba entre fevereiro de 2011 e janeiro de 2014. neste período foram atendidos 488 pacientes, 84,7% homens e 15,3% mulheres, com média de idade de 38,2 anos. Os atendimentos geralmente ocorreram à noite sem predomínio entre mecanismo aberto ou fechado e/ou em relação ao sexo ou idade. A maioria dos pacientes com trauma torácico que necessitaram de drenagem teve diagnóstico feito por anamnese e exame físico (41,1%) e foram drenados no pronto socorro (80,8%). Grande parte dos pacientes (66,2%) teve outra lesão associada, na maioria alguma víscera abdominal. Complicações estiveram presentes em 16,6% (81 pacientes), a maior parte por erro de posicionamento do dreno (9,2%). O tempo médio de internamento foi 15 dias e de drenagem, 8,1 dias, sem diferença estatística entre trauma aberto e fechado. O desfecho clínico envolveu alta na maioria dos casos. o perfil dos pacientes com trauma torácico é o de homens jovens, atendidos durante a noite, com alguma outra lesão associada. Apesar do diagnóstico e do tratamento serem feitos de modo rápido e, na maior parte das vezes, sem a necessidade de exames complexos, o tempo de drenagem, internamento e complicações foram mais alto do que na literatura, o que pode ser explicado pela drenagem no próprio pronto-socorro e pela presença de outras lesões associadas.

SWANEA (Southwest Asia-Northeast Africa) A Climatological Study. Volume 3. The Near East Mountains

DTIC Science & Technology

1991-04-01

SHIRAZ TlRA M LAT/LON: 2f 32 N 52 35 E ELEV: 4920 FT ILIHINTS JAN jFEB J MAR IAPR [MAY IJUN JJU, JAUG ISEP JOCT I NOV j DEC IAkNNJ EXT MAX 61 i75 81...M1AR APR I MAY I JUN jJUL JAUG ISEP I OCT I NOV IDE C IANN xX 5MA1 58 69 75 " ao 921 1001 98 191 j 841 67j 57’ 100 AIVG MAX .... 13 42 5 6 76 83 1 483...o t S•TATON : ESKISEHI[R T URM-’ LAT/LOI.: 39 47 N 30 34 E ELEV: 2579 FT ELEMI.-L TS !JAN FEB IMAR IAPR iHAY JUN JUL JAUG .SEP OCT NOV IDEC I NNI EXT

Design, Fabrication, Calibration, Testing and Satellite Integration of a Space-Radiation Dosimeter.

DTIC Science & Technology

1981-12-01

on aI to tuec 11i’u te I ~ .t .r e t~tnJt IIIt Heil(-V- e Nxonknlt al Ii) ao (k Iowa rd’ t ht in i )I, ii, r’ iuie scent v-ia s p uift. i ne alipi. r...exponent are interpreted conventionally: M = m 1 + 2m2 + 4m 3 + 8m 4 + 1 6m 5 and E = e1 + 2e2 +4e 3 The minimum number of input counts required to cause a...R Q,, TE L26 INIT 0 ne One - f-..t ht shot ShoIEZTT CHI ST R,.et ST CAL ST s a D Q CAL ID mux c Hli DR I .10V R Cw DR 2 DR 3 LO. C.-H-FE DR 4 One

The 89 Ma Tortugal komatiitic suite, Costa Rica: Implications for a common geological origin of the Caribbean and Eastern Pacific region from a mantle plume

NASA Astrophysics Data System (ADS)

Alvarado, Guillermo E.; Denyer, Percy; Sinton, Christopher W.

1997-05-01

Komatiites are reported for the first time in the northern part of the Gulf of Nicoya, Costa Rica. These rocks, dated at 89.7 ± 1.4 Ma (Turonian) by 40Ar/39Ar methods, occur as a large, elongated (14 km long, 1.5 km wide) N60°W striking body in the ophiolitic Nicoya Complex. These lavas have high MgO (26% 29%), Ni, and Cr, have high CaO/Al2O3 (0.98 1.08) and moderate Al2O3/TiO2 (5.55 8.44) ratios, and are depleted in Al2O3 (4% 5.5%), K2O (0.02% 0.37%), and TiO2 (0.59% 0.9%). Although these lavas are cumulates, their geochemical composition indicates an origin from a primary komatiitic magma, with a melting temperature of 1700 °C at a depth of 150 km. Similarities in the petrology and age (88 90 Ma) of Gorgona, Curaìao, and Nicoya-Tortugal mafic and ultramafic volcanic rocks suggest that these rocks had a common origin. These occurrences suggest a single hotspot center over a large area of the Caribbean and Eastern Pacific Mesozoic region due to a major thermal anomaly in the mantle, such as a hot, rising, convective plume.

Transportation Lines on the Atlantic, Gulf, and Pacific Coasts, Transportation Series 5, 1980.

DTIC Science & Technology

1982-05-01

DIP?. 6OU009. r11 77611 7 61117 79*9290 * 79*9lP, CO. 7.O 05ll PkIIP63&, PA. t,10133 6111 CA199A M ARINIPLI0NM P el . I. M INC. NIIOP9 L0f.0 P ulf" few...iUAVA4mI LA ’UlO oIlO Ol696 S PAIN~, 4 6.. 14AR146 to ROSY TOK 4 0 *3 RA C84 ? tlO go.. INC. 1106AO6d t05m. 4lls 3 spl1olEs Ulm TRANSP64? ORO M T Fr AVlNU...BrA44 69D1164 CO . I IllF TwoI IT.?4 I OALfln, El . ile 0’-- -- 1% XXVIII TABLE 1-ALPHABETICAL LIST OF TRANSPORTATION LINES 5 OPERATOR NIE ADORES 9

Solar photoassisted advanced oxidation process of azo dyes.

PubMed

Prato-Garcia, D; Buitrón, G

2009-01-01

Advanced oxidation processes assisted with natural solar radiation in CPC type reactors (parabolic collector compound), was applied for the degradation of three azo dyes: acid orange (AO7), acid red 151 (AR151) and acid blue 113 (AB113). Fenton, Fenton like and ferrioxalate-type complexes showed to be effective for degrade the azo linkage and moieties in different extensions. Initially, the best dose of reagents (Fe(3 + )-H(2)O(2)) was determined through a factorial experimental design, next, using response surface methodologies, the reagent consumption was reduced up to 40%, maintaining in all cases high decolourisation percentages (>98%) after 60 min. of phototreatment. In this work, it was also studied the effect of concentration changes of the influent between 100-300 mg/L and the operation of the photocatalytic process near neutral conditions (pH 6.0-6.5) by using ferrioxalate type complex (FeOx).

Abundância química de simbióticas na direção do bojo galáctico

NASA Astrophysics Data System (ADS)

Luna, G. J. M.; Costa, R. D. D.

2003-08-01

O estudo da distribuição de metalicidades de gigantes K no Bojo indica um largo intervalo com valores entre 0.1 a 10 vezes o valor solar. As razões elementais Ca/Fe, Si/Fe, Mg/Fe são típicas de estrelas do halo, apontando para um processo rápido de enriquecimento, via estrelas masssivas (SN's tipo II). No entanto, este cenário não combina com os resultados derivados de nebulosas planetárias do bojo tais como os de Ratag et al. (1992, A&A,255,270), Cuisinier et al.(2000, A&A,353, 543), Escudero e Costa (2001, A&A,380, 300),que obtêm abundâncias análogas às do disco. Neste cenário, o estudo de estrelas simbióticas possibilita uma abordagem particularmente apropriada para o problema das abundâncias químicas de estrelas de massa intermediária em estágios avançados da evoluçao estelar. Apresentamos aqui os resultados da determinacão das abundâncias do grupo do CNO numa extensa amostra de simbióticas do bojo. Aliás, com a disponibilidade de espectros no visível determinamos também abundâncias de Ar, Ne, S e He, fundamentais para analisar os processos de enriquecimento químico ocorridos ao longo da evolução estelar, bem como a evolução química do meio interestelar. Com os espectros UV do satelite IUE obtivemos abundâncias de C, necessárias no estudo da evolução dos sistemas. As relaçoes C/N-O/N mostram que o material nebular é produto do vento da componente gigante e não dos eventos de nova que às vezes acontecem nestes sistemas, como foi mostrado por Nussbaumer et al (1988,A&A,198,179). As abundâncias de Ar, S, Ne e O são compativeis com resultados de fontes no disco e bojo, seguindo o gradiente proposto por muitos autores na literatura a partir de diferentes objetos como cefeidas, nebulosas planetárias e anãs G. (CAPES,FAPESP,CNPq)

Reparo de aneurisma de artéria ilíaca roto em criança

PubMed Central

Hoshiko, Fernando Massaru; Zampieri, Elisa Helena Subtil; Dalio, Marcelo Bellini; Dezotti, Nei Rodrigues Alves; Joviliano, Edwaldo Edner

2017-01-01

Resumo Relatamos o caso de uma menina de 12 anos que deu entrada na unidade de emergência com quadro de abdome agudo hemorrágico, massa abdominal pulsátil e instabilidade hemodinâmica. Confirmado o diagnóstico de aneurisma roto de artéria ilíaca direita, foi realizada correção cirúrgica de emergência por reparo aberto com reconstrução extra-anatômica, utilizando enxerto sintético de fino calibre, compatível com a anatomia. O tratamento foi bem-sucedido e a criança apresentou evolução favorável em curto prazo.

75 FR 58340 - Airworthiness Directives; Koito Industries, Ltd., Seats and Seating Systems Approved Under...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-09-24

...-105, AFS-136, AFS-235, AFS-315, ARS-183, ARS-189, ARS-190, ARS-200, ARS-242, ARS-242-TA, ARS-254, ARS-255, ARS-263, ARS-276, ARS- 277, ARS-281, ARS-289, ARS-29, ARS-29-03, ARS-304, ARS-308, ARS-311, ARS-311-A, ARS-311-B, ARS-336, ARS[dash]339, ARS-341, ARS-347 ARS-352, ARS-354, ARS-357, ARS-360, ARS-384...

Trombose venosa profunda e vírus chicungunha

PubMed Central

Marques, Marcos Arêas; Adami de Sá, Fernanda Penza; Lupi, Otília; Brasil, Patricia; von Ristow, Arno

2017-01-01

Resumo Algumas infecções virais sistêmicas podem estar relacionadas ao desenvolvimento de trombose venosa profunda e/ou embolia pulmonar. Essa associação já está bem descrita em pacientes com infeções pelo vírus da imunodeficiência humana (HIV), hepatite C ou influenza. Recentemente introduzido no continente americano, o vírus chicungunha, agente etiológico da febre de chicungunha, ainda não tem essa relação bem sedimentada, mas com o aumento progressivo de sua incidência e pelo fato dessa infecção causar, muitas vezes, uma restrição severa da locomoção por poliartralgia e uma possível lesão endotelial direta, casos de tromboembolismo venoso podem começar a ser descritos. Neste relato de caso, descrevemos um paciente que desenvolveu trombose de veia poplítea direita durante internação para tratamento de febre por infecção por vírus chicungunha e poliartralgia severa. PMID:29930626

Proceedings of the International Conference on the Numerical Simulation of Plasmas (14th) Held in Annapolis, Maryland on September 3-6, 1991

DTIC Science & Technology

1991-01-01

2 - tý a .5 .= . A ’. 2 0’.. o SS ’.. . t I -. .5 :. C, 0 Oý 0 r go %C a -0 c SS 2L 2E "t-iocogo" 0 IS F6 a c So a,, 3 IL So E 2 Q Qo’ V E r r 0c c...4 ar 0 -C ’ aCCa 0 W. , US w .2 00 ~ i; E 2 ~ . o.Z-. - w a~C -0 e0 E4 Em 12 *U - -.E 2 c - act , 0 3 2. , =- b ! .. E0 E 2- ccZZ cT, w~. ýt 0 w C...00 o- c 00 F6 ~ -02 C -4 a. 71 if )A 1 G a -2 - a d= . Cc 00 -V -0 0 P- . -- Z - 2 - q 0 0J2 2 a c x -a WO.~. 0 C;W n-a- - 0 1 o ao RR 0 if * . -I

Damage to the Left Precentral Gyrus Is Associated With Apraxia of Speech in Acute Stroke.

PubMed

Itabashi, Ryo; Nishio, Yoshiyuki; Kataoka, Yuka; Yazawa, Yukako; Furui, Eisuke; Matsuda, Minoru; Mori, Etsuro

2016-01-01

Apraxia of speech (AOS) is a motor speech disorder, which is clinically characterized by the combination of phonemic segmental changes and articulatory distortions. AOS has been believed to arise from impairment in motor speech planning/programming and differentiated from both aphasia and dysarthria. The brain regions associated with AOS are still a matter of debate. The aim of this study was to address this issue in a large number of consecutive acute ischemic stroke patients. We retrospectively studied 136 patients with isolated nonlacunar infarcts in the left middle cerebral artery territory (70.5±12.9 years old, 79 males). In accordance with speech and language assessments, the patients were classified into the following groups: pure form of AOS (pure AOS), AOS with aphasia (AOS-aphasia), and without AOS (non-AOS). Voxel-based lesion-symptom mapping analysis was performed on T2-weighted images or fluid-attenuated inversion recovery images. Using the Liebermeister method, group-wise comparisons were made between the all AOS (pure AOS plus AOS-aphasia) and non-AOS, pure AOS and non-AOS, AOS-aphasia and non-AOS, and pure AOS and AOS-aphasia groups. Of the 136 patients, 22 patients were diagnosed with AOS (7 patients with pure AOS and 15 patients with AOS-aphasia). The voxel-based lesion-symptom mapping analysis demonstrated that the brain regions associated with AOS were centered on the left precentral gyrus. Damage to the left precentral gyrus is associated with AOS in acute to subacute stroke patients, suggesting a role of this brain region in motor speech production. © 2015 American Heart Association, Inc.

AoS28D, a proline-Xaa carboxypeptidase secreted by Aspergillus oryzae.

PubMed

Salamin, Karine; Eugster, Philippe J; Jousson, Olivier; Waridel, Patrice; Grouzmann, Eric; Monod, Michel

2017-05-01

Prolyl peptidases of the MEROPS S28 family are of particular interest because they are key enzymes in the digestion of proline-rich peptides. A BLAST analysis of the Aspergillus oryzae genome revealed sequences coding for four proteases of the S28 family. Three of these proteases, AoS28A, AoS28B, and AoS28C, were previously characterized as acidic prolyl endopeptidases. The fourth protease, AoS28D, showed high sequence divergence with other S28 proteases and belongs to a phylogenetically distinct cluster together with orthologous proteases from other Aspergillus species. The objective of the present paper was to characterize AoS28D protease in terms of substrate specificity and activity. AoS28D produced by gene overexpression in A. oryzae and in Pichia pastoris was a 70-kDa glycoprotein with a 10-kDa sugar moiety. In contrast with other S28 proteases, AoS28D did not hydrolyze internal Pro-Xaa bonds of several tested peptides. Similarly, to human lysosomal Pro-Xaa carboxypeptidase, AoS28D demonstrated selectivity for cleaving C-terminal Pro-Xaa bonds which are resistant to carboxypeptidases of the S10 family concomitantly secreted by A. oryzae. Therefore, AoS28D could act in synergy with these enzymes during sequential degradation of a peptide from its C-terminus.

Implications of 187Os isotopic heterogeneities in a mantle plume: evidence from Gorgona Island and Curaçao

NASA Astrophysics Data System (ADS)

Walker, Richard J.; Storey, Michael; Kerr, Andrew C.; Tarney, John; Arndt, Nicholas T.

1999-03-01

Recent work has suggested that the mafic-ultramafic volcanism in evidence throughout portions of the Caribbean, Central America, and northern South America, including the islands of Gorgona and Curaçao, was generated as part of a middle-Cretaceous, large igneous province. New Re-Os isochron results for tholeiitic basalts from Gorgona and Curaçao indicate crystallization ages of 89.2 ± 5.2 and 85.6 ± 8.1 Ma, respectively, consistent with reported Ar ages. The Gorgona ultramafic suite shows a large range in initial Os isotopic composition, with γ Os values ranging from -0.5 to +12.4. This large range reflects isotopic heterogeneities in the mantle source similar to those observed for modern ocean island basalts. In contrast to ocean island basalts, however, Os isotopic compositions do not correlate with variations in Nd, Sr, or Pb isotopic compositions, which are within the range of depleted mid-ocean ridge basalts. The processes that produced these rocks evidently resulted in the decoupling of Os isotopes from the Nd, Sr, and Pb isotopic systems. Picrites from Curaçao have very uniform, chondritic initial Os isotopic compositions, with initial γ Os values ranging only from -0.4 to ±1.4. Basalts from Curaçao, however, define an isochron with a 187Os-enriched initial isotopic composition (γ Os = +9.5). In contrast to the 187Os-enriched ultramafic rocks from Gorgona, the enrichment in these basalts could have resulted from lithospheric contamination. If the Gorgona and Curaçao rocks were derived from the same plume, Os results, combined with Sr, Nd, and Pb data indicate a heterogeneous plume, with multiple compositionally and isotopically distinct domains. The Os isotopic results require derivation of Os from a minimum of two distinct reservoirs, one with a composition very similar to the chondritic average and one with long-term enriched Re/Os. Oceanic crustal recycling has been invoked to explain most of the 187Os enrichments that have been observed in ocean island basalt sources and could potentially apply to the Gorgona suite. Crustal recycling, however, requires large proportions of very ancient recycled basaltic crust in the sources of the 187Os-enriched ultramafic rocks to explain the magnitude of 187Os enrichments observed. For example, addition of 20% oceanic crust to fertile mantle, and nearly 3 billion years are necessary to generate a reservoir with the Os isotopic composition of the most radiogenic komatiites. If the recycled oceanic crust was added to basalt-depleted mantle, as may be indicated by ɛ Nd values for the komatiites averaging about +10, even larger proportions of older crust are required. Large proportions of oceanic mafic crust in the sources of the 187Os-enriched komatiites, although petrologically conceivable under certain melting conditions, is unlikely here given the limited trace element and lithophile isotope system variations. These results raise questions about the efficacy of using Os isotopes to constrain the proportion of recycled oceanic crust in other plumes. Other possible mechanisms for generating 187Os-enriched mantle include invoking the existence of a 187Os-enriched lower mantle, and minor outer core-lower mantle interactions.

23 CFR Appendix C to Part 658 - Trucks Over 80,000 Pounds on the Interstate System and Trucks Over STAA Lengths on the National...

Code of Federal Regulations, 2011 CFR

2011-04-01

... of Utah Utah US 160 US 163 New Mexico US 163 US 160 Utah LEGAL CITATIONS ARS 28-107 ARS 28-1009 ARS 28-1011.O ARS 28-108.5 ARS 28-1009.01 ARS 28-1012 ARS 28-108.13 ARS 28-1011.A ARS 28-1013 ARS 28-108.14 ARS 28-1011.C ARS 28-1014 ARS 28-403 ARS 28-1011.F ARS 28-1031 ARS 28-405 ARS 28-1011.K ARS 28...

23 CFR Appendix C to Part 658 - Trucks Over 80,000 Pounds on the Interstate System and Trucks Over STAA Lengths on the National...

Code of Federal Regulations, 2014 CFR

2014-04-01

... of Utah Utah US 160 US 163 New Mexico US 163 US 160 Utah LEGAL CITATIONS ARS 28-107 ARS 28-1009 ARS 28-1011.O ARS 28-108.5 ARS 28-1009.01 ARS 28-1012 ARS 28-108.13 ARS 28-1011.A ARS 28-1013 ARS 28-108.14 ARS 28-1011.C ARS 28-1014 ARS 28-403 ARS 28-1011.F ARS 28-1031 ARS 28-405 ARS 28-1011.K ARS 28...

23 CFR Appendix C to Part 658 - Trucks Over 80,000 Pounds on the Interstate System and Trucks Over STAA Lengths on the National...

Code of Federal Regulations, 2013 CFR

2013-04-01

... of Utah Utah US 160 US 163 New Mexico US 163 US 160 Utah LEGAL CITATIONS ARS 28-107 ARS 28-1009 ARS 28-1011.O ARS 28-108.5 ARS 28-1009.01 ARS 28-1012 ARS 28-108.13 ARS 28-1011.A ARS 28-1013 ARS 28-108.14 ARS 28-1011.C ARS 28-1014 ARS 28-403 ARS 28-1011.F ARS 28-1031 ARS 28-405 ARS 28-1011.K ARS 28...

23 CFR Appendix C to Part 658 - Trucks Over 80,000 Pounds on the Interstate System and Trucks Over STAA Lengths on the National...

Code of Federal Regulations, 2010 CFR

2010-04-01

... of Utah Utah US 160 US 163 New Mexico US 163 US 160 Utah LEGAL CITATIONS ARS 28-107 ARS 28-1009 ARS 28-1011.O ARS 28-108.5 ARS 28-1009.01 ARS 28-1012 ARS 28-108.13 ARS 28-1011.A ARS 28-1013 ARS 28-108.14 ARS 28-1011.C ARS 28-1014 ARS 28-403 ARS 28-1011.F ARS 28-1031 ARS 28-405 ARS 28-1011.K ARS 28...

23 CFR Appendix C to Part 658 - Trucks Over 80,000 Pounds on the Interstate System and Trucks Over STAA Lengths on the National...

Code of Federal Regulations, 2012 CFR

2012-04-01

... of Utah Utah US 160 US 163 New Mexico US 163 US 160 Utah LEGAL CITATIONS ARS 28-107 ARS 28-1009 ARS 28-1011.O ARS 28-108.5 ARS 28-1009.01 ARS 28-1012 ARS 28-108.13 ARS 28-1011.A ARS 28-1013 ARS 28-108.14 ARS 28-1011.C ARS 28-1014 ARS 28-403 ARS 28-1011.F ARS 28-1031 ARS 28-405 ARS 28-1011.K ARS 28...

Modulation of the relationship between spring AO and the subsequent winter ENSO by the preceding November AO.

PubMed

Chen, Shangfeng; Chen, Wen; Yu, Bin

2018-05-02

Previous studies indicated that the spring Arctic Oscillation (AO) exerts significant influences on the subsequent winter El Niño-Southern Oscillation (ENSO). This analysis suggests that the spring AO-ENSO linkage is highly modulated by its preceding November AO. When November and the subsequent spring AO indices are in phase, the spring AO has a pronounced influence on ENSO. However, when the November and spring AO indices are out of phase, the spring AO-ENSO connection disappears. Modulation of the November AO on the spring AO-ENSO connection is mainly through the constructive and destructive superposition of the November and spring AO associated sea surface temperature (SST) anomalies in the tropical central-eastern Pacific in spring and summer, as well as the SST anomalies developed further in the tropical Pacific via the positive air-sea feedback.

Interplay Between Cytoplasmic and Nuclear Androgen Receptor Splice Variants Mediate Castration Resistance

PubMed Central

Zhan, Yang; Zhang, Guanyi; Wang, Xiaojie; Qi, Yanfeng; Bai, Shanshan; Li, Dongying; Ma, Tianfang; Sartor, Oliver; Flemington, Erik K.; Zhang, Haitao; Lee, Peng; Dong, Yan

2016-01-01

Androgen receptor splice variants (AR-Vs) are implicated in resistance of prostate cancer to androgen-directed therapies. When expressed alone in cells, some AR-Vs (e.g., AR-V7) localize primarily to the nucleus, whereas others (e.g., AR-V1, AR-V4, and AR-V6) localize mainly to the cytoplasm. Significantly, the latter are often co-expressed with the nucleus-predominant AR-Vs and the full-length AR (AR-FL). An important question to be addressed is whether the cytoplasmic-localized AR-Vs play a role in castration-resistant prostate cancer (CRPC) through interaction with the nucleus-predominant AR-Vs and AR-FL. Here, it is demonstrated that AR-V1, -V4, and -V6 can dimerize with both AR-V7 and AR-FL. Consequently, AR-V7 and androgen-bound AR-FL induced nuclear localization of AR-V1, -V4, and -V6, and these variants, in turn, mitigated the ability of the anti-androgen enzalutamide to inhibit androgen-induced AR-FL nuclear localization. Interestingly, the impact of nuclear localization of AR-V4 and -V6 on AR transactivation differs from that of AR-V1. Nuclear localization leads to an increased ability of AR-V4 and -V6 to transactivate both canonical AR targets and AR-V-specific targets and to confer castration-resistant cell growth. However, while AR-V1, which lacks inherent transcriptional activity, appears to activate AR-FL in an androgen-independent manner, it significantly antagonizes AR-V7 transactivation. Together, these data demonstrate that the complex interactions among different AR-Vs and AR-FL play a significant role in castration resistant disease. Implications This study suggests important consequences for clinical castration resistance due to simultaneous expression of AR-FL and AR-Vs in patient tumors and suggests that dissecting these interactions should help develop effective strategies to disrupt AR-V signaling. PMID:27671337

N-terminal pro-brain natriuretic peptide measurements in hemodynamically significant patent ductus arteriosus in preterm infants.

PubMed

Alenazi, Shehab Ahmed

2016-01-01

Evaluate the role of NT-proBNP levels in Preterm neonates suffering from PDA and used as a screening tool for predicting HsPDA and guiding physicians to consider early echocardiographic evaluation. This is a monocentric prospective blind study which was conducted at Arar Central Hospital, Ar'ar, Saudi Arabia, during the period between Jan 2014 to June 2014. Thirty-three (33) preterm infants born at less than 31 weeks of gestation or weighing less than 1200 g at birth infants were initially enrolled during a 6-month period. Blood samples were collected along with routine blood tests on days 1, 2, 3, and 7 of life for NT-proBNP analysis. Two echocardiographies were systematically performed on day two of life to ascertain about the status of Ductus Arteriosus. The Plasma NT-proBNP levels were high on day one of life and decline from day three to day seven of life except in those infants with significant hsPDA. Plasma NT-proNBP levels on day 2 of infants in the HsPDA group were significantly higher (<0.001) than those in non-HsPDA group. Echocardiogram parameters indicates the significant difference (p<0.002) in Left Atrial and Aortic ratio (LA/AO), Interventricular septum thickness (P<0.03), Left ventricular posterior wall thickness (p<0.05), diastole PDA gradient (p<0.005) between HsPDA and non-HsPDA. Plasma NT-proBNP level peaked during the first few days after birth and declined rapidly within a week. Therefore, its level may have a role as a screening tool to predict HsPDA and provide more information regarding its spontaneous closure or otherwise.

Biosynthesis of allene oxides in Physcomitrella patens

PubMed Central

2012-01-01

Background The moss Physcomitrella patens contains C18- as well as C20-polyunsaturated fatty acids that can be metabolized by different enzymes to form oxylipins such as the cyclopentenone cis(+)-12-oxo phytodienoic acid. Mutants defective in the biosynthesis of cyclopentenones showed reduced fertility, aberrant sporophyte morphology and interrupted sporogenesis. The initial step in this biosynthetic route is the conversion of a fatty acid hydroperoxide to an allene oxide. This reaction is catalyzed by allene oxide synthase (AOS) belonging as hydroperoxide lyase (HPL) to the cytochrome P450 family Cyp74. In this study we characterized two AOS from P. patens, PpAOS1 and PpAOS2. Results Our results show that PpAOS1 is highly active with both C18 and C20-hydroperoxy-fatty acid substrates, whereas PpAOS2 is fully active only with C20-substrates, exhibiting trace activity (~1000-fold lower kcat/KM) with C18 substrates. Analysis of products of PpAOS1 and PpHPL further demonstrated that both enzymes have an inherent side activity mirroring the close inter-connection of AOS and HPL catalysis. By employing site directed mutagenesis we provide evidence that single amino acid residues in the active site are also determining the catalytic activity of a 9-/13-AOS – a finding that previously has only been reported for substrate specific 13-AOS. However, PpHPL cannot be converted into an AOS by exchanging the same determinant. Localization studies using YFP-labeled AOS showed that PpAOS2 is localized in the plastid while PpAOS1 may be found in the cytosol. Analysis of the wound-induced cis(+)-12-oxo phytodienoic acid accumulation in PpAOS1 and PpAOS2 single knock-out mutants showed that disruption of PpAOS1, in contrast to PpAOS2, results in a significantly decreased cis(+)-12-oxo phytodienoic acid formation. However, the knock-out mutants of neither PpAOS1 nor PpAOS2 showed reduced fertility, aberrant sporophyte morphology or interrupted sporogenesis. Conclusions Our study highlights five findings regarding the oxylipin metabolism in P. patens: (i) Both AOS isoforms are capable of metabolizing C18- and C20-derived substrates with different specificities suggesting that both enzymes might have different functions. (ii) Site directed mutagenesis demonstrated that the catalytic trajectories of 9-/13-PpAOS1 and PpHPL are closely inter-connected and PpAOS1 can be inter-converted by a single amino acid exchange into a HPL. (iii) In contrast to PpAOS1, PpAOS2 is localized in the plastid where oxylipin metabolism takes place. (iv) PpAOS1 is essential for wound-induced accumulation of cis(+)-12-oxo phytodienoic acid while PpAOS2 appears not to be involved in the process. (v) Knock-out mutants of neither AOS showed a deviating morphological phenotype suggesting that there are overlapping functions with other Cyp74 enzymes. PMID:23194461

Organic reactions mediated by electrochemically generated ArS+.

PubMed

Matsumoto, Kouichi; Suga, Seiji; Yoshida, Jun-ichi

2011-04-21

Low-temperature electrochemical oxidation of ArSSAr was carried out to generate a pool of "ArS(+)". Spectroscopic studies ((1)H NMR and CSI-MS) of the resulting solution revealed the accumulation of ArS(ArSSAr)(+). The resulting "ArS(+)" pool reacted with alkenes and alkynes to give diarylthio-substituted products. The "ArS(+)" pool rapidly reacted with thioacetals to give the corresponding alkoxycarbenium ion pools, which reacted with various carbon nucleophiles (indirect cation pool method). The reaction of the alkoxycarbenium ion pools with stilbene derivatives in the presence of ArSSAr gave thiochroman derivatives. In addition to such stoichiometric reactions, a catalytic amount of "ArS(+)" serves as an initiator and a chain carrier of some cationic chain reactions involving intramolecular carbon-carbon bond formation. In situ generation of "ArS(+)" by electrochemical oxidation of ArSSAr with a catalytic amount of electricity in the presence of a substrate is also effective for such cationic chain reactions.

Functional analysis of aldehyde oxidase using expressed chimeric enzyme between monkey and rat.

PubMed

Itoh, Kunio; Asakawa, Tasuku; Hoshino, Kouichi; Adachi, Mayuko; Fukiya, Kensuke; Watanabe, Nobuaki; Tanaka, Yorihisa

2009-01-01

Aldehyde oxidase (AO) is a homodimer with a subunit molecular mass of approximately 150 kDa. Each subunit consists of about 20 kDa 2Fe-2S cluster domain storing reducing equivalents, about 40 kDa flavine adenine dinucleotide (FAD) domain and about 85 kDa molybdenum cofactor (MoCo) domain containing a substrate binding site. In order to clarify the properties of each domain, especially substrate binding domain, chimeric cDNAs were constructed by mutual exchange of 2Fe-2S/FAD and MoCo domains between monkey and rat. Chimeric monkey/rat AO was referred to one with monkey type 2Fe-2S/FAD domains and a rat type MoCo domain. Rat/monkey AO was vice versa. AO-catalyzed 2-oxidation activities of (S)-RS-8359 were measured using the expressed enzyme in Escherichia coli. Substrate inhibition was seen in rat AO and chimeric monkey/rat AO, but not in monkey AO and chimeric rat/monkey AO, suggesting that the phenomenon might be dependent on the natures of MoCo domain of rat. A biphasic Eadie-Hofstee profile was observed in monkey AO and chimeric rat/monkey AO, but not rat AO and chimeric monkey/rat AO, indicating that the biphasic profile might be related to the properties of MoCo domain of monkey. Two-fold greater V(max) values were observed in monkey AO than in chimeric rat/monkey AO, and in chimeric monkey/rat AO than in rat AO, suggesting that monkey has the more effective electron transfer system than rat. Thus, the use of chimeric enzymes revealed that 2Fe-2S/FAD and MoCo domains affect the velocity and the quantitative profiles of AO-catalyzed (S)-RS-8359 2-oxidation, respectively.

Production and characterization of two major Aspergillus oryzae secreted prolyl endopeptidases able to efficiently digest proline-rich peptides of gliadin.

PubMed

Eugster, Philippe J; Salamin, Karine; Grouzmann, Eric; Monod, Michel

2015-12-01

Prolyl endopeptidases are key enzymes in the digestion of proline-rich proteins. Fungal extracts rich in prolyl endopeptidases produced by a species such as Aspergillus oryzae used in food fermentation would be of particular interest for the development of an oral enzyme therapy product in patients affected by intolerance to gluten. Two major A. oryzae secreted prolyl endopeptidases of the MEROPS S28 peptidase family, AoS28A and AoS28B, were identified when this fungus was grown at acidic pH in a medium containing soy meal protein or wheat gliadin as the sole source of nitrogen. AoS28B was produced by 12 reference A. oryzae strains used in food fermentation. AoS28A was secreted by six of these 12 strains. This protease is the orthologue of the previously characterized Aspergillus fumigatus (AfuS28) and Aspergillus niger (AN-PEP) prolyl endopeptidases which are encoded by genes with a similar intron-exon structure. Large amounts of secreted AoS28A and AoS28B were obtained by gene overexpression in A. oryzae. AoS28A and AoS28B are endoproteases able to cleave N-terminally blocked proline substrates. Both enzymes very efficiently digested the proline-rich 33-mer of gliadin, the most representative immunotoxic peptide deriving from gliadin, with some differences in terms of specificity and optimal pH. Digestion of the gliadin peptide in short peptides with both enzymes was found to occur from its N terminus.

Addition of ArSSAr to dienes via intramolecular C-C bond formation initiated by a catalytic amount of ArS+.

PubMed

Matsumoto, Kouichi; Fujie, Shunsuke; Suga, Seiji; Nokami, Toshiki; Yoshida, Jun-ichi

2009-09-28

A catalytic amount of electrochemically generated "ArS+" ("ArS+" = ArS(ArSSAr)+) initiates a cation chain reaction of dienes that involves the addition of ArSSAr associated with stereoselective intramolecular carbon-carbon bond formation, and the direct (in-cell) electrolysis of a mixture of a diene and ArSSAr with a catalytic amount of electricity also effectively initiates the reaction.

Ar-Ar_Redux: rigorous error propagation of 40Ar/39Ar data, including covariances

NASA Astrophysics Data System (ADS)

Vermeesch, P.

2015-12-01

Rigorous data reduction and error propagation algorithms are needed to realise Earthtime's objective to improve the interlaboratory accuracy of 40Ar/39Ar dating to better than 1% and thereby facilitate the comparison and combination of the K-Ar and U-Pb chronometers. Ar-Ar_Redux is a new data reduction protocol and software program for 40Ar/39Ar geochronology which takes into account two previously underappreciated aspects of the method: 1. 40Ar/39Ar measurements are compositional dataIn its simplest form, the 40Ar/39Ar age equation can be written as: t = log(1+J [40Ar/39Ar-298.5636Ar/39Ar])/λ = log(1 + JR)/λ Where λ is the 40K decay constant and J is the irradiation parameter. The age t does not depend on the absolute abundances of the three argon isotopes but only on their relative ratios. Thus, the 36Ar, 39Ar and 40Ar abundances can be normalised to unity and plotted on a ternary diagram or 'simplex'. Argon isotopic data are therefore subject to the peculiar mathematics of 'compositional data', sensu Aitchison (1986, The Statistical Analysis of Compositional Data, Chapman & Hall). 2. Correlated errors are pervasive throughout the 40Ar/39Ar methodCurrent data reduction protocols for 40Ar/39Ar geochronology propagate the age uncertainty as follows: σ2(t) = [J2 σ2(R) + R2 σ2(J)] / [λ2 (1 + R J)], which implies zero covariance between R and J. In reality, however, significant error correlations are found in every step of the 40Ar/39Ar data acquisition and processing, in both single and multi collector instruments, during blank, interference and decay corrections, age calculation etc. Ar-Ar_Redux revisits every aspect of the 40Ar/39Ar method by casting the raw mass spectrometer data into a contingency table of logratios, which automatically keeps track of all covariances in a compositional context. Application of the method to real data reveals strong correlations (r2 of up to 0.9) between age measurements within a single irradiation batch. Propertly taking into account these correlations significantly improves the precision and accuracy of 40Ar/39Ar data, at no financial cost. A prototype version of Ar-Ar_Redux was written in R and is available from http://redux.london-geochron.com. A standalone GUI is under development.

Surgical adverse outcome reporting as part of routine clinical care.

PubMed

Kievit, J; Krukerink, M; Marang-van de Mheen, P J

2010-12-01

In The Netherlands, health professionals have created a doctor-driven standardised system to report and analyse adverse outcomes (AO). The aim is to improve healthcare by learning from past experiences. The key elements of this system are (1) an unequivocal definition of an adverse outcome, (2) appropriate contextual information and (3) a three-dimensional hierarchical classification system. First, to assess whether routine doctor-driven AO reporting is feasible. Second, to investigate how doctors can learn from AO reporting and analysis to improve the quality of care. Feasibility was assessed by how well doctors reported AO in the surgical department of a Dutch university hospital over a period of 9 years. AO incidence was analysed per patient subgroup and over time, in a time-trend analysis of three equal 3-year periods. AO were analysed case by case and statistically, to learn lessons from past events. In 19,907 surgical admissions, 9189 AOs were reported: one or more AO in 18.2% of admissions. On average, 55 lessons were learnt each year (in 4.3% of AO). More AO were reported in P3 than P1 (OR 1.39 (1.23-1.57)). Although minor AO increased, fatal AO decreased over time (OR 0.59 (0.45-0.77)). Doctor-driven AO reporting is shown to be feasible. Lessons can be learnt from case-by-case analyses of individual AO, as well as by statistical analysis of AO groups and subgroups (illustrated by time-trend analysis), thus contributing to the improvement of the quality of care. Moreover, by standardising AO reporting, data can be compared across departments or hospitals, to generate (confidential) mirror information for professionals cooperating in a peer-review setting.

Surgical adverse outcome reporting as part of routine clinical care

PubMed Central

Krukerink, M; Marang-van de Mheen, P J

2010-01-01

Background In The Netherlands, health professionals have created a doctor-driven standardised system to report and analyse adverse outcomes (AO). The aim is to improve healthcare by learning from past experiences. The key elements of this system are (1) an unequivocal definition of an adverse outcome, (2) appropriate contextual information and (3) a three-dimensional hierarchical classification system. Objectives First, to assess whether routine doctor-driven AO reporting is feasible. Second, to investigate how doctors can learn from AO reporting and analysis to improve the quality of care. Methods Feasibility was assessed by how well doctors reported AO in the surgical department of a Dutch university hospital over a period of 9 years. AO incidence was analysed per patient subgroup and over time, in a time-trend analysis of three equal 3-year periods. AO were analysed case by case and statistically, to learn lessons from past events. Results In 19 907 surgical admissions, 9189 AOs were reported: one or more AO in 18.2% of admissions. On average, 55 lessons were learnt each year (in 4.3% of AO). More AO were reported in P3 than P1 (OR 1.39 (1.23–1.57)). Although minor AO increased, fatal AO decreased over time (OR 0.59 (0.45–0.77)). Conclusions Doctor-driven AO reporting is shown to be feasible. Lessons can be learnt from case-by-case analyses of individual AO, as well as by statistical analysis of AO groups and subgroups (illustrated by time-trend analysis), thus contributing to the improvement of the quality of care. Moreover, by standardising AO reporting, data can be compared across departments or hospitals, to generate (confidential) mirror information for professionals cooperating in a peer-review setting. PMID:20430928

A Prediction of the Damping Properties of Hindered Phenol AO-60/polyacrylate Rubber (AO-60/ACM) Composites through Molecular Dynamics Simulation

NASA Astrophysics Data System (ADS)

Yang, Da-Wei; Zhao, Xiu-Ying; Zhang, Geng; Li, Qiang-Guo; Wu, Si-Zhu

2016-05-01

Molecule dynamics (MD) simulation, a molecular-level method, was applied to predict the damping properties of AO-60/polyacrylate rubber (AO-60/ACM) composites before experimental measures were performed. MD simulation results revealed that two types of hydrogen bond, namely, type A (AO-60) -OH•••O=C- (ACM), type B (AO-60) - OH•••O=C- (AO-60) were formed. Then, the AO-60/ACM composites were fabricated and tested to verify the accuracy of the MD simulation through dynamic mechanical thermal analysis (DMTA). DMTA results showed that the introduction of AO-60 could remarkably improve the damping properties of the composites, including the increase of glass transition temperature (Tg) alongside with the loss factor (tan δ), also indicating the AO-60/ACM(98/100) had the best damping performance amongst the composites which verified by the experimental.

Evolução temporal de discos circunstelares em estrelas Be

NASA Astrophysics Data System (ADS)

Fernandes, M. V. M.; Leister, N. V.; Levenhagen, R. S.

2003-08-01

A pesquisa do mecanismo que leva uma estrela do tipo Be a perder massa e formar um envelope circunstelar, nomeado como fenômeno Be, é uma questão em aberto, intrigante, e que adquire contornos interessantes em face às informações espectroscópicas de alta resolução. Nesta última década, consolida-se a idéia de que a forma destes envelopes é de tipo discóide, obedecendo a uma lei Kepleriana de velocidades, e mais ainda, recentemente há evidências de que a distribuição de matéria nestes discos pode assumir um caráter de anel. Medidas de algumas dimensões de discos circunstelares puderam ser obtidas pela análise de espectros de alta resolução e alta relação sinal-ruído para as estrelas Be: alpha Eri (HD 10144, B3Vpe), omicron And (HD 217675, B6IIIpe), e eta Cen (HD el972, B1.5Vne), no período dos anos de 1991 a 2001. Alguns modelos clássicos de envelope predizem uma distribuição de massa que decresce suavemente a partir da superfície estelar. Entretanto, considerando que a separação de picos de emissão em perfis de linhas do HeI e H-alpha, alargados por efeitos cinemáticos, é função do raio estelar e da velocidade rotacional projetada (vsini); nossos resultados sugerem a presença de um anel de matéria circunstelar, que aparece logo após a ejeção do material fotosférico, imediatamente acima da superfície estelar, e que se expande para raios maiores ao longo do tempo, eventualmente desconectando-se da superfície por uma região de densidade de matéria mínima. Tais interpretações revivem a idéia de que anéis de matéria circunstelar podem ser os responsáveis por algumas variabilidades em perfis de linhas de emissão, como as variações V/R.

The Possible Pre- and Post-UVA Radiation Protective Effect of Amaranth Oil on Human Skin Fibroblast Cells.

PubMed

Wolosik, Katarzyna; Zareba, Ilona; Surazynski, Arkadiusz; Markowska, Agnieszka

2017-07-01

The health effects of Amaranth Oil (AO) are attributed to its specific chemical composition. That makes it an outstanding natural product for the prevention and treatment of ultraviolet (UV) irradiation-related pathologies such as sunburn, photoaging, photoimmunosuppression, and photocarcinogenesis. Most of the studies are taken on animal model, and there is a lack of research on the endogenous effect of AO on fibroblast level, where UVA takes it harmful place. The aim of this study was evaluation if AO can protect or abolish UVA exposure effect on human skin fibroblast. The 0.1% AO, 0.25% AO, and 0.5% AO concentration and irradiation for 15 min under UVA-emitting lamp were studied in various condition. In all experiments, the mean values for six assays ± standard deviations were calculated. Pretreatment with various concentrations of AO was tested. The highest concentration of AO where cell survival was observed was 0.5%. Cytotoxicity assays provided evidence for pre- and post-UVA protective effect of 0.1% AO among three tested concentrations. The results also provide evidence that UVA has inhibitory effect on collagen biosynthesis in confluent skin fibroblast, but presence of 0.1% AO abolishes pre- and post-UVA effect comparing to other used AO concentration. The assessment results on DNA biosynthesis show the significant abolished post-UVA effect when 0.1% and 0.5% of AO were added. AO gives pre- and post-UVA protection in low concentration. This provides the evidence for using it not as a main protective factor against UV but as one of the combined components in cosmetic formulation. The recommended Amaranth Oil (AO) concentration in cosmetic formulation is between 0.1 and 5%Pretreatment with various concentrations of AO suggests to use the highest 0.5% concentration of AO in human skin fibroblast culturesThe 0.1% of AO in fibroblast cultures, protects and abolishes effect of ultraviolet A (UVA) exposureUVA has inhibitory effect on collagen biosynthesis in skin fibroblast, but presence of 0.1% AO abolishes pre- and post-UVA effectThe abolished post-UVA effect occurs when 0.1% and 0.5% of AO were added on DNA biosynthesis. Abbreviations used: AO: Amaranth Oil.

Ar-39-Ar-40 Ages of Two Nakhlites, MIL03346 and Y000593: A Detailed Analysis

NASA Technical Reports Server (NTRS)

Park, Jisun; Garrison, Daniel; Bogard, Donald

2007-01-01

Radiometric dating of martian nakhlites by several techniques have given similar ages of approx.1.2-1.4 Ga [e.g. 1, 2]. Unlike the case with shergottites, where the presence of martian atmosphere and inherited radiogenic Ar-40 produce apparent Ar-39-Ar-40 ages older than other radiometric ages, Ar-Ar ages of nakhlites are similar to ages derived by other techniques. However, even in some nakhlites the presence of trapped martian Ar produces some uncertainty in the Ar-Ar age. We present here an analysis of such Ar-Ar ages from the MIL03346 and Y000593 nakhlites.

Spectroscopie d'emission VUV-visible provenant de plasmas basse pression: Applications aux traitements de surfaces polymeriques

NASA Astrophysics Data System (ADS)

Fozza, Alexandru C.

The main objective of this thesis is to make a contribution to the spectroscopic study of low pressure glow discharges in the vacuum ultraviolet and to reveal the effect of this radiation on polymeric materials. This research considers the following important aspects relevant to low pressure glow discharges: (i)characterization of vacuum ultraviolet (VUV) emission of several plasmas in the wavelength range available through crystalline fluoride windows, (ii)analysis of the emission dependence on several external parameters, and (iii)study of the VUV effect, in the accessible range, on polymeric materials of interest with respect to plasma treatments. The plasmas investigated, namely, hydrogen, oxygen and their mixtures with argon, were chosen by taking into consideration the composition of the gases used in technological plasmas, and the conditions needed for polymeric material irradiation. Two separate spectrophotometric instruments, a VUV monochromator (ARC VM-502) and an optical multichannel analyzer (OMA), were used. For the chosen plasmas, we measured the variation of the intensity of the atomic lines for different gas pressures and absorbed power levels. In the case of pure gas plasmas, the pressure dependence of the atomic line intensities was attributed to changes in the electron energy distribution function (EEDF). The argon emission spectra are very sensitive to the presence of impurities. The mixture plasmas we have studied (Ar-H2 and Ar-O2) show a strong emission of atomic fines in the VUV region, stronger than those resulting from the pure molecular gases. The above mixtures show promise as photon sources for the treatment of polymer surfaces. An important external parameter for the characterization of glow discharges is the excitation frequency. The goal of the specific experiments was to directly investigate the frequency-dependence effect. The frequency-related effects on plasma emission were investigated for two plasmas: pure hydrogen and 7% H2 in Ar mixture. In the case of pure hydrogen, we observed a change from a non-stationary to a stationary electron energy distribution function. For the Ar-H2 mixture, we have shown that the EEDF is stationary and that the dissociation rate for hydrogen molecules does not depend on frequency. A difference between the excitation mechanisms of different atomic lines was proven. Among the most sensitive materials with respect to plasma generated UV radiation are polymers. We have optimized the gaseous composition for various types of VUV radiation fluxes for the photochemical treatments of polymers. We have developed a system containing a thermo-stabilized quartz crystal microbalance (QCM) and chambers for sample irradiation and gas absorption measurements. In this way we have separately measured the effects of both the active oxygen species (AO) and the VUV, as well as their synergistic actions. (Abstract shortened by UMI.)

Improving the temperature characteristics and catalytic efficiency of a mesophilic xylanase from Aspergillus oryzae, AoXyn11A, by iterative mutagenesis based on in silico design.

PubMed

Li, Xue-Qing; Wu, Qin; Hu, Die; Wang, Rui; Liu, Yan; Wu, Min-Chen; Li, Jian-Fang

2017-12-01

To improve the temperature characteristics and catalytic efficiency of a glycoside hydrolase family (GHF) 11 xylanase from Aspergillus oryzae (AoXyn11A), its variants were predicted based on in silico design. Firstly, Gly 21 with the maximum B-factor value, which was confirmed by molecular dynamics (MD) simulation on the three-dimensional structure of AoXyn11A, was subjected to site-saturation mutagenesis. Thus, one variant with the highest thermostability, AoXyn11A G21I , was selected from the mutagenesis library, E. coli/Aoxyn11A G21X (X: any one of 20 amino acids). Secondly, based on the primary structure multiple alignment of AoXyn11A with seven thermophilic GHF11 xylanases, AoXyn11A Y13F or AoXyn11A G21I-Y13F , was designed by replacing Tyr 13 in AoXyn11A or AoXyn11A G21I with Phe. Finally, three variant-encoding genes, Aoxyn11A G21I , Aoxyn11A Y13F and Aoxyn11A G21I-Y13F , were constructed by two-stage whole-plasmid PCR method, and expressed in Pichia pastoris GS115, respectively. The temperature optimum (T opt ) of recombinant (re) AoXyn11A G21I-Y13F was 60 °C, being 5 °C higher than that of reAoXyn11A G21I or reAoXyn11A Y13F , and 10 °C higher than that of reAoXyn11A. The thermal inactivation half-life (t 1/2 ) of reAoXyn11A G21I-Y13F at 50 °C was 240 min, being 40-, 3.4- and 2.5-fold longer than those of reAoXyn11A, reAoXyn11A G21I and reAoXyn11A Y13F . The melting temperature (T m ) values of reAoXyn11A, reAoXyn11A G21I , reAoXyn11A Y13F and reAoXyn11A G21I-Y13F were 52.3, 56.5, 58.6 and 61.3 °C, respectively. These findings indicated that the iterative mutagenesis of both Gly21Ile and Tyr13Phe improved the temperature characteristics of AoXyn11A in a synergistic mode. Besides those, the catalytic efficiency (k cat /K m ) of reAoXyn11A G21I-Y13F was 473.1 mL mg -1 s -1 , which was 1.65-fold higher than that of reAoXyn11A.

Book review: Advances in 40Ar/39Ar dating: From archaeology to planetary sciences

USGS Publications Warehouse

Cosca, Michael A.

2015-01-01

The recently published book Advances in 40Ar/39Ar Dating: From Archaeology to Planetary Sciences is a collection of 24 chapters authored by international scientists on topics ranging from decay constants to 40Ar/39Ar dating of extraterrestrial objects. As stated by the editors in their introduction, these chapters were assembled with the goal of providing technique-specific examples highlighting recent advances in the field of 40Ar/39Ar dating. As this is the first book truly dedicated to 40Ar/39Ar dating since the second edition printing of the argon geochronologist’s handbook Geochronology and Thermochronology by the 40Ar/39Ar Method (McDougall and Harrison 1999), a new collection of chapters highlighting recent advances in 40Ar/39Ar geochronology offers much to the interested reader.

Acetylation of androgen receptor by ARD1 promotes dissociation from HSP90 complex and prostate tumorigenesis

PubMed Central

Zhang, Guanyi; Qian, Chiping; Zhang, Haitao; Zabaleta, Jovanny; Liu, Wanguo

2016-01-01

Prostate cancer is an androgen receptor (AR)-driven disease and post-translational modification of AR is critical for AR activation. We previously reported that Arrest-defective protein 1 (ARD1) is an oncoprotein in prostate cancer. It acetylates and activates AR to promote prostate tumorigenesis. However, the ARD1-targeted residue within AR and the mechanisms of the acetylation event in prostate tumorigenesis remained unknown. In this study, we show that ARD1 acetylates AR at lysine 618 (K618) in vitro and in vivo. An AR construct with the charged lysine substitution by arginine (AR-618R) reduces RNA Pol II binding, AR transcriptional activity, prostate cancer cell growth, and xenograft tumor formation due to attenuation of AR nuclear translocation, whereas, construct mimicking neutral polar substitution acetylation at K618 by glutamine (AR-618Q) enhanced these effects beyond that of the wild-type AR. Mechanistically, ARD1 forms a ternary complex with AR and HSP90 in vitro and in vivo. Expression of ARD1 increases levels of AR acetylation and AR-HSP90 dissociation in a dose dependent manner. Moreover, the AR acetylation defective K618R mutant is unable to dissociate from HSP90 while the HSP90-dissociated AR is acetylated following ligand exposure. This work identifies a new mechanism for ligand-induced AR-HSP90 dissociation and AR activation. Targeting ARD1-mediated AR acetylation may be a potent intervention for AR-dependent prostate cancer therapy. PMID:27659526

Analytic Validation of RNA In Situ Hybridization (RISH) for AR and AR-V7 Expression in Human Prostate Cancer

PubMed Central

Guedes, Liana B.; Morais, Carlos L.; Almutairi, Fawaz; Haffner, Michael C.; Zheng, Qizhi; Isaacs, John T.; Antonarakis, Emmanuel S.; Lu, Changxue; Tsai, Harrison; Luo, Jun; De Marzo, Angelo M.; Lotan, Tamara L.

2016-01-01

Purpose RNA expression of androgen receptor splice variants may be a biomarker of resistance to novel androgen deprivation therapies in castrate resistant prostate cancer (CRPC). We analytically validated an RNA in situ hybridization (RISH) assay for total AR and AR-V7 for use in formalin fixed paraffin embedded (FFPE) prostate tumors. Experimental Design We used prostate cell lines and xenografts to validate chromogenic RISH to detect RNA containing AR exon 1 (AR-E1, surrogate for total AR RNA species) and cryptic exon 3 (AR-CE3, surrogate for AR-V7 expression). RISH signals were quantified in FFPE primary tumors and CRPC specimens, comparing to known AR and AR-V7 status by immunohistochemistry and RT-PCR. Results The quantified RISH results correlated significantly with total AR and AR-V7 levels by RT-PCR in cell lines, xenografts and autopsy metastases. Both AR-E1 and AR-CE3 RISH signals were localized in nuclear punctae in addition to the expected cytoplasmic speckles. Compared to admixed benign glands, AR-E1 expression was significantly higher in primary tumor cells with a median fold increase of 3.0 and 1.4 in two independent cohorts (p<0.0001 and p=0.04, respectively). While AR-CE3 expression was detectable in primary prostatic tumors, levels were substantially higher in a subset of CRPC metastases and cell lines, and were correlated with AR-E1 expression. Conclusions RISH for AR-E1 and AR-CE3 is an analytically valid method to examine total AR and AR-V7 RNA levels in FFPE tissues. Future clinical validation studies are required to determine whether AR RISH is a prognostic or predictive biomarker in specific clinical contexts. PMID:27166397

Identification and functional characterisation of an allene oxide synthase from grapevine (Vitis vinifera L. Sauvignon blanc).

PubMed

Dumin, Walftor; Rostas, Michael; Winefield, Christopher

2018-06-01

Jasmonic acid (JA) is known to be an important phytohormone that orchestrates plant defence mechanisms against a range of herbivores and pathogens. Studies have suggested allene oxide synthase (AOS; E.C 4.2.1.92), the first committed step in JA biosynthesis, is essential for JA biosynthesis, yet clear evidence of its role as a biosynthetic regulatory point is lacking, in the main due to conflicting results derived from transgenic studies. However other studies lend support to a biosynthetic regulatory role for AOS. These studies have suggested that certain amino acid substitutions can increase the biosynthetic capacity of the enzyme and consequently improve pathogen tolerance in plants. To explore the role of AOS in Grapevine we isolated and functionally characterised this enzyme for the first time from Vitis vinifera L. Sauvignon blanc. The cloned AOS consisted of a single 1563 bp open reading frame. Comparative sequence analysis showed that the cloned gene (VvAOS) was highly conserved compared to those from other species. Complementation of an Arabidopsis AOS null mutant (aos) with VvAOS recovered the male sterile mutant phenotype and confirmed its function. Transcript analysis showed that VvAOS was wound responsive in leaves and was detectable in most tissues, with the highest levels of transcript in the mesocarp (pulp) of mature berries. Sub-cellular localisation of the VvAOS protein indicated that VvAOS is associated with the chloroplast membrane. Unexpectedly high levels of VvAOS transcript in complemented aos lines did not lead to predicted increases in JA. We have functionally characterised the sole AOS from Grapevine. Patterns of transcript accumulation in grapevine suggest roles in growth, development as well as an important role for JA in fruit ripening. Expression of VvAOS in Arabidopsis suggest complex epigenetic interactions between transgenic and endogenous AOS alleles, providing a possible explanation for why transgenic studies of AOS have delivered conflicting data pointing to a questionable role of AOS as a key regulatory point in JA biosynthesis.

Apple fruit copper amine oxidase isoforms: peroxisomal MdAO1 prefers diamines as substrates, whereas extracellular MdAO2 exclusively utilizes monoamines.

PubMed

Zarei, Adel; Trobacher, Christopher P; Cooke, Alison R; Meyers, Ashley J; Hall, J Christopher; Shelp, Barry J

2015-01-01

4-Aminobutyrate (GABA) accumulates in apple fruit during controlled atmosphere storage. A potential source of GABA is the polyamine putrescine, which can be oxidized via copper-containing amine oxidase (CuAO), resulting in the production 4-aminobutanal/Δ(1)-pyrroline, with the consumption of O2 and release of H2O2 and ammonia. Five putative CuAO genes (MdAO genes) were cloned from apple (Malus domestica Borkh. cv. Empire) fruit, and the deduced amino acid sequences found to contain the active sites typically conserved in CuAOs. Genes encoding two of these enzymes, MdAO1 and MdAO2, were highly expressed in apple fruit and selected for further analysis. Amino acid sequence analysis predicted the presence of a C-terminal peroxisomal targeting signal 1 tripeptide in MdAO1 and an N-terminal signal peptide and N-glycosylation site in MdAO2. Transient expression of green fluorescent fusion proteins in Arabidopsis protoplasts or onion epidermal cells revealed a peroxisomal localization for MdAO1 and an extracellular localization for MdAO2. The enzymatic activities of purified recombinant MdAO1 and MdAO2 were measured continuously as H2O2 production using a coupled reaction. MdAO1 did not use monoamines or polyamines and displayed high catalytic efficiency for 1,3-diaminopropane, putrescine and cadaverine, whereas MdAO2 exclusively utilized aliphatic and aromatic monoamines, including 2-phenylethylamine and tyramine. Together, these results indicate that MdAO1 may contribute to GABA production via putrescine oxidation in the peroxisome of apple fruit under controlled atmosphere conditions. MdAO2 seems to be involved in deamination of 2-phenylethylamine, which is a step in the biosynthesis of 2-phenylethanol, a contributor to fruit flavor and flower fragrance. © The Author 2014. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Suppression of Plant Immune Responses by the Pseudomonas savastanoi pv. savastanoi NCPPB 3335 Type III Effector Tyrosine Phosphatases HopAO1 and HopAO2

PubMed Central

Castañeda-Ojeda, María Pilar; Moreno-Pérez, Alba; Ramos, Cayo; López-Solanilla, Emilia

2017-01-01

The effector repertoire of the olive pathogen P. savastanoi pv. savastanoi NCPPB 3335 includes two members of the HopAO effector family, one of the most diverse T3E families of the P. syringae complex. The study described here explores the phylogeny of these dissimilar members, HopAO1 and HopAO2, among the complex and reveals their activities as immune defense suppressors. Although HopAO1 is predominantly encoded by phylogroup 3 strains isolated from woody organs of woody hosts, both HopAO1 and HopAO2 are phylogenetically clustered according to the woody/herbaceous nature of their host of isolation, suggesting host specialization of the HopAO family across the P. syringae complex. HopAO1 and HopAO2 translocate into plant cells and show hrpL-dependent expression, which allows their classification as actively deployed type III effectors. Our data also show that HopAO1 and HopAO2 possess phosphatase activity, a hallmark of the members of this family. Both of them exert an inhibitory effect on early plant defense responses, such as ROS production and callose deposition, and are able to suppress ETI responses induced by the effectorless polymutant of P. syringae pv. tomato DC3000 (DC3000D28E) in Nicotiana. Moreover, we demonstrate that a ΔhopAO1 mutant of P. savastanoi NCPBB 3335 exhibits a reduced fitness and virulence in olive plants, which supports the relevance of this effector during the interaction of this strain with its host plants. This work contributes to the field with the first report regarding functional analysis of HopAO homologs encoded by P. syringae or P. savastanoi strains isolated from woody hosts. PMID:28529516

Minoxidil may suppress androgen receptor-related functions.

PubMed

Hsu, Cheng-Lung; Liu, Jai-Shin; Lin, An-Chi; Yang, Chih-Hsun; Chung, Wen-Hung; Wu, Wen-Guey

2014-04-30

Although minoxidil has been used for more than two decades to treat androgenetic alopecia (AGA), an androgen-androgen receptor (AR) pathway-dominant disease, its precise mechanism of action remains elusive. We hypothesized that minoxidil may influence the AR or its downstream signaling. These tests revealed that minoxidil suppressed AR-related functions, decreasing AR transcriptional activity in reporter assays, reducing expression of AR targets at the protein level, and suppressing AR-positive LNCaP cell growth. Dissecting the underlying mechanisms, we found that minoxidil interfered with AR-peptide, AR-coregulator, and AR N/C-terminal interactions, as well as AR protein stability. Furthermore, a crystallographic analysis using the AR ligand-binding domain (LBD) revealed direct binding of minoxidil to the AR in a minoxidil-AR-LBD co-crystal model, and surface plasmon resonance assays demonstrated that minoxidil directly bound the AR with a K(d) value of 2.6 µM. Minoxidil also suppressed AR-responsive reporter activity and decreased AR protein stability in human hair dermal papilla cells. The current findings provide evidence that minoxidil could be used to treat both cancer and age-related disease, and open a new avenue for applications of minoxidil in treating androgen-AR pathway-related diseases.

Minoxidil may suppress androgen receptor-related functions

PubMed Central

Hsu, Cheng-Lung; Liu, Jai-Shin; Lin, An-Chi; Yang, Chih-Hsun; Chung, Wen-Hung; Wu, Wen-Guey

2014-01-01

Although minoxidil has been used for more than two decades to treat androgenetic alopecia (AGA), an androgen-androgen receptor (AR) pathway-dominant disease, its precise mechanism of action remains elusive. We hypothesized that minoxidil may influence the AR or its downstream signaling. These tests revealed that minoxidil suppressed AR-related functions, decreasing AR transcriptional activity in reporter assays, reducing expression of AR targets at the protein level, and suppressing AR-positive LNCaP cell growth. Dissecting the underlying mechanisms, we found that minoxidil interfered with AR-peptide, AR-coregulator, and AR N/C-terminal interactions, as well as AR protein stability. Furthermore, a crystallographic analysis using the AR ligand-binding domain (LBD) revealed direct binding of minoxidil to the AR in a minoxidil-AR-LBD co-crystal model, and surface plasmon resonance assays demonstrated that minoxidil directly bound the AR with a Kd value of 2.6 μM. Minoxidil also suppressed AR-responsive reporter activity and decreased AR protein stability in human hair dermal papilla cells. The current findings provide evidence that minoxidil could be used to treat both cancer and age-related disease, and open a new avenue for applications of minoxidil in treating androgen-AR pathway-related diseases. PMID:24742982

76 FR 27077 - Agency Information Collection Activities: Form AR-11 and Form AR-11SR, Extension of an Existing...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-05-10

... Collection Activities: Form AR-11 and Form AR- 11SR, Extension of an Existing Information Collection; Comment Request ACTION: 60-Day Notice of Information Collection under Review: Form AR- 11 and Form AR-11SR, Alien... evaluating whether to revise the Form AR-11 and Form AR-11SR (Forms AR-11). Should USCIS decide to revise...

Arsenic resistance strategy in Pantoea sp. IMH: Organization, function and evolution of ars genes.

PubMed

Wang, Liying; Zhuang, Xuliang; Zhuang, Guoqiang; Jing, Chuanyong

2016-12-14

Pantoea sp. IMH is the only bacterium found in genus Pantoea with a high As resistance capacity, but its molecular mechanism is unknown. Herein, the organization, function, and evolution of ars genes in IMH are studied starting with analysis of the whole genome. Two ars systems - ars1 (arsR1B1C1H1) and ars2 (arsR2B2C2H2) - with low sequence homology and two arsC-like genes, were found in the IMH genome. Both ars1 and ars2 are involved in the As resistance, where ars1 is the major contributor at 15 °C and ars2 at 30 °C. The difference in the behavior of these two ars systems is attributed to the disparate activities of their arsR promoters at different temperatures. Sequence analysis based on concatenated ArsRBC indicates that ars1 and ars2 clusters may be acquired from Franconibacter helveticus LMG23732 and Serratia marcescens (plasmid R478), respectively, by horizontal gene transfer (HGT). Nevertheless, two arsC-like genes, probably arising from the duplication of arsC, do not contribute to the As resistance. Our results indicate that Pantoea sp. IMH acquired two different As resistance genetic systems by HGT, allowing the colonization of changing ecosystems, and highlighting the flexible adaptation of microorganisms to resist As.

Arsenic resistance strategy in Pantoea sp. IMH: Organization, function and evolution of ars genes

PubMed Central

Wang, Liying; Zhuang, Xuliang; Zhuang, Guoqiang; Jing, Chuanyong

2016-01-01

Pantoea sp. IMH is the only bacterium found in genus Pantoea with a high As resistance capacity, but its molecular mechanism is unknown. Herein, the organization, function, and evolution of ars genes in IMH are studied starting with analysis of the whole genome. Two ars systems - ars1 (arsR1B1C1H1) and ars2 (arsR2B2C2H2) - with low sequence homology and two arsC-like genes, were found in the IMH genome. Both ars1 and ars2 are involved in the As resistance, where ars1 is the major contributor at 15 °C and ars2 at 30 °C. The difference in the behavior of these two ars systems is attributed to the disparate activities of their arsR promoters at different temperatures. Sequence analysis based on concatenated ArsRBC indicates that ars1 and ars2 clusters may be acquired from Franconibacter helveticus LMG23732 and Serratia marcescens (plasmid R478), respectively, by horizontal gene transfer (HGT). Nevertheless, two arsC-like genes, probably arising from the duplication of arsC, do not contribute to the As resistance. Our results indicate that Pantoea sp. IMH acquired two different As resistance genetic systems by HGT, allowing the colonization of changing ecosystems, and highlighting the flexible adaptation of microorganisms to resist As. PMID:27966630

Simulation of DKIST solar adaptive optics system

NASA Astrophysics Data System (ADS)

Marino, Jose; Carlisle, Elizabeth; Schmidt, Dirk

2016-07-01

Solar adaptive optics (AO) simulations are a valuable tool to guide the design and optimization process of current and future solar AO and multi-conjugate AO (MCAO) systems. Solar AO and MCAO systems rely on extended object cross-correlating Shack-Hartmann wavefront sensors to measure the wavefront. Accurate solar AO simulations require computationally intensive operations, which have until recently presented a prohibitive computational cost. We present an update on the status of a solar AO and MCAO simulation tool being developed at the National Solar Observatory. The simulation tool is a multi-threaded application written in the C++ language that takes advantage of current large multi-core CPU computer systems and fast ethernet connections to provide accurate full simulation of solar AO and MCAO systems. It interfaces with KAOS, a state of the art solar AO control software developed by the Kiepenheuer-Institut fuer Sonnenphysik, that provides reliable AO control. We report on the latest results produced by the solar AO simulation tool.

Androgen receptor (AR) cistrome in prostate differentiation and cancer progression.

PubMed

Wang, Fengtian; Koul, Hari K

2017-01-01

Despite the progress in development of better AR-targeted therapies for prostate cancer (PCa), there is no curative therapy for castration-resistant prostate cancer (CRPC). Therapeutic resistance in PCa can be characterized in two broad categories of AR therapy resistance: the first and most prevalent one involves restoration of AR activity despite AR targeted therapy, and the second one involves tumor progression despite blockade of AR activity. As such AR remains the most attractive drug target for CRPC. Despite its oncogenic role, AR signaling also contributes to the maturation and differentiation of prostate luminal cells during development. Recent evidence suggests that AR cistrome is altered in advanced PCa. Alteration in AR may result from AR amplification, alternative splicing, mutations, post-translational modification of AR, and altered expression of AR co-factors. We reasoned that such alterations would result in the transcription of disparate AR target genes and as such may contribute to the emergence of castration-resistance. In the present study, we evaluated the expression of genes associated with canonical or non-canonical AR cistrome in relationship with PCa progression and prostate development by analyzing publicly available datasets. We discovered a transcription switch from canonical AR cistrome target genes to the non-canonical AR cistrome target genes during PCa progression. Using Gene Set Enrichment Analysis (GSEA), we discovered that canonical AR cistrome target genes are enriched in indolent PCa patients and the loss of canonical AR cistrome is associated with tumor metastasis and poor clinical outcome. Analysis of the datasets involving prostate development, revealed that canonical AR cistrome target genes are significantly enriched in prostate luminal cells and can distinguish luminal cells from basal cells, suggesting a pivotal role for canonical AR cistrome driven genes in prostate development. These data suggest that the expression of canonical AR cistrome related genes play an important role in maintaining the prostate luminal cell identity and might restrict the lineage plasticity observed in lethal PCa. Understanding the molecular mechanisms that dictate AR cistrome may lead to development of new therapeutic strategies aimed at restoring canonical AR cistrome, rewiring the oncogenic AR signaling and overcome resistance to AR targeted therapies.

Cross-cultural adaptation and validation of the Ankle Osteoarthritis Scale for use in French-speaking populations.

PubMed

Angers, Magalie; Svotelis, Amy; Balg, Frederic; Allard, Jean-Pascal

2016-04-01

The Ankle Osteoarthritis Scale (AOS) is a self-administered score specific for ankle osteoarthritis (OA) with excellent reliability and strong construct and criterion validity. Many recent randomized multicentre trials have used the AOS, and the involvement of the French-speaking population is limited by the absence of a French version. Our goal was to develop a French version and validate the psychometric properties to assure equivalence to the original English version. Translation was performed according to American Association of Orthopaedic Surgeons (AAOS) 2000 guidelines for cross-cultural adaptation. Similar to the validation process of the English AOS, we evaluated the psychometric properties of the French version (AOS-Fr): criterion validity (AOS-Fr v. Western Ontario and McMaster Universities Arthritis Index [WOMAC] and SF-36 scores), construct validity (AOS-Fr correlation to single heel-lift test), and reliability (AOS-Fr test-retest). Sixty healthy individuals tested a prefinal version of the AOS-Fr for comprehension, leading to modifications and a final version that was approved by C. Saltzman, author of the AOS. We then recruited patients with ankle OA for evaluation of the AOS-Fr psychometric properties. Twenty-eight patients with ankle OA participated in the evaluation. The AOS-Fr showed strong criterion validity (AOS:WOMAC r = 0.709 and AOS:SF-36 r = -0.654) and construct validity (r = 0.664) and proved to be reliable (test-retest intraclass correlation coefficient = 0.922). The AOS-Fr is a reliable and valid score equivalent to the English version in terms of psychometric properties, thus is available for use in multicentre trials.

The influence of emotional stress on Doppler-derived aortic peak velocity in boxer dogs.

PubMed

Pradelli, D; Quintavalla, C; Crosta, M C; Mazzoni, L; Oliveira, P; Scotti, L; Brambilla, P; Bussadori, C

2014-01-01

Subaortic stenosis (SAS) is a common congenital heart disease in Boxers. Doppler-derived aortic peak velocity (AoPV) is a diagnostic criterion for the disease. To investigate the influence of emotional stress during echocardiographic examination on AoPV in normal and SAS-affected Boxers. To evaluate the effects of aortic root diameters on AoPV in normal Boxers. DOGS: Two hundred and fifteen normal and 19 SAS-affected Boxers. The AoPV was recorded at the beginning of echocardiographic examination (T0), and when the emotional stress of the dog was assumed to decrease based on behavioral parameters and heart rate (T1). AoPV0-AoPV1 was calculated. In normal dogs, stroke volume index was calculated at T0 and T1. Aortic root diameters were measured and their relationship with AoPV and AoPV0-AoPV1 was evaluated. In normal dogs, AoPV was higher at T0 (median, 1.95 m/s; range, 1.60-2.50 m/s) than at T1 (median, 1.76 m/s; range, 1.40-2.20 m/s; P < .0001; reduction 9.2%). The stroke volume index at T0 also was greater than at T1 (P < .0001). Weak negative correlations were detected between aortic root size and aortic velocities. In SAS-affected dogs, AoPV0 was higher than AoPV1 (P < .0001; reduction 7.3%). Aortic peak velocity was affected by emotional stress during echocardiographic examination both in SAS-affected and normal Boxers. In normal Boxers, aortic root size weakly affected AoPVs, but did not affect AoPV0-AoPV1. Stroke volume seems to play a major role in stress-related AoPV increases in normal Boxers. Emotional stress should be taken into account when screening for SAS in the Boxer breed. Copyright © 2014 by the American College of Veterinary Internal Medicine.

Calibration of Nu-Instruments Noblesse multicollector mass spectrometers for argon isotopic measurements using a newly developed reference gas

USGS Publications Warehouse

Coble, M.A.; Grove, M.; Calvert, A.T.

2011-01-01

The greatest challenge limiting 40Ar/39Ar multicollection measurements is the availability of appropriate standard gasses to intercalibrate detectors. In particular, use of zoom lens ion-optics to steer and focus ion beams into a fixed detector array (i.e., Nu Instruments Noblesse) makes intercalibration of multiple detectors challenging because different ion-optic tuning conditions are required for optimal peak shape and sensitivity at different mass stations. We have found that detector efficiency and mass discrimination are affected by changes in ion-optic tuning parameters. Reliance upon an atmospheric Ar standard to calibrate the Noblesse is problematic because there is no straightforward way to relate atmospheric 40Ar and 36Ar to measurements of 40Ar and 39Ar if they are measured on separate detectors. After exploring alternative calibration approaches, we have concluded that calibration of the Noblesse is best performed using exactly the same source, detector, and ion-optic tuning settings as those used in routine 40Ar/39Ar analysis. To accomplish this, we have developed synthetic reference gasses containing 40Ar, 39Ar and 38Ar produced by mixing gasses derived from neutron-irradiated sanidine with an enriched 38Ar spike. We present a new method for calibrating the Noblesse based on use of both atmospheric Ar and the synthetic reference gasses. By combining atmospheric Ar and synthetic reference gas in different ways, we can directly measure 40Ar/39Ar, 38Ar/39Ar, and 36Ar/39Ar correction factors over ratios that vary from 0.5 to 460. These correction factors are reproducible to better than ??0.5??? (2?? standard error) over intervals spanning ~24h but can vary systematically by ~4% over 2weeks of continuous use when electron multiplier settings are held constant. Monitoring this variation requires daily calibration of the instrument. Application of the calibration method to 40Ar/39Ar multicollection measurements of widely used sanidine reference materials ACs-2, FCs-2, and TCs-2 demonstrate that calculated 40Ar*/39ArK can be accurately corrected to yield model 40Ar/39Ar ages consistent with those reported by Earthtime 40Ar/39Ar laboratories. Replicate analyses of 8-12 single-crystal sanidine ages are reproduced to within 1-2??? (2?? standard error) under optimal analytical conditions. This calibration technique is applicable over a wide range of isotopic ratios and signal sizes. Finally, the reference gas has the added advantage of facilitating straightforward characterization of electron multiplier dead time over a wide dynamic range. ?? 2011 Elsevier B.V.

Androgen Receptor Variant AR-V9 Is Coexpressed with AR-V7 in Prostate Cancer Metastases and Predicts Abiraterone Resistance.

PubMed

Kohli, Manish; Ho, Yeung; Hillman, David W; Van Etten, Jamie L; Henzler, Christine; Yang, Rendong; Sperger, Jamie M; Li, Yingming; Tseng, Elizabeth; Hon, Ting; Clark, Tyson; Tan, Winston; Carlson, Rachel E; Wang, Liguo; Sicotte, Hugues; Thai, Ho; Jimenez, Rafael; Huang, Haojie; Vedell, Peter T; Eckloff, Bruce W; Quevedo, Jorge F; Pitot, Henry C; Costello, Brian A; Jen, Jin; Wieben, Eric D; Silverstein, Kevin A T; Lang, Joshua M; Wang, Liewei; Dehm, Scott M

2017-08-15

Purpose: Androgen receptor (AR) variant AR-V7 is a ligand-independent transcription factor that promotes prostate cancer resistance to AR-targeted therapies. Accordingly, efforts are under way to develop strategies for monitoring and inhibiting AR-V7 in castration-resistant prostate cancer (CRPC). The purpose of this study was to understand whether other AR variants may be coexpressed with AR-V7 and promote resistance to AR-targeted therapies. Experimental Design: We utilized complementary short- and long-read sequencing of intact AR mRNA isoforms to characterize AR expression in CRPC models. Coexpression of AR-V7 and AR-V9 mRNA in CRPC metastases and circulating tumor cells was assessed by RNA-seq and RT-PCR, respectively. Expression of AR-V9 protein in CRPC models was evaluated with polyclonal antisera. Multivariate analysis was performed to test whether AR variant mRNA expression in metastatic tissues was associated with a 12-week progression-free survival endpoint in a prospective clinical trial of 78 CRPC-stage patients initiating therapy with the androgen synthesis inhibitor, abiraterone acetate. Results: AR-V9 was frequently coexpressed with AR-V7. Both AR variant species were found to share a common 3' terminal cryptic exon, which rendered AR-V9 susceptible to experimental manipulations that were previously thought to target AR-V7 uniquely. AR-V9 promoted ligand-independent growth of prostate cancer cells. High AR-V9 mRNA expression in CRPC metastases was predictive of primary resistance to abiraterone acetate (HR = 4.0; 95% confidence interval, 1.31-12.2; P = 0.02). Conclusions: AR-V9 may be an important component of therapeutic resistance in CRPC. Clin Cancer Res; 23(16); 4704-15. ©2017 AACR . ©2017 American Association for Cancer Research.

Analysis of an acyl-CoA binding protein in Aspergillus oryzae that undergoes unconventional secretion.

PubMed

Kwon, Hee Su; Kawaguchi, Kouhei; Kikuma, Takashi; Takegawa, Kaoru; Kitamoto, Katsuhiko; Higuchi, Yujiro

2017-11-04

Acyl-CoA binding protein (ACBP) plays important roles in the metabolism of lipids in eukaryotic cells. In the industrially important filamentous fungus Aspergillus oryzae, although we have previously demonstrated that the A. oryzae ACBP (AoACBP) localizes to punctate structures and exhibits long-range motility, which is dependent on autophagy-related proteins, the physiological role of AoACBP remains elusive. Here, we describe identification and characterization of another ACBP from A. oryzae; we named this ACBP as AoAcb2 and accordingly renamed AoACBP as AoAcb1. The deduced amino acid sequence of AoAcb2 lacked a signal peptide. Phylogenetic analysis classified AoAcb2 into a clade that was same as the ACBP Acb1 of the model yeast Saccharomyces cerevisiae, but was different from that of AoAcb1. In contrast to punctate localization of AoAcb1, AoAcb2 was found to be dispersedly distributed in the cytoplasm, as was previously observed for the S. cerevisiae Acb1. Since we could not generate an Aoacb2 disruptant, we created an Aoacb2 conditional mutant that exhibited less growth under Aoacb2-repressed condition, suggesting that Aoacb2 is an essential gene for growth. Moreover, we observed that A. oryzae AoAcb2, but not A. oryzae AoAcb1, was secreted under carbon-starved condition, suggesting that AoAcb2 might be secreted via the unconventional protein secretion (UPS) pathway, just like S. cerevisiae Acb1. We also demonstrated that the unconventional secretion of AoAcb2 was dependent on the t-SNARE AoSso1, but was independent of the autophagy-related protein AoAtg1, suggesting that the unconventional secretion of AoAcb2, unlike that of S. cerevisiae Acb1, via the UPS pathway, is not regulated by the autophagy machinery. Thus, the filamentous fungus A. oryzae harbors two types of ACBPs, one of which appears to be essential for growth and undergoes unconventional secretion. Copyright © 2017 Elsevier Inc. All rights reserved.

Androgen Receptor and its Splice Variant, AR-V7, Differentially Regulate FOXA1 Sensitive Genes in LNCaP Prostate Cancer Cells

PubMed Central

Krause, William C.; Shafi, Ayesha A.; Nakka, Manjula; Weigel, Nancy L.

2014-01-01

Prostate cancer (PCa) is an androgen-dependent disease, and tumors that are resistant to androgen ablation therapy often remain androgen receptor (AR) dependent. Among the contributors to castration-resistant PCa are AR splice variants that lack the ligand-binding domain (LBD). Instead, they have small amounts of unique sequence derived from cryptic exons or from out of frame translation. The AR-V7 (or AR3) variant is constitutively active and is expressed under conditions consistent with CRPC. AR-V7 is reported to regulate a transcriptional program that is similar but not identical to that of AR. However, it is unknown whether these differences are due to the unique sequence in AR-V7, or simply to loss of the LBD. To examine transcriptional regulation by AR-V7, we have used lentiviruses encoding AR-V7 (amino acids 1-627 of AR with the 16 amino acids unique to the variant) to prepare a derivative of the androgen-dependent LNCaP cells with inducible expression of AR-V7. An additional cell line was generated with regulated expression of AR-NTD (amino acids 1-660 of AR); this mutant lacks the LBD but does not have the AR-V7 specific sequence. We find that AR and AR-V7 have distinct activities on target genes that are co-regulated by FOXA1. Transcripts regulated by AR-V7 were similarly regulated by AR-NTD, indicating that loss of the LBD is sufficient for the observed differences. Differential regulation of target genes correlates with preferential recruitment of AR or AR-V7 to specific cis-regulatory DNA sequences providing an explanation for some of the observed differences in target gene regulation. PMID:25008967

Variation in the terrestrial isotopic composition and atomic weight of argon

USGS Publications Warehouse

Böhlke, John Karl

2014-01-01

The isotopic composition and atomic weight of argon (Ar) are variable in terrestrial materials. Those variations are a source of uncertainty in the assignment of standard properties for Ar, but they provide useful information in many areas of science. Variations in the stable isotopic composition and atomic weight of Ar are caused by several different processes, including (1) isotope production from other elements by radioactive decay (radiogenic isotopes) or other nuclear transformations (e.g., nucleogenic isotopes), and (2) isotopic fractionation by physical-chemical processes such as diffusion or phase equilibria. Physical-chemical processes cause correlated mass-dependent variations in the Ar isotope-amount ratios (40Ar/36Ar, 38Ar/36Ar), whereas nuclear transformation processes cause non-mass-dependent variations. While atmospheric Ar can serve as an abundant and homogeneous isotopic reference, deviations from the atmospheric isotopic ratios in other Ar occurrences limit the precision with which a standard atomic weight can be given for Ar. Published data indicate variation of Ar atomic weights in normal terrestrial materials between about 39.7931 and 39.9624. The upper bound of this interval is given by the atomic mass of 40Ar, as some samples contain almost pure radiogenic 40Ar. The lower bound is derived from analyses of pitchblende (uranium mineral) containing large amounts of nucleogenic 36Ar and 38Ar. Within this interval, measurements of different isotope ratios (40Ar/36Ar or 38Ar/36Ar) at various levels of precision are widely used for studies in geochronology, water–rock interaction, atmospheric evolution, and other fields.

The Chromosomal Arsenic Resistance Genes of Thiobacillus ferrooxidans Have an Unusual Arrangement and Confer Increased Arsenic and Antimony Resistance to Escherichia coli

PubMed Central

Butcher, Bronwyn G.; Deane, Shelly M.; Rawlings, Douglas E.

2000-01-01

The chromosomal arsenic resistance genes of the acidophilic, chemolithoautotrophic, biomining bacterium Thiobacillus ferrooxidans were cloned and sequenced. Homologues of four arsenic resistance genes, arsB, arsC, arsH, and a putative arsR gene, were identified. The T. ferrooxidans arsB (arsenite export) and arsC (arsenate reductase) gene products were functional when they were cloned in an Escherichia coli ars deletion mutant and conferred increased resistance to arsenite, arsenate, and antimony. Therefore, despite the fact that the ars genes originated from an obligately acidophilic bacterium, they were functional in E. coli. Although T. ferrooxidans is gram negative, its ArsC was more closely related to the ArsC molecules of gram-positive bacteria. Furthermore, a functional trxA (thioredoxin) gene was required for ArsC-mediated arsenate resistance in E. coli; this finding confirmed the gram-positive ArsC-like status of this resistance and indicated that the division of ArsC molecules based on Gram staining results is artificial. Although arsH was expressed in an E. coli-derived in vitro transcription-translation system, ArsH was not required for and did not enhance arsenic resistance in E. coli. The T. ferrooxidans ars genes were arranged in an unusual manner, and the putative arsR and arsC genes and the arsBH genes were translated in opposite directions. This divergent orientation was conserved in the four T. ferrooxidans strains investigated. PMID:10788346

The potential of AR-V7 as a therapeutic target.

PubMed

Uo, Takuma; Plymate, Stephen R; Sprenger, Cynthia C

2018-03-01

The androgen receptor variant AR-V7 is gaining attention as a potential predictive marker for as well as one of the resistance mechanisms to the most current anti-androgen receptor (AR) therapies in castration-resistant prostate cancer (CRPC). Accordingly, development of next-generation drugs that directly or indirectly target AR-V7 signaling is urgently needed. Areas covered: We review proposed mechanisms of drug resistance in relation to AR-V7 status, the mechanisms of generation of AR-V7, and its transcriptome, cistrome, and interactome. Pharmacological agents that interfere with these processes are being developed to counteract pan AR and AR-V7-specific signaling. Also, we address the current status of the preclinical and clinical studies targeting AR-V7 signaling. Expert opinion: AR-V7 is considered a true therapeutic target, however, it remains to be determined if AR-V7 is a principal driver or merely a bystander requiring heterodimerization with co-expressed full-length AR or other variants to drive CRPC progression. While untangling AR-V7 biology, multiple strategies are being developed to counteract drug resistance, including selective blockade of AR-V7 signaling as well as inhibition of pan-AR signaling. Ideally anti-AR therapies will be combined with agents preventing activation and enrichment of AR negative tumor cells that are otherwise depressed by AR activity axis.

TALEN-engineered AR gene rearrangements reveal endocrine uncoupling of androgen receptor in prostate cancer

PubMed Central

Nyquist, Michael D.; Li, Yingming; Hwang, Tae Hyun; Manlove, Luke S.; Vessella, Robert L.; Silverstein, Kevin A. T.; Voytas, Daniel F.; Dehm, Scott M.

2013-01-01

Androgen receptor (AR) target genes direct development and survival of the prostate epithelial lineage, including prostate cancer (PCa). Thus, endocrine therapies that inhibit the AR ligand-binding domain (LBD) are effective in treating PCa. AR transcriptional reactivation is central to resistance, as evidenced by the efficacy of AR retargeting in castration-resistant PCa (CRPC) with next-generation endocrine therapies abiraterone and enzalutamide. However, resistance to abiraterone and enzalutamide limits this efficacy in most men, and PCa remains the second-leading cause of male cancer deaths. Here we show that AR gene rearrangements in CRPC tissues underlie a completely androgen-independent, yet AR-dependent, resistance mechanism. We discovered intragenic AR gene rearrangements in CRPC tissues, which we modeled using transcription activator-like effector nuclease (TALEN)-mediated genome engineering. This modeling revealed that these AR gene rearrangements blocked full-length AR synthesis, but promoted expression of truncated AR variant proteins lacking the AR ligand-binding domain. Furthermore, these AR variant proteins maintained the constitutive activity of the AR transcriptional program and a CRPC growth phenotype independent of full-length AR or androgens. These findings demonstrate that AR gene rearrangements are a unique resistance mechanism by which AR transcriptional activity can be uncoupled from endocrine regulation in CRPC. PMID:24101480

Transcriptional and posttranscriptional regulation of Bacillus sp. CDB3 arsenic-resistance operon ars1

PubMed Central

Yu, Xuefei; Zheng, Wei; Bhat, Somanath; Aquilina, J. Andrew

2015-01-01

Bacillus sp. CDB3 possesses a novel eight-gene ars cluster (ars1, arsRYCDATorf7orf8) with some unusual features in regard to expression regulation. This study demonstrated that the cluster is a single operon but can also produce a short three-gene arsRYC transcript. A hairpin structure formed by internal inverted repeats between arsC and arsD was shown to diminish the expression of the full operon, thereby probably acting as a transcription attenuator. A degradation product of the arsRYC transcript was also identified. Electrophoretic mobility shift analysis demonstrated that ArsR interacts with the ars1 promoter forming a protein-DNA complex that could be impaired by arsenite. However, no interaction was detected between ArsD and the ars1 promoter, suggesting that the CDB3 ArsD protein may not play a regulatory role. Compared to other ars gene clusters, regulation of the Bacillus sp. CDB3 ars1 operon is more complex. It represents another example of specific mRNA degradation in the transporter gene region and possibly the first case of attenuator-mediated regulation of ars operons. PMID:26355338

40Ar/36Ar analyses of historic lava flows

USGS Publications Warehouse

Dalrymple, G.B.

1969-01-01

The ratio 40Ar/36Ar was measured for 26 subaerial historic lava flows. Approximately one-third of the samples had 40Ar/36Ar ratios either higher or lower than the atmospheric value of 295.5 at the 95% confidence level. Excess radiogenic 40Ar in five flows ranged from about 1 ?? 10-13 to 1.5 ?? 10-12 mol/g. Possible excess 36Ar in three flows was on the order of 10-16 to 10-15 mol/g. Upper 95% confidence limits for excess 40Ar in samples with normal 40Ar/36Ar ratios are generally less than 3 ?? 10-13 mol/g. The origin of the excess 36Ar is unknown but it may be due either to the incorporation of primitive argon that has been stored in the mantle in very low potassium environments or to enrichment in 36Ar as atmospheric argon diffuses into the rocks after they cool. ?? 1969.

TBECH, 1,2-dibromo-4-(1,2 dibromoethyl) cyclohexane, alters androgen receptor regulation in response to mutations associated with prostate cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kharlyngdoh, Joubert Banjop; Asnake, Solomon; Prad

Point mutations in the AR ligand-binding domain (LBD) can result in altered AR structures leading to changes of ligand specificity and functions. AR mutations associated to prostate cancer (PCa) have been shown to result in receptor activation by non-androgenic substances and anti-androgenic drugs. Two AR mutations known to alter the function of anti-androgens are the AR{sub T877A} mutation, which is frequently detected mutation in PCa tumors and the AR{sub W741C} that is rare and has been derived in vitro following exposure of cells to the anti-androgen bicalutamide. AR activation by non-androgenic environmental substances has been suggested to affect PCa progression.more » In the present study we investigated the effect of AR mutations (AR{sub W741C} and AR{sub T877A}) on the transcriptional activation following exposure of cells to an androgenic brominated flame retardant, 1,2-dibromo-4-(1,2 dibromoethyl) cyclohexane (TBECH, also named DBE-DBCH). The AR mutations resulted in higher interaction energies and increased transcriptional activation in response to TBECH diastereomer exposures. The AR{sub T877A} mutation rendered AR highly responsive to low levels of DHT and TBECH and led to increased AR nuclear translocation. Gene expression analysis showed a stronger induction of AR target genes in LNCaP cells (AR{sub T877A}) compared to T-47D cells (AR{sub WT}) following TBECH exposure. Furthermore, AR knockdown experiments confirmed the AR dependency of these responses. The higher sensitivity of AR{sub T877A} and AR{sub W741C} to low levels of TBECH suggests that cells with these AR mutations are more susceptible to androgenic endocrine disrupters. - Highlights: • TBECH, is an endocrine disrupting compound that differ in activity depending on AR structure and sequence. • TBECH interaction with the human AR-LBD containing the mutations W741C and T877A is increased compared to the wild type receptor • The mutations, W741C and T877A, are more potent than the wild type receptor at inducing AR nuclear translocation and transcriptional activation following TBECH exposure. • TBECH mediates action on androgen response genes via AR signaling.« less

Subcellular localization of acyl-CoA binding protein in Aspergillus oryzae is regulated by autophagy machinery.

PubMed

Kawaguchi, Kouhei; Kikuma, Takashi; Higuchi, Yujiro; Takegawa, Kaoru; Kitamoto, Katsuhiko

2016-11-04

In eukaryotic cells, acyl-CoA binding protein (ACBP) is important for cellular activities, such as in lipid metabolism. In the industrially important fungus Aspergillus oryzae, the ACBP, known as AoACBP, has been biochemically characterized, but its physiological function is not known. In the present study, although we could not find any phenotype of AoACBP disruptants in the normal growth conditions, we examined the subcellular localization of AoACBP to understand its physiological function. Using an enhanced green fluorescent protein (EGFP)-tagged AoACBP construct we showed that AoACBP localized to punctate structures in the cytoplasm, some of which moved inside the cells in a microtubule-dependent manner. Further microscopic analyses showed that AoACBP-EGFP co-localized with the autophagy marker protein AoAtg8 tagged with red fluorescent protein (mDsRed). Expression of AoACBP-EGFP in disruptants of autophagy-related genes revealed aggregation of AoACBP-EGFP fluorescence in the cytoplasm of Aoatg1, Aoatg4 and Aoatg8 disruptant cells. However, in cells harboring disruption of Aoatg15, which encodes a lipase for autophagic body, puncta of AoACBP-EGFP fluorescence accumulated in vacuoles, indicating that AoACBP is transported to vacuoles via the autophagy machinery. Collectively, these results suggest the existence of a regulatory mechanism between AoACBP localization and autophagy. Copyright © 2016 Elsevier Inc. All rights reserved.

A possible cause of the AO polarity reversal from winter to summer in 2010 and its relation to hemispheric extreme summer weather

NASA Astrophysics Data System (ADS)

Otomi, Yuriko; Tachibana, Yoshihiro; Nakamura, Tetsu

2013-04-01

In 2010, the Northern Hemisphere, in particular Russia and Japan, experienced an abnormally hot summer characterized by record-breaking warm temperatures and associated with a strongly positive Arctic Oscillation (AO), that is, low pressure in the Arctic and high pressure in the midlatitudes. In contrast, the AO index the previous winter and spring (2009/2010) was record-breaking negative. The AO polarity reversal that began in summer 2010 can explain the abnormally hot summer. The winter sea surface temperatures (SST) in the North Atlantic Ocean showed a tripolar anomaly pattern—warm SST anomalies over the tropics and high latitudes and cold SST anomalies over the midlatitudes—under the influence of the negative AO. The warm SST anomalies continued into summer 2010 because of the large oceanic heat capacity. A model simulation strongly suggested that the AO-related summertime North Atlantic oceanic warm temperature anomalies remotely caused blocking highs to form over Europe, which amplified the positive summertime AO. Thus, a possible cause of the AO polarity reversal might be the "memory" of the negative winter AO in the North Atlantic Ocean, suggesting an interseasonal linkage of the AO in which the oceanic memory of a wintertime negative AO induces a positive AO in the following summer. Understanding of this interseasonal linkage may aid in the long-term prediction of such abnormal summer events.

A possible cause of the AO polarity reversal from winter to summer in 2010 and its relation to hemispheric extreme hot summer

NASA Astrophysics Data System (ADS)

Tachibana, Yoshihiro; Otomi, Yuriko; Nakamura, Tetsu

2013-04-01

In 2010, the Northern Hemisphere, in particular Russia and Japan, experienced an abnormally hot summer characterized by record-breaking warm temperatures and associated with a strongly positive Arctic Oscillation (AO), that is, low pressure in the Arctic and high pressure in the midlatitudes. In contrast, the AO index the previous winter and spring (2009/2010) was record-breaking negative. The AO polarity reversal that began in summer 2010 can explain the abnormally hot summer. The winter sea surface temperatures (SST) in the North Atlantic Ocean showed a tripolar anomaly pattern—warm SST anomalies over the tropics and high latitudes and cold SST anomalies over the midlatitudes—under the influence of the negative AO. The warm SST anomalies continued into summer 2010 because of the large oceanic heat capacity. A model simulation strongly suggested that the AO-related summertime North Atlantic oceanic warm temperature anomalies remotely caused blocking highs to form over Europe, which amplified the positive summertime AO. Thus, a possible cause of the AO polarity reversal might be the "memory" of the negative winter AO in the North Atlantic Ocean, suggesting an interseasonal linkage of the AO in which the oceanic memory of a wintertime negative AO induces a positive AO in the following summer. Understanding of this interseasonal linkage may aid in the long-term prediction of such abnormal summer events.

Both alpha(1A)- and alpha(1B)-adrenergic receptors crosstalk to down regulate beta(1)-ARs in mouse heart: coupling to differential PTX-sensitive pathways.

PubMed

Rorabaugh, Boyd R; Gaivin, Robert J; Papay, Robert S; Shi, Ting; Simpson, Paul C; Perez, Dianne M

2005-11-01

Adrenergic receptors (ARs) play an important role in the regulation of cardiac function. Cardiac inotropy is primarily regulated by beta(1)-ARs. However, alpha(1)-ARs may play an important role in inotropy during heart failure. Previous work has suggested that the alpha(1B)-AR modulates beta(1)-AR function in the heart. The potential role of the alpha(1A)-AR has not been previously studied. We used transgenic mice that express constitutively active mutant (CAM) forms of the alpha(1A)-AR or alpha(1B)-AR regulated by their endogenous promoters. Expression of the CAM alpha(1A)-AR or CAM alpha(1B)-AR had no effect on basal cardiac function (developed pressure, +dP/dT, -dP/dT, heart rate, flow rate). However, both alpha(1)-AR subtypes significantly decreased isoproterenol-stimulated +dP/dT. Pertussis toxin had no effect on +dP/dT in CAM alpha(1A)-AR hearts but restored +dP/dT to non-transgenic values in CAM alpha(1B)-AR hearts. Radioligand binding indicated a selective decrease in the density of beta(1)-ARs in both CAM mice. However, G-proteins, cAMP, or the percentage of high and low affinity states were unchanged in either transgenic compared with control. These data demonstrate that CAM alpha(1A)- and alpha(1B)-ARs both down regulate beta(1)-AR-mediated inotropy in the mouse heart. However, alpha(1)-AR subtypes are coupled to different beta-AR mediated signaling pathways with the alpha(1B)-AR being pertussis toxin sensitive.

Controlling Androgen receptor nuclear localization by dendrimer conjugates

NASA Astrophysics Data System (ADS)

Wang, Haoyu

Androgen Receptor (AR) antagonists, such as bicalutamide and flutamide have been used widely in the treatment of prostate cancer. Although initial treatment is effective, prostate cancer cells often acquire antiandrogen resistance with prolonged treatment. AR over-expression and AR mutations contribute to the development of antiandrogen resistant cancer. Second generation antiandrogens such as enzalutamide are more effective and show reduced AR nuclear localization. In this study, derivatives of PAN52, a small molecule antiandrogen previously developed in our lab, were conjugated to the surface of generation 4 and generation 6 PAMAM dendrimers to obtain antiandrogen PAMAM dendrimer conjugates (APDC). APDCs readily enter cells and associate with AR in the cytoplasm. Due to their large size and positive charge, they can not enter the nucleus, thus retaining AR in the cytoplasm. In addition, APDCs are effective in decreasing AR mediated transcription and cell proliferation. APDC is the first AR antagonists that inhibit DHT-induced nuclear localization of AR. By inhibiting AR nuclear localization, APDC represents a new class of antiandrogens that offer an alternative approach to addressing antiandrogen-resistant prostate cancer. Lysine post-translational modification of AR Nuclear Localization Sequence (NLS) has great impact on AR cellular localization. It is of interest to understand which modifications modulate AR translocation into the nucleus. In this study, we prepared dendrimer-based acetyltransferase mimetic (DATM), DATM is able to catalytically acetylate AR in CWR22Rv1 cells, which will be a useful tool for studying AR modification effect on AR cellular localization. Derivatives of DATM, which transfer other chemical groups to AR, can be prepared similarly, and with more dendrimer based AR modification tools prepared in future, we will be able to understand and control AR cellular localization through AR modification.

Baicalein suppresses the androgen receptor (AR)-mediated prostate cancer progression via inhibiting the AR N-C dimerization and AR-coactivators interaction.

PubMed

Xu, Defeng; Chen, Qiulu; Liu, Yalin; Wen, Xingqiao

2017-12-01

Androgen receptor (AR) plays a critical role in prostate cancer (PCa) development and progression. Androgen deprivation therapy with antiandrogens to reduce androgen biosynthesis or prevent androgens from binding to AR are widely used to suppress AR-mediated PCa growth. However, most of ADT may eventually fail with development of the castration resistance after 12-24 months. Here we found that a natural product baicalein can effectively suppress the PCa progression via targeting the androgen-induced AR transactivation with little effect to AR protein expression. PCa cells including LNCaP, CWR22Rv1, C4-2, PC-3, and DU145, were treated with baicalein and luciferase assay was used to evaluate their effect on the AR transactivation. Cell growth and IC 50 were determined by MTT assay after 48 hrs treatment. RT-PCR was used to evaluate the mRNA levels of AR target genes including PSA, TMPRSS2, and TMEPA1. Western blot was used to determine AR and PSA protein expression. The natural product of baicalein can selectively inhibit AR transactivation with little effect on the other nuclear receptors, including ERα, and GR. At a low concentration, 2.5 μM of baicalein effectively suppresses the growth of AR-positive PCa cells, and has little effect on AR-negative PCa cells. Mechanism dissection suggest that baicalein can suppress AR target genes (PSA, TMPRSS2, and TMEPA1) expression in both androgen responsive LNCaP cells and castration resistant CWR22Rv1 cells, that may involve the inhibiting the AR N/C dimerization and AR-coactivators interaction. Baicalein may be developed as an effective anti-AR therapy via its ability to inhibit AR transactivation and AR-mediated PCa cell growth.

Celastrol Induces Autophagy by Targeting AR/miR-101 in Prostate Cancer Cells

PubMed Central

Guo, Jianquan; Huang, Xuemei; Wang, Hui; Yang, Huanjie

2015-01-01

Autophagy is an evolutionarily conserved process responsible for the degradation and recycling of cytoplasmic components through autolysosomes. Targeting AR axis is a standard strategy for prostate cancer treatment; however, the role of AR in autophagic processes is still not fully understood. In the present study, we found that AR played a negative role in AR degrader celastrol-induced autophagy. Knockdown of AR in AR-positive prostate cancer cells resulted in enhanced autophagy. Ectopic expression of AR in AR-negative prostate cancer cells, or gain of function of the AR signaling in AR-positive cells, led to suppression of autophagy. Since miR-101 is an inhibitor of autophagy and its expression was decreased along with AR in the process of celastrol-induced autophagy, we hypothesize that AR inhibits autophagy through transactivation of miR-101. AR binding site was defined in the upstream of miR-101 gene by luciferase reporter and ChIP assays. MiR-101 expression correlated with AR status in prostate cancer cell lines. The inhibition of celastrol-induced autophagy by AR was compromised by blocking miR-101; while transfection of miR-101 led to inhibition of celastrol-induced autophagy in spite of AR depletion. Furthermore, mutagenesis of the AR binding site in miR-101 gene led to decreased suppression of autophagy by AR. Finally, autophagy inhibition by miR-101 mimic was found to enhance the cytotoxic effect of celastrol in prostate cancer cells. Our results demonstrate that AR inhibits autophagy via transactivation of miR-101, thus combination of miR-101 mimics with celastrol may represent a promising therapeutic approach for treating prostate cancer. PMID:26473737

Functional analysis of fructosyl-amino acid oxidases of Aspergillus oryzae.

PubMed

Akazawa, Shin-Ichi; Karino, Tetsuya; Yoshida, Nobuyuki; Katsuragi, Tohoru; Tani, Yoshiki

2004-10-01

Three active fractions of fructosyl-amino acid oxidase (FAOD-Ao1, -Ao2a, and -Ao2b) were isolated from Aspergillus oryzae strain RIB40. N-terminal and internal amino acid sequences of FAOD-Ao2a corresponded to those of FAOD-Ao2b, suggesting that these two isozymes were derived from the same protein. FAOD-Ao1 and -Ao2 were different in substrate specificity and subunit assembly; FAOD-Ao2 was active toward N(epsilon)-fructosyl N(alpha)-Z-lysine and fructosyl valine (Fru-Val), whereas FAOD-Ao1 was not active toward Fru-Val. The genes encoding the FAOD isozymes (i.e., FAOAo1 and FAOAo2) were cloned by PCR with an FAOD-specific primer set. The deduced amino acid sequences revealed that FAOD-Ao1 was 50% identical to FAOD-Ao2, and each isozyme had a peroxisome-targeting signal-1, indicating their localization in peroxisomes. The genes was expressed in Escherichia coli and rFaoAo2 showed the same characteristics as FAOD-Ao2, whereas rFaoAo1 was not active. FAOAo2 disruptant was obtained by using ptrA as a selective marker. Wild-type strain grew on the medium containing Fru-Val as the sole carbon and nitrogen sources, but strain Delta faoAo2 did not grow. Addition of glucose or (NH(4))(2)SO(4) to the Fru-Val medium did not affect the assimilation of Fru-Val by wild-type, indicating glucose and ammonium repressions did not occur in the expression of the FAOAo2 gene. Furthermore, conidia of the wild-type strain did not germinate on the medium containing Fru-Val and NaNO(2) as the sole carbon and nitrogen sources, respectively, suggesting that Fru-Val may also repress gene expression of nitrite reductase. These results indicated that FAOD is needed for utilization of fructosyl-amino acids as nitrogen sources in A. oryzae.

Into the blue: AO science with MagAO in the visible

NASA Astrophysics Data System (ADS)

Close, Laird M.; Males, Jared R.; Follette, Katherine B.; Hinz, Phil; Morzinski, Katie; Wu, Ya-Lin; Kopon, Derek; Riccardi, Armando; Esposito, Simone; Puglisi, Alfio; Pinna, Enrico; Xompero, Marco; Briguglio, Runa; Quiros-Pacheco, Fernando

2014-08-01

We review astronomical results in the visible (λ<1μm) with adaptive optics. Other than a brief period in the early 1990s, there has been little astronomical science done in the visible with AO until recently. The most productive visible AO system to date is our 6.5m Magellan telescope AO system (MagAO). MagAO is an advanced Adaptive Secondary system at the Magellan 6.5m in Chile. This secondary has 585 actuators with < 1 msec response times (0.7 ms typically). We use a pyramid wavefront sensor. The relatively small actuator pitch (~23 cm/subap) allows moderate Strehls to be obtained in the visible (0.63-1.05 microns). We use a CCD AO science camera called "VisAO". On-sky long exposures (60s) achieve <30mas resolutions, 30% Strehls at 0.62 microns (r') with the VisAO camera in 0.5" seeing with bright R < 8 mag stars. These relatively high visible wavelength Strehls are made possible by our powerful combination of a next generation ASM and a Pyramid WFS with 378 controlled modes and 1000 Hz loop frequency. We'll review the key steps to having good performance in the visible and review the exciting new AO visible science opportunities and refereed publications in both broad-band (r,i,z,Y) and at Halpha for exoplanets, protoplanetary disks, young stars, and emission line jets. These examples highlight the power of visible AO to probe circumstellar regions/spatial resolutions that would otherwise require much larger diameter telescopes with classical infrared AO cameras.

Asparagus IRX9, IRX10, and IRX14A Are Components of an Active Xylan Backbone Synthase Complex that Forms in the Golgi Apparatus1[OPEN

PubMed Central

Zeng, Wei; Picard, Kelsey L.; Song, Lili; Wu, Ai-Min; Farion, Isabela M.; Zhao, Jia; Ford, Kris; Bacic, Antony

2016-01-01

Heteroxylans are abundant components of plant cell walls and provide important raw materials for the food, pharmaceutical, and biofuel industries. A number of studies in Arabidopsis (Arabidopsis thaliana) have suggested that the IRREGULAR XYLEM9 (IRX9), IRX10, and IRX14 proteins, as well as their homologs, are involved in xylan synthesis via a Golgi-localized complex termed the xylan synthase complex (XSC). However, both the biochemical and cell biological research lags the genetic and molecular evidence. In this study, we characterized garden asparagus (Asparagus officinalis) stem xylan biosynthesis genes (AoIRX9, AoIRX9L, AoIRX10, AoIRX14A, and AoIRX14B) by heterologous expression in Nicotiana benthamiana. We reconstituted and partially purified an active XSC and showed that three proteins, AoIRX9, AoIRX10, and AoIRX14A, are necessary for xylan xylosyltranferase activity in planta. To better understand the XSC structure and its composition, we carried out coimmunoprecipitation and bimolecular fluorescence complementation analysis to show the molecular interactions between these three IRX proteins. Using a site-directed mutagenesis approach, we showed that the DxD motifs of AoIRX10 and AoIRX14A are crucial for the catalytic activity. These data provide, to our knowledge, the first lines of biochemical and cell biological evidence that AoIRX9, AoIRX10, and AoIRX14A are core components of a Golgi-localized XSC, each with distinct roles for effective heteroxylan biosynthesis. PMID:26951434

β-Adrenergic Receptor-Mediated Cardiac Contractility is Inhibited via Vasopressin Type 1A-Receptor-Dependent Signaling

PubMed Central

Tilley, Douglas G.; Zhu, Weizhong; Myers, Valerie D.; Barr, Larry A.; Gao, Erhe; Li, Xue; Song, Jianliang; Carter, Rhonda L.; Makarewich, Catherine A.; Yu, Daohai; Troupes, Constantine D.; Grisanti, Laurel A.; Coleman, Ryan C.; Koch, Walter J.; Houser, Steven R.; Cheung, Joseph Y.; Feldman, Arthur M.

2014-01-01

Background Enhanced arginine vasopressin (AVP) levels are associated with increased mortality during end-stage human heart failure (HF), and cardiac AVP type 1A receptor (V1AR) expression becomes increased. Additionally, mice with cardiac-restricted V1AR overexpression develop cardiomyopathy and decreased β-adrenergic receptor (βAR) responsiveness. This led us to hypothesize that V1AR signaling regulated βAR responsiveness and in doing so contributes to HF development. Methods and Results Transaortic constriction resulted in decreased cardiac function and βAR density and increased cardiac V1AR expression, effects reversed by a V1AR-selective antagonist. Molecularly, V1AR stimulation led to decreased βAR ligand affinity, as well as βAR-induced Ca2+ mobilization and cAMP generation in isolated adult cardiomyocytes, effects recapitulated via ex vivo Langendorff analysis. V1AR-mediated regulation of βAR responsiveness was demonstrated to occur in a previously unrecognized Gq protein-independent/GRK-dependent manner. Conclusions This newly discovered relationship between cardiac V1AR and βAR may be informative for the treatment of patients with acute decompensated HF and elevated AVP. PMID:25205804

DOE Office of Scientific and Technical Information (OSTI.GOV)

Aciego, S.M.; Jourdan, F.; DePaolo, D.J.

Late Quaternary, post-shield lavas from the Mauna Kea and Kohala volcanoes on the Big Island of Hawaii have been dated using the {sup 40}Ar/{sup 39}Ar and U-Th/He methods. The objective of the study is to compare the recently demonstrated U-Th/He age method, which uses basaltic olivine phenocrysts, with {sup 40}Ar/{sup 39}Ar ages measured on groundmass from the same samples. As a corollary, the age data also increase the precision of the chronology of volcanism on the Big Island. For the U-Th/He ages, U, Th and He concentrations and isotopes were measured to account for U-series disequilibrium and initial He. Singlemore » analyses U-Th/He ages for Hamakua lavas from Mauna Kea are 87 {+-} 40 ka to 119 {+-} 23 ka (2{sigma} uncertainties), which are in general equal to or younger than {sup 40}Ar/{sup 39}Ar ages. Basalt from the Polulu sequence on Kohala gives a U-Th/He age of 354 {+-} 54 ka and a {sup 40}Ar/{sup 39}Ar age of 450 {+-} 40 ka. All of the U-Th/He ages, and all but one spurious {sup 40}Ar/{sup 39}Ar ages conform to the previously proposed stratigraphy and published {sup 14}C and K-Ar ages. The ages also compare favorably to U-Th whole rock-olivine ages calculated from {sup 238}U - {sup 230}Th disequilibria. The U-Th/He and {sup 40}Ar/{sup 39}Ar results agree best where there is a relatively large amount of radiogenic {sup 40}Ar (>10%), and where the {sup 40}Ar/{sup 36}Ar intercept calculated from the Ar isochron diagram is close to the atmospheric value. In two cases, it is not clear why U-Th/He and {sup 40}Ar/{sup 39}Ar ages do not agree within uncertainty. U-Th/He and {sup 40}Ar/{sup 39}Ar results diverge the most on a low-K transitional tholeiitic basalt with abundant olivine. For the most alkalic basalts with negligible olivine phenocrysts, U-Th/He ages were unattainable while {sup 40}Ar/{sup 39}Ar results provide good precision even on ages as low as 19 {+-} 4 ka. Hence, the strengths and weaknesses of the U-Th/He and {sup 40}Ar/{sup 39}Ar methods are complimentary for basalts with ages of order 100-500 ka.« less

Androgen receptor polyglutamine repeat length affects receptor activity and C2C12 cell development.

PubMed

Sheppard, Ryan L; Spangenburg, Espen E; Chin, Eva R; Roth, Stephen M

2011-10-20

Testosterone (T) has an anabolic effect on skeletal muscle and is believed to exert its local effects via the androgen receptor (AR). The AR harbors a polymorphic stretch of glutamine repeats demonstrated to inversely affect receptor transcriptional activity in prostate and kidney cells. The effects of AR glutamine repeat length on skeletal muscle are unknown. In this study we examined the effect of AR CAG repeat length on AR function in C2C12 cells. AR expression vectors harboring 14, 24, and 33 CAG repeats were used to assess AR transcriptional activity. C2C12 cell proliferation, differentiation, gene expression, myotube formation, and myonuclear fusion index were assessed. Transcriptional activity increased with increasing repeat length and in response to testosterone (AR14 = 3.91 ± 0.26, AR24 = 25.21 ± 1.72, AR33 = 36.08 ± 3.22 relative light units; P < 0.001). Ligand activation was increased for AR33 (2.10 ± 0.04) compared with AR14 (1.54 ± 0.09) and AR24 (1.57 ± 0.05, P < 0.001). AR mRNA expression was elevated in each stably transfected line. AR33 cell proliferation (20,512.3 ± 1,024.0) was decreased vs. AR14 (27,604.17 ± 1,425.3; P < 0.001) after 72 h. Decreased CK activity in AR14 cells (54.9 ± 2.9 units/μg protein) in comparison to AR33 (70.8 ± 8.1) (P < 0.05) was noted. The myonuclear fusion index was lower for AR14 (15.21 ± 3.24%) and AR33 (9.97 ± 3.14%) in comparison to WT (35.07 ± 5.60%, P < 0.001). AR14 and AR33 cells also displayed atypical myotube morphology. RT-PCR revealed genotype differences in myostatin and myogenin expression. We conclude that AR polyglutamine repeat length is directly associated with transcriptional activity and alters the growth and development of C2C12 cells. This polymorphism may contribute to the heritability of muscle mass in humans.

The effect of SEM imaging on the Ar/Ar system in feldspars

NASA Astrophysics Data System (ADS)

Flude, S.; Sherlock, S.; Lee, M.; Kelley, S. P.

2010-12-01

Complex microtextures form in K-feldspar crystals as they cool and are affected by deuteric alteration. This complex structure is the cause of variable closure temperatures for Ar-Ar, a phenomenon which has been utilized in multi domain diffusion (MDD) modelling to recover thermal histories [1]. However, there has been substantial controversy regarding the precise interaction between feldspar microtextures and Ar-diffusion [2,3]. A number of studies have addressed this issue using coupled SEM imaging and Ar/Ar UV laser ablation microprobe (UV-LAMP) analysis on the same sample, to enable direct comparison of microtextures with Ar/Ar age data [4]. Here we have tested the idea that SEM work may affect Ar/Ar ages, leading to inaccurate results in subsequent Ar/Ar analyses. Three splits of alkali feldspar from the Dartmoor Granite in SW England were selected for Ar/Ar UV-LAMP analysis. Split 1 (“control”) was prepared as a polished thick section for Ar/Ar analysis. Split 2 (“SEM”) was prepared as a polished thick section, was chemically-mechanically polished with colloidal silica and underwent SEM imaging (uncoated) and focussed ion beam (FIB) milling (gold coated); electron beam damage in the SEM was maximised by leaving the sample at high magnification for eight minutes. Split 3 (“Etch”) is a cleavage fragment that was etched with HF vapour and underwent low to moderate magnification SEM imaging. The control split gave a range of laser-spot ages consistent with the expected cooling age of the granite and high yields of radiogenic 40Ar* (>90%). The area of the “SEM” split that experienced significant electron beam damage gave younger than expected ages and 40Ar* yields as low as 57%. These are interpreted as a combination of implantation of atmospheric Ar and local redistribution of K within the sample. The area of “SEM” that underwent FIB milling gave ages and 40Ar* yields comparable to the control split, suggesting that the Au-coat minimises FIB damage and that colloidal-polishing and low-magnification SEM imaging do not affect the Ar/Ar system. The “Etch” split gave younger than expected ages and 40Ar* yields as low as 58%, suggesting that HF etching also disrupts the Ar/Ar system. These results suggest that SEM techniques involving intense electron bombardment of an uncoated sample, such as charge contrast imaging and electron backscatter diffraction (EBSD), may disrupt the Ar/Ar system in the sample, leading to spurious results. Etching samples with HF, as is often done for routine Ar/Ar preparation of volcanic phenocrysts, introduces atmospheric Ar and may result in differential loss or gain of K and Ar isotopes, leading to spurious results. References [1] Lovera and Richter, 1989, J. Geophys. Res. 94, 17917-17935. [2] Parsons. et al., 1999, Cont. Min. Pet. 136, 92-110. [3] Mark et al., 2008, Geochim. Cosmochim. Acta, 72 2695-2710. [4] Reddy et al., 2001, Cont. Min. Pet., 141 186-200.

Audiovisual spoken word training can promote or impede auditory-only perceptual learning: prelingually deafened adults with late-acquired cochlear implants versus normal hearing adults

PubMed Central

Bernstein, Lynne E.; Eberhardt, Silvio P.; Auer, Edward T.

2014-01-01

Training with audiovisual (AV) speech has been shown to promote auditory perceptual learning of vocoded acoustic speech by adults with normal hearing. In Experiment 1, we investigated whether AV speech promotes auditory-only (AO) perceptual learning in prelingually deafened adults with late-acquired cochlear implants. Participants were assigned to learn associations between spoken disyllabic C(=consonant)V(=vowel)CVC non-sense words and non-sense pictures (fribbles), under AV and then AO (AV-AO; or counter-balanced AO then AV, AO-AV, during Periods 1 then 2) training conditions. After training on each list of paired-associates (PA), testing was carried out AO. Across all training, AO PA test scores improved (7.2 percentage points) as did identification of consonants in new untrained CVCVC stimuli (3.5 percentage points). However, there was evidence that AV training impeded immediate AO perceptual learning: During Period-1, training scores across AV and AO conditions were not different, but AO test scores were dramatically lower in the AV-trained participants. During Period-2 AO training, the AV-AO participants obtained significantly higher AO test scores, demonstrating their ability to learn the auditory speech. Across both orders of training, whenever training was AV, AO test scores were significantly lower than training scores. Experiment 2 repeated the procedures with vocoded speech and 43 normal-hearing adults. Following AV training, their AO test scores were as high as or higher than following AO training. Also, their CVCVC identification scores patterned differently than those of the cochlear implant users. In Experiment 1, initial consonants were most accurate, and in Experiment 2, medial consonants were most accurate. We suggest that our results are consistent with a multisensory reverse hierarchy theory, which predicts that, whenever possible, perceivers carry out perceptual tasks immediately based on the experience and biases they bring to the task. We point out that while AV training could be an impediment to immediate unisensory perceptual learning in cochlear implant patients, it was also associated with higher scores during training. PMID:25206344

Audiovisual spoken word training can promote or impede auditory-only perceptual learning: prelingually deafened adults with late-acquired cochlear implants versus normal hearing adults.

PubMed

Bernstein, Lynne E; Eberhardt, Silvio P; Auer, Edward T

2014-01-01

Training with audiovisual (AV) speech has been shown to promote auditory perceptual learning of vocoded acoustic speech by adults with normal hearing. In Experiment 1, we investigated whether AV speech promotes auditory-only (AO) perceptual learning in prelingually deafened adults with late-acquired cochlear implants. Participants were assigned to learn associations between spoken disyllabic C(=consonant)V(=vowel)CVC non-sense words and non-sense pictures (fribbles), under AV and then AO (AV-AO; or counter-balanced AO then AV, AO-AV, during Periods 1 then 2) training conditions. After training on each list of paired-associates (PA), testing was carried out AO. Across all training, AO PA test scores improved (7.2 percentage points) as did identification of consonants in new untrained CVCVC stimuli (3.5 percentage points). However, there was evidence that AV training impeded immediate AO perceptual learning: During Period-1, training scores across AV and AO conditions were not different, but AO test scores were dramatically lower in the AV-trained participants. During Period-2 AO training, the AV-AO participants obtained significantly higher AO test scores, demonstrating their ability to learn the auditory speech. Across both orders of training, whenever training was AV, AO test scores were significantly lower than training scores. Experiment 2 repeated the procedures with vocoded speech and 43 normal-hearing adults. Following AV training, their AO test scores were as high as or higher than following AO training. Also, their CVCVC identification scores patterned differently than those of the cochlear implant users. In Experiment 1, initial consonants were most accurate, and in Experiment 2, medial consonants were most accurate. We suggest that our results are consistent with a multisensory reverse hierarchy theory, which predicts that, whenever possible, perceivers carry out perceptual tasks immediately based on the experience and biases they bring to the task. We point out that while AV training could be an impediment to immediate unisensory perceptual learning in cochlear implant patients, it was also associated with higher scores during training.

A review of astronomical science with visible light adaptive optics

NASA Astrophysics Data System (ADS)

Close, Laird M.

2016-07-01

We review astronomical results in the visible (λ<1μm) with adaptive optics. Other than a brief period in the early 1990s, there has been little (<1 paper/yr) night-time astronomical science published with AO in the visible from 2000-2013 (outside of the solar or Space Surveillance Astronomy communities where visible AO is the norm, but not the topic of this invited review). However, since mid-2013 there has been a rapid increase visible AO with over 50 refereed science papers published in just 2.5 years (visible AO is experiencing a rapid growth rate very similar to that of NIR AO science from 1997-2000 Close 2000). Currently the most productive small (D < 2 m) visible light AO telescope is the UV-LGS Robo-AO system (Baranec, et al. 2016) on the robotic Palomar D=1.5 m telescope (currently relocated to the Kitt Peak 1.8m; Salama et al. 2016). Robo-AO uniquely offers the ability to target >15 objects/hr, which has enabled large (>3000 discrete targets) companion star surveys and has resulted in 23 refereed science publications. The most productive large telescope visible AO system is the D=6.5m Magellan telescope AO system (MagAO). MagAO is an advanced Adaptive Secondary Mirror (ASM) AO system at the Magellan 6.5m in Chile (Morzinski et al. 2016). This ASM secondary has 585 actuators with < 1 msec response times (0.7 ms typically). MagAO utilizes a 1 kHz pyramid wavefront sensor. The relatively small actuator pitch ( 22 cm/subap) allows moderate Strehls to be obtained in the visible (0.63-1.05 microns). Long exposures (60s) achieve <30mas resolutions, 30% Strehls at 0.62 microns (r') with the VisAO camera in 0.5" seeing with bright R <= 9 mag stars. These capabilities have led to over 22 MagAO refereed science publications in the visible. The largest (D=8m) telescope to achieve regular visible AO science is SPHERE/ZIMPOL. ZIMPOL is a polarimeter fed by the 1.2 kHz SPHERE ExAO system (Fusco et al. 2016). ZIMPOL's ability to differentiate scattered polarized light from starlight allows the sensitive detection of circumstellar disks, stellar surfaces, and envelopes of evolved AGB stars. Here we review the key steps to having good performance in the visible and review the exciting new AO visible science opportunities and science results in the fields of: exoplanet detection; circumstellar and protoplanetary disks; young stars; AGB stars; emission line jets; and stellar surfaces. The recent rapid increase in the scientific publications and power of visible AO is due to the maturity of the next-generation of AO systems and our new ability probe circumstellar regions with very high (10-30 mas) spatial resolutions that would otherwise require much larger (>10m) diameter telescopes in the infrared.

Discovery Proteomics Identifies a Molecular Link between the Coatomer Protein Complex I and Androgen Receptor-dependent Transcription*

PubMed Central

Hsiao, Jordy J.; Smits, Melinda M.; Ng, Brandon H.; Lee, Jinhee; Wright, Michael E.

2016-01-01

Aberrant androgen receptor (AR)-dependent transcription is a hallmark of human prostate cancers. At the molecular level, ligand-mediated AR activation is coordinated through spatial and temporal protein-protein interactions involving AR-interacting proteins, which we designate the “AR-interactome.” Despite many years of research, the ligand-sensitive protein complexes involved in ligand-mediated AR activation in prostate tumor cells have not been clearly defined. Here, we describe the development, characterization, and utilization of a novel human LNCaP prostate tumor cell line, N-AR, which stably expresses wild-type AR tagged at its N terminus with the streptavidin-binding peptide epitope (streptavidin-binding peptide-tagged wild-type androgen receptor; SBP-AR). A bioanalytical workflow involving streptavidin chromatography and label-free quantitative mass spectrometry was used to identify SBP-AR and associated ligand-sensitive cytosolic proteins/protein complexes linked to AR activation in prostate tumor cells. Functional studies verified that ligand-sensitive proteins identified in the proteomic screen encoded modulators of AR-mediated transcription, suggesting that these novel proteins were putative SBP-AR-interacting proteins in N-AR cells. This was supported by biochemical associations between recombinant SBP-AR and the ligand-sensitive coatomer protein complex I (COPI) retrograde trafficking complex in vitro. Extensive biochemical and molecular experiments showed that the COPI retrograde complex regulates ligand-mediated AR transcriptional activation, which correlated with the mobilization of the Golgi-localized ARA160 coactivator to the nuclear compartment of prostate tumor cells. Collectively, this study provides a bioanalytical strategy to validate the AR-interactome and define novel AR-interacting proteins involved in ligand-mediated AR activation in prostate tumor cells. Moreover, we describe a cellular system to study how compartment-specific AR-interacting proteins influence AR activation and contribute to aberrant AR-dependent transcription that underlies the majority of human prostate cancers. PMID:27365400

Acridine Orange/exosomes increase the delivery and the effectiveness of Acridine Orange in human melanoma cells: A new prototype for theranostics of tumors.

PubMed

Iessi, Elisabetta; Logozzi, Mariantonia; Lugini, Luana; Azzarito, Tommaso; Federici, Cristina; Spugnini, Enrico Pierluigi; Mizzoni, Davide; Di Raimo, Rossella; Angelini, Daniela F; Battistini, Luca; Cecchetti, Serena; Fais, Stefano

2017-12-01

Specifically targeted drug delivery systems with low immunogenicity and toxicity are deemed to increase efficacy of cancer chemotherapy. Acridine Orange (AO) is an acidophilic dye with a strong tumoricidal action following excitation with a light source at 466 nm. However, to date the clinical use of AO is limited by the potential side effects elicited by systemic administration. The endogenous nanocarrier exosomes have been recently introduced as a natural delivery system for therapeutic molecules. In this article, we show the outcome of the administration to human melanoma cells of AO charged Exosomes (Exo-AO), in both monolayer and spheroid models. The results showed an extended drug delivery time of Exo-AO to melanoma cells as compared to the free AO, improving the cytotoxicity of AO. This study shows that Exo-AO have a great potential for a real exploitation as a new theranostic approach against tumors based on AO delivered through the exosomes.

Heterodimerization with beta2-adrenergic receptors promotes surface expression and functional activity of alpha1D-adrenergic receptors.

PubMed

Uberti, Michelle A; Hague, Chris; Oller, Heide; Minneman, Kenneth P; Hall, Randy A

2005-04-01

The alpha1D-adrenergic receptor (alpha1D-AR) is a G protein-coupled receptor (GPCR) that is poorly trafficked to the cell surface and largely nonfunctional when heterologously expressed by itself in a variety of cell types. We screened a library of approximately 30 other group I GPCRs in a quantitative luminometer assay for the ability to promote alpha1D-AR cell surface expression. Strikingly, these screens revealed only two receptors capable of inducing robust increases in the amount of alpha1D-AR at the cell surface: alpha1B-AR and beta2-AR. Confocal imaging confirmed that coexpression with beta2-AR resulted in translocation of alpha1D-AR from intracellular sites to the plasma membrane. Additionally, coimmunoprecipitation studies demonstrated that alpha1D-AR and beta2-AR specifically interact to form heterodimers when coexpressed in HEK-293 cells. Ligand binding studies revealed an increase in total alpha1D-AR binding sites upon coexpression with beta2-AR, but no apparent effect on the pharmacological properties of the receptors. In functional studies, coexpression with beta2-AR significantly enhanced the coupling of alpha1D-AR to norepinephrine-stimulated Ca2+ mobilization. Heterodimerization of beta2-AR with alpha1D-AR also conferred the ability of alpha1D-AR to cointernalize upon beta2-AR agonist stimulation, revealing a novel mechanism by which these different adrenergic receptor subtypes may regulate each other's activity. These findings demonstrate that the selective association of alpha1D-AR with other receptors is crucial for receptor surface expression and function and also shed light on a novel mechanism of cross talk between alpha1- and beta2-ARs that is mediated through heterodimerization and cross-internalization.

Cooperative Dynamics of AR and ER Activity in Breast Cancer

PubMed Central

D’Amato, Nicholas C.; Gordon, Michael A.; Babbs, Beatrice L.; Spoelstra, Nicole S.; Carson Butterfield, Kiel T.; Torkko, Kathleen C.; Phan, Vernon T.; Barton, Valerie N.; Rogers, Thomas J.; Sartorius, Carol A; Elias, Anthony D.; Gertz, Jason; Jacobsen, Britta M.; Richer, Jennifer K.

2016-01-01

Androgen receptor (AR) is expressed in 90% of estrogen receptor alpha positive (ER+) breast tumors, but its role in tumor growth and progression remains controversial. Use of two anti-androgens that inhibit AR nuclear localization, enzalutamide and MJC13, revealed that AR is required for maximum ER genomic binding. Here, a novel global examination of AR chromatin binding found that estradiol induced AR binding at unique sites compared to dihydrotestosterone (DHT). Estradiol-induced AR binding sites were enriched for estrogen response elements and had significant overlap with ER binding sites. Furthermore, AR inhibition reduced baseline and estradiol-mediated proliferation in multiple ER+/AR+ breast cancer cell lines, and synergized with tamoxifen and fulvestrant. In vivo, enzalutamide significantly reduced viability of tamoxifen-resistant MCF7 xenograft tumors and an ER+/AR+ patient-derived model. Enzalutamide also reduced metastatic burden following cardiac injection. Lastly, in a comparison of ER+/AR+ primary tumors versus patient-matched local recurrences or distant metastases, AR expression was often maintained even when ER was reduced or absent. These data provide pre-clinical evidence that anti-androgens that inhibit AR nuclear localization affect both AR and ER, and are effective in combination with current breast cancer therapies. In addition, single agent efficacy may be possible in tumors resistant to traditional endocrine therapy, since clinical specimens of recurrent disease demonstrate AR expression in tumors with absent or refractory ER. Implications This study suggests that AR plays a previously-unrecognized role in supporting E2-mediated ER activity in ER+/AR+ breast cancer cells, and that enzalutamide may be an effective therapeutic in ER+/AR+ breast cancers. PMID:27565181

Galeterone and VNPT55 induce proteasomal degradation of AR/AR-V7, induce significant apoptosis via cytochrome c release and suppress growth of castration resistant prostate cancer xenografts in vivo

PubMed Central

Kwegyir-Afful, Andrew K.; Ramalingam, Senthilmurugan; Purushottamachar, Puranik; Ramamurthy, Vidya P.; Njar, Vincent C.O.

2015-01-01

Galeterone (Gal) is a first-in-class multi-target oral small molecule that will soon enter pivotal phase III clinical trials in castration resistant prostate cancer (CRPC) patients. Gal disrupts androgen receptor (AR) signaling via inhibition of CYP17, AR antagonism and AR degradation. Resistance to current therapy is attributed to up-regulation of full-length AR (fAR), splice variants AR (AR-Vs) and AR mutations. The effects of gal and VNPT55 were analyzed on f-AR and AR-Vs (AR-V7/ARv567es) in LNCaP, CWR22Rv1 and DU145 (transfected with AR-Vs) human PC cells in vitro and CRPC tumor xenografts. Galeterone/VNPT55 decreased fAR/AR-V7 mRNA levels and implicates Mdm2/CHIP enhanced ubiquitination of posttranslational modified receptors, targeting them for proteasomal degradation. Gal and VNPT55 also induced significant apoptosis in PC cells via increased Bax/Bcl2 ratio, cytochrome-c release with concomitant cleavage of caspase 3 and PARP. More importantly, gal and VNPT55 exhibited strong in vivo anti-CRPC activities, with no apparent host toxicities. This study demonstrate that gal and VNPT55 utilize cell-based mechanisms to deplete both fAR and AR-Vs. Importantly, the preclinical activity profiles, including profound apoptotic induction and inhibition of CRPC xenografts suggest that these agents offer considerable promise as new therapeutics for patients with CRPC and those resistant to current therapy. PMID:26196320

Histone demethylase JMJD1A promotes alternative splicing of AR variant 7 (AR-V7) in prostate cancer cells.

PubMed

Fan, Lingling; Zhang, Fengbo; Xu, Songhui; Cui, Xiaolu; Hussain, Arif; Fazli, Ladan; Gleave, Martin; Dong, Xuesen; Qi, Jianfei

2018-05-15

Formation of the androgen receptor splicing variant 7 (AR-V7) is one of the major mechanisms by which resistance of prostate cancer to androgen deprivation therapy occurs. The histone demethylase JMJD1A (Jumonji domain containing 1A) functions as a key coactivator for AR by epigenetic regulation of H3K9 methylation marks. Here, we describe a role for JMJD1A in AR-V7 expression. While JMJD1A knockdown had no effect on full-length AR (AR-FL), it reduced AR-V7 levels in prostate cancer cells. Reexpression of AR-V7 in the JMJD1A-knockdown cells elevated expression of select AR targets and partially rescued prostate cancer cell growth in vitro and in vivo. The AR-V7 protein level correlated positively with JMJD1A in a subset of human prostate cancer specimens. Mechanistically, we found that JMJD1A promoted alternative splicing of AR-V7 through heterogeneous nuclear ribonucleoprotein F (HNRNPF), a splicing factor known to regulate exon inclusion. Knockdown of JMJD1A or HNRNPF inhibited splicing of AR-V7, but not AR-FL, in a minigene reporter assay. JMJD1A was found to interact with and promote the recruitment of HNRNPF to a cryptic exon 3b on AR pre-mRNA for the generation of AR-V7. Taken together, the role of JMJD1A in AR-FL coactivation and AR-V7 alternative splicing highlights JMJD1A as a potentially promising target for prostate cancer therapy.

DKIST Adaptive Optics System: Simulation Results

NASA Astrophysics Data System (ADS)

Marino, Jose; Schmidt, Dirk

2016-05-01

The 4 m class Daniel K. Inouye Solar Telescope (DKIST), currently under construction, will be equipped with an ultra high order solar adaptive optics (AO) system. The requirements and capabilities of such a solar AO system are beyond those of any other solar AO system currently in operation. We must rely on solar AO simulations to estimate and quantify its performance.We present performance estimation results of the DKIST AO system obtained with a new solar AO simulation tool. This simulation tool is a flexible and fast end-to-end solar AO simulator which produces accurate solar AO simulations while taking advantage of current multi-core computer technology. It relies on full imaging simulations of the extended field Shack-Hartmann wavefront sensor (WFS), which directly includes important secondary effects such as field dependent distortions and varying contrast of the WFS sub-aperture images.

Syndromes dominated by apraxia of speech show distinct characteristics from agrammatic PPA

PubMed Central

Duffy, Joseph R.; Strand, Edythe A.; Machulda, Mary M.; Senjem, Matthew L.; Lowe, Val J.; Jack, Clifford R.; Whitwell, Jennifer L.

2013-01-01

Objective: We assessed whether clinical and imaging features of subjects with apraxia of speech (AOS) more severe than aphasia (dominant AOS) are more similar to agrammatic primary progressive aphasia (agPPA) or to primary progressive AOS (PPAOS). Methods: Sixty-seven subjects (PPAOS = 18, dominant AOS = 10, agPPA = 9, age-matched controls = 30) who all had volumetric MRI, diffusion tensor imaging, F18-fluorodeoxyglucose and C11-labeled Pittsburgh compound B (PiB)-PET scanning, as well as neurologic and speech and language assessments, were included in this case-control study. AOS was classified as either type 1, predominated by sound distortions and distorted sound substitutions, or type 2, predominated by syllabically segmented prosodic speech patterns. Results: The dominant AOS subjects most often had AOS type 2, similar to PPAOS. In contrast, agPPA subjects most often had type 1 (p = 0.01). Both dominant AOS and PPAOS showed focal imaging abnormalities in premotor cortex, whereas agPPA showed widespread involvement affecting premotor, prefrontal, temporal and parietal lobes, caudate, and insula. Only the dominant AOS and PPAOS groups showed midbrain atrophy compared with controls. No differences were observed in PiB binding across all 3 groups, with the majority being PiB negative. Conclusion: These results suggest that dominant AOS is more similar to PPAOS than agPPA, with dominant AOS and PPAOS exhibiting a clinically distinguishable subtype of progressive AOS compared with agPPA. PMID:23803320

Differential regulation of metabolic pathways by androgen receptor (AR) and its constitutively active splice variant, AR-V7, in prostate cancer cells

PubMed Central

Shafi, Ayesha A.; Putluri, Vasanta; Arnold, James M.; Tsouko, Efrosini; Maity, Suman; Roberts, Justin M.; Coarfa, Cristian; Frigo, Daniel E.; Putluri, Nagireddy; Sreekumar, Arun; Weigel, Nancy L.

2015-01-01

Metastatic prostate cancer (PCa) is primarily an androgen-dependent disease, which is treated with androgen deprivation therapy (ADT). Tumors usually develop resistance (castration-resistant PCa [CRPC]), but remain androgen receptor (AR) dependent. Numerous mechanisms for AR-dependent resistance have been identified including expression of constitutively active AR splice variants lacking the hormone-binding domain. Recent clinical studies show that expression of the best-characterized AR variant, AR-V7, correlates with resistance to ADT and poor outcome. Whether AR-V7 is simply a constitutively active substitute for AR or has novel gene targets that cause unique downstream changes is unresolved. Several studies have shown that AR activation alters cell metabolism. Using LNCaP cells with inducible expression of AR-V7 as a model system, we found that AR-V7 stimulated growth, migration, and glycolysis measured by ECAR (extracellular acidification rate) similar to AR. However, further analyses using metabolomics and metabolic flux assays revealed several differences. Whereas AR increased citrate levels, AR-V7 reduced citrate mirroring metabolic shifts observed in CRPC patients. Flux analyses indicate that the low citrate is a result of enhanced utilization rather than a failure to synthesize citrate. Moreover, flux assays suggested that compared to AR, AR-V7 exhibits increased dependence on glutaminolysis and reductive carboxylation to produce some of the TCA (tricarboxylic acid cycle) metabolites. These findings suggest that these unique actions represent potential therapeutic targets. PMID:26378018

Extraction, fractionation and re-fractionation of Artemisia nilagirica for anticancer activity and HPLC-ESI-QTOF-MS/MS determination.

PubMed

Sahu, Neha; Meena, Sanjeev; Shukla, Vijaya; Chaturvedi, Priyank; Kumar, Brijesh; Datta, Dipak; Arya, K R

2018-03-01

Medicinal plants used in traditional medicines are affordable, easily accessible, safer, less toxic and considered as a rich or efficient source of bioactive molecules for modern therapeutics. Artemisia nilagirica (AR) has a long history of use in Indian traditional medicine to combat a wide variety of diseases including cancer. Considering the vast potential of traditional healing plants to deliver safer, less toxic and efficient chemotherapeutics, we have examined anticancer activity of ethanolic extract, bioactive fractions and sub-fractions of AR against different human cancer cell lines along with their phytochemical analysis to understand the insights of novel anticancer activities for further preclinical studies. Fresh plant material of AR was procured from the wild, dried and ground. The grinded materials was extracted in ethanol (AR-01) and fractionated into butanol (AR-02), ethyl acetate (AR-03), hexane (AR-04) and water (AR-05). The cytotoxicity was evaluated against three different human cancer cell lines, i.e. colon (DLD-1), lung (A-549), and breast (MCF-7) using Sulforhodamine B (SRB) assay along with non-cancerous VERO cells as control and doxorubicin (DOX) as positive control. As we observed strong cytotoxicity of AR-03 and AR-04 fractions against tested cells and marked cytotoxic effects particularly in colon cancer cell lines, we further re-fractionated, AR-03 into (AR-03A, AR-03B, AR-03C, AR-03D, AR-03E) and AR-04 into (AR-04A, AR-04B, AR-04C) sub-fractions by column chromatography and investigated against the same panel of cell lines in addition to one more colon cancer cell line (HT-29). Phytochemical analysis was performed through HPLC-ESI-QTOF-MS/MS fragmentation. Ethyl acetate (AR-03) and hexane (AR-04) fractions were found to be the most cytotoxic against all the tested cell lines. Further, AR-03E and AR-04A sub-fractions were found more specific cytotoxic selectively against DLD-1 cancer cell lines at 100µg/ml concentration. HPLC-ESI-QTOF-MS/MS determination revealed the presence of 17 compounds in AR-01. Among them, 4 compounds were reported for the first time in this species. However, 3 identified compounds (artemorin, β-santonin and caryophyllene oxide) in AR-03E sub-fraction were commonly present in each bioactive fraction and may be considered as potential and safest cytotoxic agents for anticancer activity. Experimental evidences reported in this paper for anticancer activity validate the traditional wisdom of Artemisia nilagirica as an anticancer herbal drug. To our knowledge, this is our first novel observation of cytotoxicity and selectivity of ethyl acetate and hexane sub-fraction of AR-01 i.e. AR-03E and AR-04A respectively against DLD-1 human cancer cell lines. HPLC-ESI-QTOF-MS/MS determination attributes the identification of cytotoxic compounds which may be used for further preclinical studies. Copyright © 2017 Elsevier B.V. All rights reserved.

Targeting chromatin binding regulation of constitutively active AR variants to overcome prostate cancer resistance to endocrine-based therapies

PubMed Central

Chan, Siu Chiu; Selth, Luke A.; Li, Yingming; Nyquist, Michael D.; Miao, Lu; Bradner, James E.; Raj, Ganesh V.; Tilley, Wayne D.; Dehm, Scott M.

2015-01-01

Androgen receptor (AR) variants (AR-Vs) expressed in prostate cancer (PCa) lack the AR ligand binding domain (LBD) and function as constitutively active transcription factors. AR-V expression in patient tissues or circulating tumor cells is associated with resistance to AR-targeting endocrine therapies and poor outcomes. Here, we investigated the mechanisms governing chromatin binding of AR-Vs with the goal of identifying therapeutic vulnerabilities. By chromatin immunoprecipitation and sequencing (ChIP-seq) and complementary biochemical experiments, we show that AR-Vs display a binding preference for the same canonical high-affinity androgen response elements (AREs) that are preferentially engaged by AR, albeit with lower affinity. Dimerization was an absolute requirement for constitutive AR-V DNA binding and transcriptional activation. Treatment with the bromodomain and extraterminal (BET) inhibitor JQ1 resulted in inhibition of AR-V chromatin binding and impaired AR-V driven PCa cell growth in vitro and in vivo. Importantly, this was associated with a novel JQ1 action of down-regulating AR-V transcript and protein expression. Overall, this study demonstrates that AR-Vs broadly restore AR chromatin binding events that are otherwise suppressed during endocrine therapy, and provides pre-clinical rationale for BET inhibition as a strategy for inhibiting expression and chromatin binding of AR-Vs in PCa. PMID:25908785

40Ar/39Ar Dating of Volcanic Glass

NASA Astrophysics Data System (ADS)

Morgan, L. E.; Renne, P. R.; Watkins, J. M.

2007-12-01

Application of the 40Ar/39Ar method to volcanic glasses has been somewhat stigmatized following several studies demonstrating secondary mobility of K and Ar. Much of the stigma is unwarranted, however, since most studies only impugned the reliability of the K-Ar and 40Ar/39Ar techniques when applied to glass shards rather than obsidian clasts with low surface area to volume ratios. We provide further evidence for problematic K loss and/or 39Ar recoil ejection from glass shards in 40Ar/39Ar step heating results for comagmatic feldspars and shards. In an extreme case, the plateau age of the feldspars (0.17 ± 0.03 Ma at 2σ) is significantly younger than the plateau age of the glass (0.85 ± 0.05 Ma at 2σ). If the feldspar age is reasonably interpreted as the eruption age of the ash, it is likely that the glass shards experienced K and/or 39Ar loss. Electron microprobe analyses of the glass shards have low totals (~93%) and no systematic lateral variability (i.e., diffusion gradients) in K, suggesting that the lengthscale of the glass shards is smaller than the lengthscale of K diffusion. Obsidian clasts should not be as susceptible to K loss since any hydrated (K-depleted) volume represents a small fraction of the total material and can often be physically removed prior to analysis. Samples described here are detrital obsidian clasts from the Afar region of Ethiopia. Evidence from Fourier Transform Infrared Spectroscopy (FTIR), and previous work by Anovitz (1999), confirm that the scale of water and potassium mobility are often small in comparison to the size of obsidian clasts but large enough to effect the bulk composition of glass shards. This expectation is confirmed in another tuff wherein comagmatic obsidian clasts and sanidine phenocrysts yield indistinguishable 40Ar/39Ar ages of 4.4 Ma High abundances of non-radiogenic 40Ar, and kinetic fractionation of Ar isotopes during quenching and/or laboratory degassing resulting in incomplete equilibration between atmospheric and magmatic argon, may also hinder accurate 40Ar/39Ar geochronology of volcanic glasses. Clasts derived from single flows (as determined by extrusion age and trace element geochemistry) display variations as much as 3-4 orders of magnitude in atmospheric 40Ar concentrations. The clasts were likely sourced from different parts of the flows with varying proximity to the surface and thus differing thermal and atmospheric uptake histories. Because radiogenic and non-radiogenic components of 40Ar are energetically indistinct in glass, most samples fail to yield isochrons due to limited range in 40Ar: 39Ar: 36Ar. Most yield plateau ages, whose validity rests on the assumption of atmospheric initial 40Ar/36Ar. Some samples yield inverse isochrons with sub-atmospheric 40Ar/36Ar intercepts; unirradiated subsamples of these same samples also have sub-atmospheric 38Ar/36Ar ratios that are too high to be explained by mass fractionation. While the effects of non-radiogenic 40Ar remain poorly understood, this sample set yielded 32 out of 41 clasts having plateau and isochron ages within 2σ error of each other, and potentially problematic samples are generally identified with non-atmospheric isochron 40Ar/36Ar intercepts.

Selective inhibition of alpha1B-adrenergic receptor expression and function using a phosphorothioate antisense oligodeoxynucleotide.

PubMed

Gonzalez-Cabrera, P J; Iversen, P L; Liu, M F; Scofield, M A; Jeffries, W B

1998-06-01

To investigate alpha1B-adrenoceptor function, we developed a phosphorothioate antisense oligodeoxynucleotide (AO) to inhibit the expression of the alpha1B-adrenoceptor subtype in DDT1 MF2 cells. We measured the cellular uptake of the AO and its effect on alpha1B-adrenoceptor mRNA expression, protein density, and coupling to phospholipase C. Cells treated with either a control oligodeoxynucleotide (CO) or medium alone served as control groups. Confocal microscopy demonstrated that DDT1 MF2 cells internalized carboxyfluorescein-labeled (FAM) AO within 30 min. Analysis of cellular lysates showed that approximately 50% of the intracellular FAM-AO was present as an intact 18-mer for up to 48 hr. Incubation of cells with AO for 48 hr decreased alpha1B-adrenoceptor density ([3H]prazosin Bmax) versus control groups by 12% (1 microM AO) and 72% (10 microM AO). In time course experiments, AO (10 microM) reduced alpha1B-adrenoceptor density by 28, 64, and 68% versus controls after 24, 48, and 72 hr of exposure, respectively. alpha1B-Adrenoceptor mRNA concentration (measured by RT-PCR) was reduced by 25% in cells treated for 48 hr with 10 microM AO versus controls. AO pretreatment (10 microM, 48 hr) reduced the maximum response to agonist-stimulated [3H]inositol phosphate accumulation. The maximal response of the full agonist norepinephrine was reduced by 30% after AO treatment, and by 73% for the partial agonist naphazoline. In contrast, AO did not affect histamine-stimulated total [3H]inositol phosphate accumulation. Thus, AO effectively reduced alpha1B-adrenoceptor subtype expression and function in vitro, suggesting a potential to selectively inhibit alpha1B-adrenoceptor function in vivo.

Androgen Receptor-Mediated Growth Suppression of HPr-1AR and PC3-Lenti-AR Prostate Epithelial Cells

PubMed Central

Bolton, Eric C.

2015-01-01

The androgen receptor (AR) mediates the developmental, physiologic, and pathologic effects of androgens including 5α-dihydrotestosterone (DHT). However, the mechanisms whereby AR regulates growth suppression and differentiation of luminal epithelial cells in the prostate gland and proliferation of malignant versions of these cells are not well understood, though they are central to prostate development, homeostasis, and neoplasia. Here, we identify androgen-responsive genes that restrain cell cycle progression and proliferation of human prostate epithelial cell lines (HPr-1AR and PC3-Lenti-AR), and we investigate the mechanisms through which AR regulates their expression. DHT inhibited proliferation of HPr-1AR and PC3-Lenti-AR, and cell cycle analysis revealed a prolonged G1 interval. In the cell cycle, the G1/S-phase transition is initiated by the activity of cyclin D and cyclin-dependent kinase (CDK) complexes, which relieve growth suppression. In HPr-1AR, cyclin D1/2 and CDK4/6 mRNAs were androgen-repressed, whereas CDK inhibitor, CDKN1A, mRNA was androgen-induced. The regulation of these transcripts was AR-dependent, and involved multiple mechanisms. Similar AR-mediated down-regulation of CDK4/6 mRNAs and up-regulation of CDKN1A mRNA occurred in PC3-Lenti-AR. Further, CDK4/6 overexpression suppressed DHT-inhibited cell cycle progression and proliferation of HPr-1AR and PC3-Lenti-AR, whereas CDKN1A overexpression induced cell cycle arrest. We therefore propose that AR-mediated growth suppression of HPr-1AR involves cyclin D1 mRNA decay, transcriptional repression of cyclin D2 and CDK4/6, and transcriptional activation of CDKN1A, which serve to decrease CDK4/6 activity. AR-mediated inhibition of PC3-Lenti-AR proliferation occurs through a similar mechanism, albeit without down-regulation of cyclin D. Our findings provide insight into AR-mediated regulation of prostate epithelial cell proliferation. PMID:26372468

40Ar/39Ar and unspiked 40K-40Ar dating of upper Pleistocene volcanic activity in the Bas-Vivarais (Ardèche, France)

NASA Astrophysics Data System (ADS)

Sasco, Romain; Guillou, Hervé; Nomade, Sébastien; Scao, Vincent; Maury, René C.; Kissel, Catherine; Wandres, Camille

2017-07-01

Fifteen basanitic and tephritic flows from Bas-Vivarais, the youngest volcanic field in the French Massif Central together with the Chaîne des Puys, were dated by 40Ar/39Ar and 40K-40Ar on separated groundmass, and studied for paleomagnetism. An almost systematic discrepancy between the two types of ages is observed, the 40K-40Ar method providing ages up to 8.5 times the 40Ar/39Ar ones. Microscopic observations and geochemical analyses lead us to conclude that most of the K-Ar ages measured on Bas-Vivarais samples are in error due to extraneous argon originating from contamination by xenocrysts from disintegrated crustal and mantle xenoliths. However, 40Ar/39Ar experiments do not evidence any excess argon, suggesting two possibilities: 1, the extraneous argon contribution was eliminated during the pre-degassing of the samples at 600 °C prior to the step heating experiments, 2 - K-Ar ages may be older because larger quantities of xenocrysts, potential carriers of extraneous argon were involved in the K-Ar experiments than in the 40Ar/39Ar ones. 40Ar/39Ar ages are thus little or not affected by contamination and provide reliable ages for the studied volcanoes. Combined 40Ar/39Ar datings and magnetic directions for each flow point out to three successive stages in the volcanic evolution of Bas-Vivarais. Stage 1, limited to the northern part of the field, has a mean age of 187.3 ± 19.0 ka. In its southern part, Stages 2 and 3 emplaced magmas at 31.1 ± 3.9 ka and 23.9 ± 8.1 ka, respectively. These two last stages are consistent with available 14C dates but not with previous thermoluminescence data.

In situ dating on Mars: A new approach to the K–Ar method utilizing cosmogenic argon

DOE PAGES

Cassata, William S.

2013-08-22

In this paper, cosmogenic argon isotopes are produced in feldspars via nuclear reactions between cosmic rays and Ca and K atoms within the lattice. These cosmogenic isotopes can be used as proxies for K and Ca, much like nuclear reactor-derived 39Ar and 37Ar are used as proxies for K and Ca, respectively, in 40Ar/ 39Ar geochronology. If Ca and K are uniformly distributed, then the ratio of radiogenic 40Ar ( 40Ar*) to cosmogenic 38Ar or 36Ar ( 38Ar cos or 36Ar cos) is proportional to the difference between the radioisotopic and exposure ages, as well as the K/Ca ratio ofmore » the degassing phase. Thus cosmogenic, radiogenic, and trapped Ar isotopes, all of which can be measured remotely and are stable over geologic time, are sufficient to generate an isochron-like diagram from which the isotopic composition of the trapped component may be inferred. Finally, such data also provide a means to assess the extent to which the system has remained closed with respect to 40Ar*, thereby mitigating otherwise unquantifiable uncertainties that complicate the conventional K–Ar dating method.« less

Establishment of a novel immortalized human prostatic epithelial cell line stably expressing androgen receptor and its application for the functional screening of androgen receptor modulators

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yu, Shan; Wang, Ming-Wei; Yao, Xiaoqiang

2009-05-15

In this study, we developed a human prostatic epithelial cell line BPH-1-AR stably expressing AR by lentiviral transduction. Characterization by immunoblot and RT-PCR showed that AR was stably expressed in all representative BPH-1-AR clones. Androgen treatment induced a secretory differentiation phenotype in BPH-1-AR cells but suppressed their cell proliferation. Treatments with AR agonists induced transactivation of a transfected PSA-gene promoter reporter in BPH-1-AR cells, whereas this transactivation was suppressed by an AR antagonist flutamide, indicating that the transduced AR in BPH-1-AR cells was functional. Finally, we utilized BPH-1-AR cells to evaluate the androgenic activities and growth effects of five newlymore » developed non-steroidal compounds. Results showed that these compounds showed androgenic activities and growth-inhibitory effects on BPH-1-AR cells. Our results showed that BPH-1-AR cell line would be a valuable in vitro model for the study of androgen-regulated processes in prostatic epithelial cells and identification of compounds with AR-modulating activities.« less

Identification of a new androgen receptor (AR) co-regulator BUD31 and related peptides to suppress wild-type and mutated AR-mediated prostate cancer growth via peptide screening and X-ray structure analysis.

PubMed

Hsu, Cheng-Lung; Liu, Jai-Shin; Wu, Po-Long; Guan, Hong-Hsiang; Chen, Yuh-Ling; Lin, An-Chi; Ting, Huei-Ju; Pang, See-Tong; Yeh, Shauh-Der; Ma, Wen-Lung; Chen, Chung-Jung; Wu, Wen-Guey; Chang, Chawnshang

2014-12-01

Treatment with individual anti-androgens is associated with the development of hot-spot mutations in the androgen receptor (AR). Here, we found that anti-androgens-mt-ARs have similar binary structure to the 5α-dihydrotestosterone-wt-AR. Phage display revealed that these ARs bound to similar peptides, including BUD31, containing an Fxx(F/H/L/W/Y)Y motif cluster with Tyr in the +5 position. Structural analyses of the AR-LBD-BUD31 complex revealed formation of an extra hydrogen bond between the Tyr+5 residue of the peptide and the AR. Functional studies showed that BUD31-related peptides suppressed AR transactivation, interrupted AR N-C interaction, and suppressed AR-mediated cell growth. Combination of peptide screening and X-ray structure analysis may serve as a new strategy for developing anti-ARs that simultaneously suppress both wt and mutated AR function. Copyright © 2014 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Re-Evaluation of Ar-39 - Ar-40 Ages for Apollo Lunar Rocks 15415 and 60015

NASA Technical Reports Server (NTRS)

Park, J.; Nyquist, L. E.; Bogard, D. D.; Garrison, D. H.; Shih, C.-Y.

2010-01-01

We re-analyzed 39Ar-40Ar ages of Apollo lunar highland samples 15415 and 60015, two ferroan anorthosites analyzed previously in the 1970 s, with a more detailed approach and with revised decay constants. From these samples we carefully prepared 100-200 mesh mineral separates for analysis at the Noble Gas Laboratory at NASA-Johnson Space Center. The Ar-39-Ar-40 age spectra for 15415 yielded an age of 3851 +/- 38 Ma with 33-99% of Ar39 release, roughly in agreement with previously reported Ar-Ar ages. For 60015, we obtained an age of 3584 +/- 152 Ma in 23-98% of Ar39 release, also in agreement with previously reported Ar-Ar ages of approximately 3.5 Ga. Highland anorthosites like these are believed by many to be the original crust of the moon, formed by plagioclase floatation atop a magma ocean, however the Ar-Ar ages of 15415 and 60015 are considerably younger than lunar crust formation. By contrast, recently recovered lunar anorthosites such as Dhofar 489, Dhofar 908, and Yamato 86032 yield older Ar-Ar ages, up to 4.35 Ga, much closer to time of formation of the lunar crust. It follows that the Ar-Ar ages of the Apollo samples must have been reset by secondary heating, and that this heating affected highland anorthosites at both the Apollo 15 and Apollo 16 landing sites but did not affect lunar highland meteorites. One obvious consideration is that while the Apollo samples were collected from the near side of the moon, these lunar meteorites are thought to have originated from the lunar far side

Mediation of tubuloglomerular feedback by adenosine: evidence from mice lacking adenosine 1 receptors.

PubMed

Sun, D; Samuelson, L C; Yang, T; Huang, Y; Paliege, A; Saunders, T; Briggs, J; Schnermann, J

2001-08-14

Adenosine is a determinant of metabolic control of organ function increasing oxygen supply through the A2 class of adenosine receptors and reducing oxygen demand through A1 adenosine receptors (A1AR). In the kidney, activation of A1AR in afferent glomerular arterioles has been suggested to contribute to tubuloglomerular feedback (TGF), the vasoconstriction elicited by elevations in [NaCl] in the macula densa region of the nephron. To further elucidate the role of A1AR in TGF, we have generated mice in which the entire A1AR coding sequence was deleted by homologous recombination. Homozygous A1AR mutants that do not express A1AR mRNA transcripts and do not respond to A1AR agonists are viable and without gross anatomical abnormalities. Plasma and urinary electrolytes were not different between genotypes. Likewise, arterial blood pressure, heart rates, and glomerular filtration rates were indistinguishable between A1AR(+/+), A1AR(+/-), and A1AR(-/-) mice. TGF responses to an increase in loop of Henle flow rate from 0 to 30 nl/min, whether determined as change of stop flow pressure or early proximal flow rate, were completely abolished in A1AR(-/-) mice (stop flow pressure response, -6.8 +/- 0.55 mmHg and -0.4 +/- 0.2 in A1AR(+/+) and A1AR(-/-) mice; early proximal flow rate response, -3.4 +/- 0.4 nl/min and +0.02 +/- 0.3 nl/min in A1AR(+/+) and A1AR(-/-) mice). Absence of TGF responses in A1AR-deficient mice suggests that adenosine is a required constituent of the juxtaglomerular signaling pathway. A1AR null mutant mice are a promising tool to study the functional role of A1AR in different target tissues.

Androgen receptor splice variants circumvent AR blockade by microtubule-targeting agents

PubMed Central

Zhang, Guanyi; Liu, Xichun; Li, Jianzhuo; Ledet, Elisa; Alvarez, Xavier; Qi, Yanfeng; Fu, Xueqi; Sartor, Oliver; Dong, Yan; Zhang, Haitao

2015-01-01

Docetaxel-based chemotherapy is established as a first-line treatment and standard of care for patients with metastatic castration-resistant prostate cancer. However, half of the patients do not respond to treatment and those do respond eventually become refractory. A better understanding of the resistance mechanisms to taxane chemotherapy is both urgent and clinical significant, as taxanes (docetaxel and cabazitaxel) are being used in various clinical settings. Sustained signaling through the androgen receptor (AR) has been established as a hallmark of CRPC. Recently, splicing variants of AR (AR-Vs) that lack the ligand-binding domain (LBD) have been identified. These variants are constitutively active and drive prostate cancer growth in a castration-resistant manner. In taxane-resistant cell lines, we found the expression of a major variant, AR-V7, was upregulated. Furthermore, ectopic expression of two clinically relevant AR-Vs (AR-V7 and ARV567es), but not the full-length AR (AR-FL), reduced the sensitivities to taxanes in LNCaP cells. Treatment with taxanes inhibited the transcriptional activity of AR-FL, but not those of AR-Vs. This could be explained, at least in part, due to the inability of taxanes to block the nuclear translocation of AR-Vs. Through a series of deletion constructs, the microtubule-binding activity was mapped to the LBD of AR. Finally, taxane-induced cytoplasm sequestration of AR-FL was alleviated when AR-Vs were present. These findings provide evidence that constitutively active AR-Vs maintain the AR signaling axis by evading the inhibitory effects of microtubule-targeting agents, suggesting that these AR-Vs play a role in resistance to taxane chemotherapy. PMID:26160840

The Direct Inhibitory Effect of Dutasteride or Finasteride on Androgen Receptor Activity is Cell Line Specific

PubMed Central

Chhipa, Rishi Raj; Halim, Danny; Cheng, Jinrong; Zhang, Huan Yi; Mohler, James L.; Ip, Clement; Wu, Yue

2014-01-01

BACKGROUND Finasteride and dutasteride were developed originally as 5α-reductase inhibitors to block the conversion of testosterone to dihydrotestosterone (DHT). These drugs may possess off-target effects on the androgen receptor (AR) due to their structural similarity to DHT. METHODS A total of 4 human prostate cancer cell models were examined: LNCaP (T877A mutant AR), 22Rv1 (H874Y mutant AR), LAPC4 (wild type AR) and VCaP (wild type AR). Cells were cultured in 10% charcoal-stripped fetal bovine serum, either with or without DHT added to the medium. AR activity was evaluated using the ARE-luciferase assay or the expression of AR regulated genes. RESULTS Dutasteride was more potent than finasteride in interfering with DHT-stimulated AR signaling. Disruption of AR function was accompanied by decreased cell growth. Cells that rely on DHT for protection against death were particularly vulnerable to dutasteride. Different prostate cancer cell models exhibited different sensitivities to dutasteride and finasteride. LNCaP was most sensitive, LAPC4 and VCaP were intermediate, while 22Rv1 was least sensitive. Regardless of the AR genotype, if AR was transfected into drug-sensitive cells, AR was inhibited by drug treatment; and if AR was transfected into drug-resistant cells, AR was not inhibited. CONCLUSIONS The direct inhibitory effect of dutasteride or finasteride on AR signaling is cell line specific. Mutations in the ligand binding domain of AR do not appear to play a significant role in influencing the AR antagonistic effect of these drugs. Subcellular constituent is an important factor in determining the drug effect on AR function. PMID:23813737

High-content screening identifies Src family kinases as potential regulators of AR-V7 expression and androgen-independent cell growth

PubMed Central

Szafran, Adam T.; Stephan, Cliff; Bolt, Michael; Mancini, Maureen G.; Marcelli, Marco; Mancini, Michael A.

2018-01-01

Background AR-V7 is an androgen receptor (AR) splice variant that lacks the ligand-binding domain and is isolated from prostate cancer cell lines. Increased expression of AR-V7 is associated with the transition from hormone-sensitive prostate cancer to more advanced castration-resistant prostate cancer (CRPC). Due to the loss of the ligand-binding domain, AR-V7 is not responsive to traditional AR-targeted therapies, and the mechanisms that regulate AR-V7 are still incompletely understood. Therefore, we aimed to explore existing classes of small molecules that may regulate AR-V7 expression and intracellular localization and their potential therapeutic role in CRPC. Methods We used AR high-content analysis (AR-HCA) to characterize the effects of a focused library of well-characterized clinical compounds on AR-V7 expression at the single-cell level in PC3 prostate cancer cells stably expressing green fluorescent protein (GFP)-AR-V7 (GFP-AR-V7:PC3). In parallel, an orthogonal AR-HCA screen of a small interfering (si)RNA library targeting 635 protein kinases was performed in GFP-AR-V7:PC3. The effect of the Src-Abl inhibitor PD 180970 was further characterized using cell-proliferation assays, quantitative PCR, and western blot analysis in multiple hormone-sensitive and CRPC cell lines. Results Compounds that tended to target Akt, Abl, and Src family kinases (SFKs) decreased overall AR-V7 expression, nuclear translocation, absolute nuclear level, and/or altered nuclear distribution. We identified 20 protein kinases that, when knocked down, either decreased nuclear GFP-AR-V7 levels or altered AR-V7 nuclear distribution, a set that included the SFKs Src and Fyn. The Src-Abl dual kinase inhibitor PD180970 decreased expression of AR-V7 by greater than 46% and decreased ligand-independent transcription of AR target genes in the 22RV1 human prostate carcinoma cell line. Further, PD180970 inhibited androgen-independent cell proliferation in endogenous–AR-V7–expressing prostate cancer cell lines and also overcame bicalutamide resistance observed in the 22RV1 cell line. Conclusions SFKs, especially Src and Fyn, may be important upstream regulators of AR-V7 expression and represent promising targets in a subset of CRPCs expressing high levels of AR-V7. PMID:27699828

Modulating Endoplasmic Reticulum-Golgi Cargo Receptors for Improving Secretion of Carrier-Fused Heterologous Proteins in the Filamentous Fungus Aspergillus oryzae

PubMed Central

Hoang, Huy-Dung; Maruyama, Jun-ichi

2014-01-01

Filamentous fungi are excellent hosts for industrial protein production due to their superior secretory capacity; however, the yield of heterologous eukaryotic proteins is generally lower than that of fungal or endogenous proteins. Although activating protein folding machinery in the endoplasmic reticulum (ER) improves the yield, the importance of intracellular transport machinery for heterologous protein secretion is poorly understood. Here, using Aspergillus oryzae as a model filamentous fungus, we studied the involvement of two putative lectin-like cargo receptors, A. oryzae Vip36 (AoVip36) and AoEmp47, in the secretion of heterologous proteins expressed in fusion with the endogenous enzyme α-amylase as the carrier. Fluorescence microscopy revealed that mDsRed-tagged AoVip36 localized in the Golgi compartment, whereas AoEmp47 showed localization in both the ER and the Golgi compartment. Deletion of AoVip36 and AoEmp47 improved heterologous protein secretion, but only AoVip36 deletion had a negative effect on the secretion of α-amylase. Analysis of ER-enriched cell fractions revealed that AoVip36 and AoEmp47 were involved in the retention of heterologous proteins in the ER. However, the overexpression of each cargo receptor had a different effect on heterologous protein secretion: AoVip36 enhanced the secretion, whereas AoEmp47 promoted the intracellular retention. Taken together, our data suggest that AoVip36 and AoEmp47 hinder the secretion of heterologous proteins by promoting their retention in the ER but that AoVip36 also promotes the secretion of heterologous proteins. Moreover, we found that genetic deletion of these putative ER-Golgi cargo receptors significantly improves heterologous protein production. The present study is the first to propose that ER-Golgi transport is a bottleneck for heterologous protein production in filamentous fungi. PMID:25362068

Anaerobic metabolism during short all-out efforts in tethered running: Comparison of energy expenditure and mechanical parameters between different sprint durations for testing.

PubMed

Sousa, Filipe Antônio Barros; Vasque, Rubens Eduardo; Gobatto, Claudio Alexandre

2017-01-01

This study's aims to verify the energy expenditure, metabolic distress and usefulness to evaluate the anaerobic constructs for different all-out durations in running efforts. Twelve active male underwent four testing sessions, one for familiarization and three performing one all-out (AO) tethered running sprint lasting 30s, 20s or 10s. Oxygen consumption, excess post exercise oxygen consumption, and lactate production were retained to analyse metabolic function, together with mechanical power and work as performance parameters. Paired results were compared via one-way ANOVA for repeated measures (Tukey-HSD post-hoc), effect sizes and ICC for absolute agreement. Statistical significance was accepted at p ≤ 0.05. Despite total and energy expenditure from oxidative pathway being significantly higher for longer durations (p < 0.001; ES > 0.7), glycolytic energy expenditure presented an agreement between AO30s and AO20s (ICC-A = 0.63*), while the paired comparisons to AO10s have presented significant differences (p < 0.01; ES > 1.0). Phosphagen energy expenditure were similar between all-out durations (p = 0.12; ICC-A = 0.62*; ES < 0.5). Maximum mechanical power was higher in AO10s than in AO30s (p = 0.03; ES = 0.6), not being different between AO10s and AO20s (p = 0.67; ICC-A = 0.88*; ES = 0.2) and between AO20s and AO30s (p = 0.18; ICC-A = 0.56*; ES = 0.4). In addition, agreement between work in the first ten seconds was confirmed via ICC only between AO10s and AO20s (p = 0.50; ICC-A = 0.86*; ES = 0.3), but not for the other paired comparisons (p < 0.1; ICC < 0.45; ES > 0.5). AO20s is a better alternative to estimate anaerobic power and capacity in one single test, with similar oxidative demand than AO30s.

Genome mining and motif truncation of glycoside hydrolase family 5 endo-β-1,4-mannanase encoded by Aspergillus oryzae RIB40 for potential konjac flour hydrolysis or feed additive.

PubMed

Tang, Cun-Duo; Shi, Hong-Ling; Tang, Qing-Hai; Zhou, Jun-Shi; Yao, Lun-Guang; Jiao, Zhu-Jin; Kan, Yun-Chao

2016-11-01

Two novel glycosyl hydrolase family 5 (GH5) β-mannanases (AoMan5A and AoMan5B) were identified from Aspergillus oryzae RIB40 by genome mining. The AoMan5A contains a predicted family 1 carbohydrate binding module (CBM-1), located at its N-terminal. The AoMan5A, AoMan5B and truncated mutant AoMan5AΔCL (truncating the N-terminal CBM and linker of AoMan5A) were expressed retaining the N-terminus of the native protein in Pichia pastoris GS115 by pPIC9K M . The specific enzyme activity of the purified reAoMan5A, reAoMan5B and reAoMan5AΔCL towards locust bean gum at pH 3.6 and 40°C for 10min, was 8.3, 104.2 and 15.8U/mg, respectively. The temperature properties of the reAoMan5AΔCL were improved by truncating CBM. They can degrade the pretreated konjac flour and produce prebiotics. In addition, they had excellent stability under simulative gastric fluid and simulative prilling process. All these properties make these recombinant β-mannanases potential additives for use in the food and feed industries. Copyright © 2016. Published by Elsevier Inc.

Up-Regulated Expression of AOS-LOXa and Increased Eicosanoid Synthesis in Response to Coral Wounding

PubMed Central

Lõhelaid, Helike; Teder, Tarvi; Tõldsepp, Kadri; Ekins, Merrick; Samel, Nigulas

2014-01-01

In octocorals, a catalase–like allene oxide synthase (AOS) and an 8R-lipoxygenase (LOX) gene are fused together encoding for a single AOS-LOX fusion protein. Although the AOS-LOX pathway is central to the arachidonate metabolism in corals, its biological function in coral homeostasis is unclear. Using an acute incision wound model in the soft coral Capnella imbricata, we here test whether LOX pathway, similar to its role in plants, can contribute to the coral damage response and regeneration. Analysis of metabolites formed from exogenous arachidonate before and after fixed time intervals following wounding indicated a significant increase in AOS-LOX activity in response to mechanical injury. Two AOS-LOX isoforms, AOS-LOXa and AOS-LOXb, were cloned and expressed in bacterial expression system as active fusion proteins. Transcription levels of corresponding genes were measured in normal and stressed coral by qPCR. After wounding, AOS-LOXa was markedly up-regulated in both, the tissue adjacent to the incision and distal parts of a coral colony (with the maximum reached at 1 h and 6 h post wounding, respectively), while AOS-LOXb was stable. According to mRNA expression analysis, combined with detection of eicosanoid product formation for the first time, the AOS-LOX was identified as an early stress response gene which is induced by mechanical injury in coral. PMID:24551239

Compact MEMS-based adaptive optics: optical coherence tomography for clinical use

NASA Astrophysics Data System (ADS)

Chen, Diana C.; Olivier, Scot S.; Jones, Steven M.; Zawadzki, Robert J.; Evans, Julia W.; Choi, Stacey S.; Werner, John S.

2008-02-01

We describe a compact MEMS-based adaptive optics (AO) optical coherence tomography (OCT) system with improved AO performance and ease of clinical use. A typical AO system consists of a Shack-Hartmann wavefront sensor and a deformable mirror that measures and corrects the ocular and system aberrations. Because of limitations on current deformable mirror technologies, the amount of real-time ocular-aberration compensation is restricted and small in previous AO-OCT instruments. In this instrument, we incorporate an optical apparatus to correct the spectacle aberrations of the patients such as myopia, hyperopia and astigmatism. This eliminates the tedious process of using trial lenses in clinical imaging. Different amount of spectacle aberration compensation was achieved by motorized stages and automated with the AO computer for ease of clinical use. In addition, the compact AO-OCT was optimized to have minimum system aberrations to reduce AO registration errors and improve AO performance.

The RNA helicase DDX39B and its paralog DDX39A regulate androgen receptor splice variant AR-V7 generation.

PubMed

Nakata, Daisuke; Nakao, Shoichi; Nakayama, Kazuhide; Araki, Shinsuke; Nakayama, Yusuke; Aparicio, Samuel; Hara, Takahito; Nakanishi, Atsushi

2017-01-29

Mounting evidence suggests that constitutively active androgen receptor (AR) splice variants, typified by AR-V7, are associated with poor prognosis and resistance to androgen deprivation therapy in prostate cancer patients. However, mechanisms governing the generation of AR splice variants are not fully understood. In this study, we aimed to investigate the dynamics of AR splice variant generation using the JDCaP prostate cancer model that expresses AR splice variants under androgen depletion. Microarray analysis of JDCaP xenografts before and after expression of AR splice variants suggested that dysregulation of RNA processing pathways is likely involved in AR splice variant generation. To explore factors contributing to generation of AR-V7 mRNA, we conducted a focused RNA interference screen in AR-V7-positive JDCaP-hr cells using an shRNA library targeting spliceosome-related genes. This screen identified DDX39B as a regulator of AR-V7 mRNA expression. Simultaneous knockdown of DDX39B and its paralog DDX39A drastically and selectively downregulated AR-V7 mRNA expression in multiple AR-V7-positive prostate cancer cell lines. DDX39B was upregulated in relapsed JDCaP xenografts expressing AR splice variants, suggesting its role in expression of AR splice variants. Taken together, our findings offer insight into the mechanisms of AR splice variant generation and identify DDX39 as a potential drug target for the treatment of AR splice variant-positive prostate cancer. Copyright © 2016 Elsevier Inc. All rights reserved.

International consensus statement on allergy and rhinology: allergic rhinitis-executive summary.

PubMed

Wise, Sarah K; Lin, Sandra Y; Toskala, Elina

2018-02-01

The available allergic rhinitis (AR) literature continues to grow. Critical evaluation and understanding of this literature is important to appropriately utilize this knowledge in the care of AR patients. The International Consensus statement on Allergy and Rhinology: Allergic Rhinitis (ICAR:AR) has been produced as a multidisciplinary international effort. This Executive Summary highlights and summarizes the findings of the comprehensive ICAR:AR document. The ICAR:AR document was produced using previously described methodology. Specific topics were developed relating to AR. Each topic was assigned a literature review, evidence-based review (EBR), or evidence-based review with recommendations (EBRR) format as dictated by available evidence and purpose within the ICAR:AR document. Following iterative reviews of each topic, the ICAR:AR document was synthesized and reviewed by all authors for consensus. Over 100 individual topics related to AR diagnosis, pathophysiology, epidemiology, disease burden, risk factors, allergy testing modalities, treatment, and other conditions/comorbidities associated with AR were addressed in the comprehensive ICAR:AR document. Herein, the Executive Summary provides a synopsis of these findings. In the ICAR:AR critical review of the literature, several strengths were identified. In addition, significant knowledge gaps exist in the AR literature where current practice is not based on the best quality evidence; these should be seen as opportunities for additional research. The ICAR:AR document evaluates the strengths and weaknesses of the AR literature. This Executive Summary condenses these findings into a short summary. The reader is also encouraged to consult the comprehensive ICAR:AR document for a thorough description of this work. © 2018 ARS-AAOA, LLC.

K/Ar dating of lunar soils. II

NASA Technical Reports Server (NTRS)

Alexander, E. C., Jr.; Bates, A.; Coscio, M. R., Jr.; Dragon, J. C.; Murthy, V. R.; Pepin, R. O.; Venkatesan, T. R.

1976-01-01

An attempt is made to identify those K/Ar techniques which extract the most reliable chronological information from lunar soils and to define the situations in which the best data are obtainable. Results are presented for determinations of the exposure and K/Ar ages of five lunar soil samples, which were performed by applying correlation techniques for a two-component argon structure to stepwise-heated and neutron-irradiated aliquots of grain-sized separates. It is found that ages deduced from Ar-40/surface-correlated Ar-36 vs K-40/surface-correlated Ar-36 and analogous plots of data from grain-sized separates appear to be the best available K/Ar ages of submature to mature lunar soils, that ages deduced from Ar-40 vs Ar-36 and analogous plots which assume a uniform K content can be significantly in error, and that stepwise-heating (Ar-40)-(Ar-39) experiments yield useful information only for simple immature soils where the K-Ar systematics are dominated by a single component.

Therapeutic targeting of sunitinib-induced AR phosphorylation in renal cell carcinoma.

PubMed

Adelaiye-Ogala, Remi; Damayanti, Nur P; Orillion, Ashley R; Arisa, Sreevani; Chintala, Sreenivasulu; Titus, Mark A; Kao, Chinghai; Pili, Roberto

2018-03-23

Androgen receptor (AR) plays a crucial role in the development and progression of prostate cancer. AR expression has also been reported in other solid tumors, including renal cell carcinoma (RCC), but its biological role here remains unclear. Through integrative analysis of a reverse phase protein array (RPPA), we discovered increased expression of AR in an RCC patient-derived xenograft model of acquired resistance to the receptor tyrosine kinase inhibitor (RTKi) sunitinib. AR expression was increased in RCC cell lines with either acquired or intrinsic sunitinib resistance in vitro. An AR signaling gene array profiler indicated elevated levels of AR target genes in sunitinib-resistant cells. Sunitinib-induced AR transcriptional activity was associated with increased phosphorylation of serine 81 (pS81) on AR. Additionally, AR overexpression resulted in acquired sunitinib resistance, and the AR antagonist enzalutamide-induced AR degradation and attenuated AR downstream activity in sunitinib-resistant cells, also indicated by decreased secretion of human kallikrein 2 (KLK2). Enzalutamide-induced AR degradation was rescued by either proteasome inhibition or by knockdown of the AR ubiquitin ligase speckle-type POZ protein (SPOP). In vivo treatment with enzalutamide and sunitinib demonstrated that this combination efficiently induced tumor regression in an RCC model following acquired sunitinib resistance. Overall, our results suggest the potential role of AR as a target for therapeutic interventions, in combination with RTKi, to overcome drug resistance in RCC. Copyright ©2018, American Association for Cancer Research.

Lack of β2-AR Increases Anxiety-Like Behaviors and Rewarding Properties of Cocaine.

PubMed

Zhu, Huiwen; Liu, Zhiyuan; Zhou, Yiming; Yin, Xuming; Xu, Bo; Ma, Lan; Liu, Xing

2017-01-01

It is well known that β-adrenoceptors (β-ARs) play a critical role in emotional arousal and stressful events, but the specific contributions of the β2-AR subtype to the psychological disorders are largely unknown. To investigate whether β2-AR are involved in anxiety-like behavior and reward to addictive drugs, we conducted a series of behavioral tests on β2-AR knock-out (KO) mice. β2-AR KO mice exhibited increased preference for the dark compartment and closed arm in tests of Light/Dark box and elevated plus maze, indicating that β2-AR deletion elevates level of anxiety or innate fear. β2-AR KO mice also showed decreased immobility in tail suspension test (TST), suggesting that β2-AR deletion inhibits depression-like behavior. Interestingly, β2-AR ablation did not change basal locomotion but significantly increased locomotor activity induced by acute cocaine administration. β2-AR KO mice showed enhanced place preference for cocaine, which could be attenuated by β1-selective AR antagonist betaxolol. Consistently, β2-AR agonist suppressed cocaine-conditioned place preference (CPP). These data indicate that β2-AR deletion enhances acute response and reward to cocaine. Our results suggest that β2-AR regulates anxiety level, depression-like behavior and hedonic properties of cocaine, implicating that β2-AR are the potential targets for the treatment of emotional disorders and cocaine addiction.

Direct Measurement of Recoil Effects on Ar-Ar Standards

NASA Astrophysics Data System (ADS)

Hall, C. M.

2011-12-01

Advances in the precision possible with the Ar-Ar method using new techniques and equipment have led to considerable effort to improve the accuracy of the calibration of interlaboratory standards. However, ultimately the accuracy of the method relies on the measurement of 40Ar*/39ArK ratios on primary standards that have been calibrated with the K-Ar method and, in turn, on secondary standards that are calibrated against primary standards. It is usually assumed that an Ar-Ar total gas age is equivalent to a K-Ar age, but this assumes that there is zero loss of Ar due to recoil. Instead, traditional Ar-Ar total gas ages are in fact Ar retention ages [1] and not, strictly speaking, comparable to K-Ar ages. There have been efforts to estimate the importance of this effect on standards along with prescriptions for minimizing recoil effects [2,3], but these studies have relied on indirect evidence for 39Ar recoil. We report direct measurements of 39Ar recoil for a set of primary and secondary standards using the vacuum encapsulation techniques of [1] and show that significant adjustments to ages assigned to some standards may be needed. The fraction f of 39Ar lost due to recoil for primary standards MMhb-1 hornblende and GA-1550 biotite are 0.00367 and 0.00314 respectively. It is possible to modify the assumed K-Ar ages of these standards so that when using their measured Ar retention 40Ar*/39ArK ratios, one obtains a correct K-Ar age for an unknown, assuming that the unknown sample has zero loss of 39Ar due to recoil. Assuming a primary K-Ar age for MMhb-1 of 520.4 Ma, the modified age would be 522.1 Ma and assuming a primary K-Ar age for GA-1550 of 98.79 Ma [4] yields a modified effective age of 99.09 Ma. Measured f values for secondary standards FCT-3 biotite, FCT-2 sanidine and TCR-2 sanidine are 0.00932, 0.00182 and 0.00039 respectively. Using an R value for FCT-3 biotite relative to MMhb-1 [5], the K-Ar age for this standard would be 27.83 Ma and using R values for FCT and TC sanidines [4] against GA-1550, their K-Ar ages would be 28.06 Ma and 28.41 Ma respectively. For retrospective recalculation purposes, the effective Ar-Ar age of these samples that should yield correct K-Ar ages for unknowns with zero recoil loss would be 28.09 Ma, 28.11 Ma and 28.42 Ma for FCT-3 biotite, FCT-2 sanidine and TCR-2 sanidine respectively. The measured f for FCT-3 appears to explain the R value of it relative to FCT sanidine of 1.0086 found by [8]. From the low T portion of the Ar release spectra of the biotite and amphibole standards, it is clear that the dominant recoil artifact affecting Ar release is the re-implantation mechanism seen in clay samples [1,6,7] and not the loss of 39Ar at the surface of the grain. The geometry of neighboring grains during irradiation and internal defects may predominate in controlling recoil loss. [1] Dong et al., 1995, Science, 267, 355-359. [2] Paine et al., 2006, Geochim.Cosmochim. Acta, 70, 1507-1517. [3] Jourdan et al., 2007, Geochim. Cosmochim. Acta, 71, 2791-2808 [4] Renne et al., 1998, Chem. Geol., 145 117-152. [5] Hall & Farrell, 1995, Earth Planet. Sci. Lett., 133, 327-338. [6] Hall et al., 1997, Earth Planet. Sci. Lett., 148, 287-298. [7] Hall et al., 2000, Econ. Geol., 95, 1739-1752. [8] Di Vincenzo & Roman Skála, 2009, Geochim. Cosmochim. Acta, 73, 493-513.

An alternative hypothesis for high-T 40Ar/39Ar age spectrum discordance in polyphase extraterrestrial materials

NASA Astrophysics Data System (ADS)

Cassata, W. S.; Shuster, D. L.; Renne, P. R.; Weiss, B. P.

2009-12-01

A common feature observed in 40Ar/39Ar age spectra of extraterrestrial (ET) rocks is a conspicuous decrease in the ages of high temperature extractions relative to lower temperature steps and a correlated increase in Ca/K, often succeeded by a monotonic increase in ages. This feature is routinely attributed to recoil-implanted 39Ar from a potassium (K)-rich donor phase into a K-poor receptor phase (e.g., 1,2). While 39Ar recoil redistribution is undoubtedly manifested in many terrestrial and ET 40Ar/39Ar whole-rock age spectra, it cannot easily explain the magnitude of high release temperature 40Ar*/39ArK anomalies observed in Martian meteorites ALH 84001 and Nakhla, as well as other course-grained meteorites and lunar rocks. Depending on the aliquot and sample, 50 - 100% of the pyroxene release spectra in ALH 84001 and Nakhla appear strongly perturbed to lower ages. As the mean recoil distance of 39Ar ~0.1 µm, the recoil hypothesis demands that a high-K phase be ubiquitously distributed amongst sub-micron to micron sized pyroxene crystals to account for the observed pyroxene age spectra. However, in both Nakhla and ALH 84001, pyroxene is often completely isolated from high-K phases and individual grains commonly exceed 100 µm in diameter. 40Ar/39Ar analyses of pyroxene-bearing terrestrial basalts, wherein fine-grained pyroxene and plagioclase are intimately adjoined, show that recoil-implanted 39Ar into pyroxene produces much less precipitous anomalies in 40Ar*/39ArK, as predicted by the recoil lengthscale. An alternative hypothesis is that whole-rock age spectra of ET samples with anomalously low ages at high temperatures may reflect diffusive 40Ar distributions within considerably degassed pyroxene grains. Owing to apparent differences in activation energies between glass and/or plagioclase and pyroxene, 40Ar may diffuse more rapidly from pyroxene under certain high-temperature conditions (i.e., above the temperature at which the extrapolated Ar Arrhenius relationships intersect). Thus, very brief, high-temperature shock-heating events may preferentially degas pyroxene without significantly resetting glass and plagioclase 40Ar/39Ar age spectra. This effect would be enhanced by highly localized shock-heating focused along pyroxene (sub)grain boundaries, as has been inferred in other cases (e.g., 3). The shock and impact origin of this feature may explain its frequent appearance in ET samples, regardless of grain size, as well as the general absence of terrestrial analogs. We will present new 40Ar/39Ar data from Martian meteorites and physical models to distinguish between these competing hypotheses. References Cited: 1. Turner & Cadogan, 1974, Possible effects of 39Ar recoil in 40Ar-39Ar dating. Proc. 5th LPSC, 1601- 1615. 2. Huneke & Smith, 1976, The realities of recoil: 39Ar recoil out of small grains and anomalous age patterns in 40Ar-39Ar dating. Proc. 7th LPSC, 1987-2008. 3. Min et al., 2003, Single grain (U-Th)/He ages from phosphates in Acapulco meteorite and implications for thermal history. EPSL 209, 323-336.

40Ar* loss in experimentally deformed muscovite and biotite with implications for 40Ar/39Ar geochronology of naturally deformed rocks

USGS Publications Warehouse

Cosca, M.; Stunitz, H.; Bourgeix, A.-L.; Lee, J.P.

2011-01-01

The effects of deformation on radiogenic argon (40Ar*) retentivity in mica are described from high pressure experiments performed on rock samples of peraluminous granite containing euhedral muscovite and biotite. Cylindrical cores, ???15mm in length and 6.25mm in diameter, were drilled from granite collected from the South Armorican Massif in northwestern France, loaded into gold capsules, and weld-sealed in the presence of excess water. The samples were deformed at a pressure of 10kb and a temperature of 600??C over a period 29 of hours within a solid medium assembly in a Griggs-type triaxial hydraulic deformation apparatus. Overall shortening in the experiments was approximately 10%. Transmitted light and secondary and backscattered electron imaging of the deformed granite samples reveals evidence of induced defects and for significant physical grain size reduction by kinking, cracking, and grain segmentation of the micas.Infrared (IR) laser (CO2) heating of individual 1.5-2.5mm diameter grains of muscovite and biotite separated from the undeformed granite yield well-defined 40Ar/39Ar plateau ages of 311??2Ma (2??). Identical experiments on single grains separated from the experimentally deformed granite yield results indicating 40Ar* loss of 0-35% in muscovite and 2-3% 40Ar* loss in biotite. Intragrain in situ ultraviolet (UV) laser ablation 40Ar/39Ar ages (??4-10%, 1??) of deformed muscovites range from 309??13 to 264??7Ma, consistent with 0-16% 40Ar* loss relative to the undeformed muscovite. The in situ UV laser ablation 40Ar/39Ar ages of deformed biotite vary from 301 to 217Ma, consistent with up to 32% 40Ar* loss. No spatial correlation is observed between in situ 40Ar/39Ar age and position within individual grains. Using available argon diffusion data for muscovite the observed 40Ar* loss in the experimentally treated muscovite can be utilized to predict average 40Ar* diffusion dimensions. Maximum 40Ar/39Ar ages obtained by UV laser ablation overlap those of the undeformed muscovite, indicating argon loss of <1% and an average effective grain radius for 40Ar* diffusion ???700??m. The UV laser ablation and IR laser incremental 40Ar/39Ar ages indicating 40Ar* loss of 16% and 35%, respectively, are consistent with an average diffusion radius ???100??m. These results support a hypothesis of grain-scale 40Ar* diffusion distances in undeformed mica and a heterogeneous mechanical reduction in the intragrain effective diffusion length scale for 40Ar* in deformed mica. Reduction in the effective diffusion length scale in naturally deformed samples occurs most probably through production of mesoscopic and submicroscopic defects such as, e.g., stacking faults. A network of interconnected defects, continuously forming and annealing during dynamic deformation likely plays an important role in controlling both 40Ar* retention and intragrain distribution in deformed mica. Intragrain 40Ar/39Ar ages, when combined with estimates of diffusion kinetics and distances, may provide a means of establishing thermochronological histories from individual micas. ?? 2011.

The Adaptive Optics Summer School Laboratory Activities

NASA Astrophysics Data System (ADS)

Ammons, S. M.; Severson, S.; Armstrong, J. D.; Crossfield, I.; Do, T.; Fitzgerald, M.; Harrington, D.; Hickenbotham, A.; Hunter, J.; Johnson, J.; Johnson, L.; Li, K.; Lu, J.; Maness, H.; Morzinski, K.; Norton, A.; Putnam, N.; Roorda, A.; Rossi, E.; Yelda, S.

2010-12-01

Adaptive Optics (AO) is a new and rapidly expanding field of instrumentation, yet astronomers, vision scientists, and general AO practitioners are largely unfamiliar with the root technologies crucial to AO systems. The AO Summer School (AOSS), sponsored by the Center for Adaptive Optics, is a week-long course for training graduate students and postdoctoral researchers in the underlying theory, design, and use of AO systems. AOSS participants include astronomers who expect to utilize AO data, vision scientists who will use AO instruments to conduct research, opticians and engineers who design AO systems, and users of high-bandwidth laser communication systems. In this article we describe new AOSS laboratory sessions implemented in 2006-2009 for nearly 250 students. The activity goals include boosting familiarity with AO technologies, reinforcing knowledge of optical alignment techniques and the design of optical systems, and encouraging inquiry into critical scientific questions in vision science using AO systems as a research tool. The activities are divided into three stations: Vision Science, Fourier Optics, and the AO Demonstrator. We briefly overview these activities, which are described fully in other articles in these conference proceedings (Putnam et al., Do et al., and Harrington et al., respectively). We devote attention to the unique challenges encountered in the design of these activities, including the marriage of inquiry-like investigation techniques with complex content and the need to tune depth to a graduate- and PhD-level audience. According to before-after surveys conducted in 2008, the vast majority of participants found that all activities were valuable to their careers, although direct experience with integrated, functional AO systems was particularly beneficial.

Patterns of poststroke brain damage that predict speech production errors in apraxia of speech and aphasia dissociate.

PubMed

Basilakos, Alexandra; Rorden, Chris; Bonilha, Leonardo; Moser, Dana; Fridriksson, Julius

2015-06-01

Acquired apraxia of speech (AOS) is a motor speech disorder caused by brain damage. AOS often co-occurs with aphasia, a language disorder in which patients may also demonstrate speech production errors. The overlap of speech production deficits in both disorders has raised questions on whether AOS emerges from a unique pattern of brain damage or as a subelement of the aphasic syndrome. The purpose of this study was to determine whether speech production errors in AOS and aphasia are associated with distinctive patterns of brain injury. Forty-three patients with history of a single left-hemisphere stroke underwent comprehensive speech and language testing. The AOS Rating Scale was used to rate speech errors specific to AOS versus speech errors that can also be associated with both AOS and aphasia. Localized brain damage was identified using structural magnetic resonance imaging, and voxel-based lesion-impairment mapping was used to evaluate the relationship between speech errors specific to AOS, those that can occur in AOS or aphasia, and brain damage. The pattern of brain damage associated with AOS was most strongly associated with damage to cortical motor regions, with additional involvement of somatosensory areas. Speech production deficits that could be attributed to AOS or aphasia were associated with damage to the temporal lobe and the inferior precentral frontal regions. AOS likely occurs in conjunction with aphasia because of the proximity of the brain areas supporting speech and language, but the neurobiological substrate for each disorder differs. © 2015 American Heart Association, Inc.

Adaptive optics scanning laser ophthalmoscopy in fundus imaging, a review and update.

PubMed

Zhang, Bing; Li, Ni; Kang, Jie; He, Yi; Chen, Xiao-Ming

2017-01-01

Adaptive optics scanning laser ophthalmoscopy (AO-SLO) has been a promising technique in funds imaging with growing popularity. This review firstly gives a brief history of adaptive optics (AO) and AO-SLO. Then it compares AO-SLO with conventional imaging methods (fundus fluorescein angiography, fundus autofluorescence, indocyanine green angiography and optical coherence tomography) and other AO techniques (adaptive optics flood-illumination ophthalmoscopy and adaptive optics optical coherence tomography). Furthermore, an update of current research situation in AO-SLO is made based on different fundus structures as photoreceptors (cones and rods), fundus vessels, retinal pigment epithelium layer, retinal nerve fiber layer, ganglion cell layer and lamina cribrosa. Finally, this review indicates possible research directions of AO-SLO in future.

Adaptive optics scanning laser ophthalmoscopy in fundus imaging, a review and update

PubMed Central

Zhang, Bing; Li, Ni; Kang, Jie; He, Yi; Chen, Xiao-Ming

2017-01-01

Adaptive optics scanning laser ophthalmoscopy (AO-SLO) has been a promising technique in funds imaging with growing popularity. This review firstly gives a brief history of adaptive optics (AO) and AO-SLO. Then it compares AO-SLO with conventional imaging methods (fundus fluorescein angiography, fundus autofluorescence, indocyanine green angiography and optical coherence tomography) and other AO techniques (adaptive optics flood-illumination ophthalmoscopy and adaptive optics optical coherence tomography). Furthermore, an update of current research situation in AO-SLO is made based on different fundus structures as photoreceptors (cones and rods), fundus vessels, retinal pigment epithelium layer, retinal nerve fiber layer, ganglion cell layer and lamina cribrosa. Finally, this review indicates possible research directions of AO-SLO in future. PMID:29181321

Elevated nitrogen metabolism and nitric oxide production are involved in Arabidopsis resistance to acid rain.

PubMed

Qiao, Fang; Zhang, Xi-Min; Liu, Xiang; Chen, Juan; Hu, Wen-Jun; Liu, Ting-Wu; Liu, Ji-Yun; Zhu, Chun-Quan; Ghoto, Kabir; Zhu, Xue-Yi; Zheng, Hai-Lei

2018-06-01

Acid rain (AR) can induce great damages to plants and could be classified into different types according to the different SO 4 2- /NO 3 - ratio. However, the mechanism of plants' responding to different types of AR has not been elucidated clearly. Here, we found that nitric-rich simulated AR (N-SiAR) induced less leaves injury as lower necrosis percentage, better physiological parameters and reduced oxidative damage in the leaves of N-SiAR treated Arabidopsis thaliana compared with sulfate and nitrate mixed (SN-SiAR) or sulfuric-rich (S-SiAR) simulated AR treated ones. Of these three types of SiAR, N-SiAR treated Arabidopsis maintained the highest of nitrogen (N) content, nitrate reductase (NR) and nitrite reductase (NiR) activity as well as N metabolism related genes expression level. Nitric oxide (NO) content showed that N-SiAR treated seedlings had a higher NO level compared to SN-SiAR or S-SiAR treated ones. A series of NO production and elimination related reagents and three NO production-related mutants were used to further confirm the role of NO in regulating acid rain resistance in N-SiAR treated Arabidopsis seedlings. Taken together, we concluded that an elevated N metabolism and enhanced NO production are involved in the tolerance to different types of AR in Arabidopsis. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Enzalutamide inhibits androgen receptor-positive bladder cancer cell growth.

PubMed

Kawahara, Takashi; Ide, Hiroki; Kashiwagi, Eiji; El-Shishtawy, Kareem A; Li, Yi; Reis, Leonardo O; Zheng, Yichun; Miyamoto, Hiroshi

2016-10-01

Emerging preclinical evidence suggests that androgen-mediated androgen receptor (AR) signals promote bladder cancer progression. However, little is known about the efficacy of an AR signaling inhibitor, enzalutamide, in the growth of bladder cancer cells. In this study, we compared the effects of enzalutamide and 2 other classic antiandrogens, flutamide and bicalutamide, on androgen-induced bladder cancer cell proliferation, migration, and invasion as well as tumor growth in vivo. Thiazolyl blue cell viability assay, flow cytometry, scratch wound-healing assay, transwell invasion assay, real-time polymerase chain reaction, and reporter gene assay were performed in AR-positive (e.g., UMUC3, TCCSUP, and 647V-AR) and AR-negative (e.g., UMUC3-AR-short hairpin RNA [shRNA], TCCSUP-AR-shRNA, 647V) bladder cancer lines treated with dihydrotestosterone and each AR antagonist. We also used a mouse xenograft model for bladder cancer. Dihydrotestosterone increased bladder cancer cell proliferation, migration, and invasion indicating that endogenous or exogenous AR was functional. Enzalutamide, hydroxyflutamide, and bicalutamide showed similar inhibitory effects, without significant agonist activity, on androgen-mediated cell viability/apoptosis, cell migration, and cell invasion in AR-positive lines. No significant effects of dihydrotestosterone as well as AR antagonists on the growth of AR-negative cells were seen. Correspondingly, in UMUC3 cells, these AR antagonists down-regulated androgen-induced expression of AR, matrix metalloproteinase-2, and interleukin-6. Androgen-enhanced AR-mediated transcriptional activity was also blocked by each AR antagonist exhibiting insignificant agonist activity. In UMUC3 xenograft-bearing mice, oral gavage treatment with each antiandrogen retarded tumor growth, and only enzalutamide demonstrated a statistically significant suppression compared with mock treatment. Our current data support recent observations indicating the involvement of the AR pathway in bladder cancer growth and further suggest that AR antagonists, including enzalutamide, are of therapeutic benefit in AR-positive bladder cancer. Copyright © 2016 Elsevier Inc. All rights reserved.

Evaluation of C3a receptor expression on human leucocytes by the use of novel monoclonal antibodies

PubMed Central

ZWIRNER, J; GÖTZE, O; BEGEMANN, G; KAPP, A; KIRCHHOFF, K; WERFEL, T

1999-01-01

Varying results have been published in the past regarding the reactivity of different leucocyte subpopulations, including neutrophils, monocytes and B lymphocytes, to the anaphylatoxin C3a and its degradation product C3a(desArg). To better characterize the cellular distribution of C3a receptor (C3aR) expression, monoclonal antibodies against two different epitopes on the third extracellular domain of the human C3aR were generated. Quantification of C3aR as compared with C5aR densities was performed on peripheral blood leucocytes by quantitative indirect immunofluorescence. Eosinophils and basophils expressed similar numbers of C3aR and C5aR molecules/cell. On eosinophils 10 700±4500 (mean±SD) C3aR and 14 700±4100 C5aR were found, whereas basophils carried 8100±2100 C3aR and 13 500±3800 C5aR. Monocytes expressed approximately six times more C5aR than C3aR molecules on their surface (6000±2500 C3aR versus 34 100±9300 C5aR molecules) whereas on neutrophils, the expression of C5aR was more than 20 times higher than the expression of C3aR (3100±1000 C3aR versus 63 500±12 200 C5aR). No C3aR expression was detectable on peripheral blood-derived B lymphocytes and on tonsillar B cells before and after stimulation with interleukin-2/Staphylococcus aureus Cowan strain I. Our findings correspond well with the paucity of data on C3a-induced functional activities in monocytes and neutrophils and suggest that eosinophilic and basophilic granulocytes represent the primary effector cells in the peripheral blood which can be stimulated by C3a. PMID:10447728

Cellular localization and detergent dependent oligomerization of rice allene oxide synthase-1.

PubMed

Yoeun, Sereyvath; Kim, Jeong-Il; Han, Oksoo

2015-01-01

Allene oxide synthase-1 from Oryza sativa (OsAOS1) localizes to the chloroplast, but lacks a putative chloroplast targeting sequence typically found in dicot AOS. Here, kinetic parameters and the oligomerization state/subunit composition of OsAOS1 were characterized in vitro in the absence or presence of detergent micelles. The catalytic efficiency (k(cat)/K(m)) of OsAOS1 reached a maximum near the critical micelle concentration for polyoxyethylene 10 tridecyl ether. Native gel analysis showed that OsAOS1 exists as a multimer in the absence of detergent micelles. The multimeric form of OsAOS1 was stably cross-linked in the absence of detergents, while only monomeric OsAOS1 was detected in the presence of detergent micelles. Gel filtration analysis indicated that the oligomeric state of OsAOS1 depends strongly on the detergents and that the monomer becomes the predominant form in the presence of detergent micelles. These data suggest that the detergent-dependent oligomeric state of OsAOS1 is an important factor for the regulation of its catalytic efficiency.

Paleotemperatures at the lunar surfaces from open system behavior of cosmogenic 38Ar and radiogenic 40Ar

DOE PAGES

Shuster, David L.; Cassata, William S.

2015-02-10

The simultaneous diffusion of both cosmogenic 38Ar and radiogenic 40Ar from solid phases is controlled by the thermal conditions of rocks while residing near planetary surfaces. Combined observations of 38Ar/ 37Ar and 40Ar/ 39Ar ratios during stepwise degassing analyses of neutron-irradiated Apollo samples can distinguish between diffusive loss of Ar due to solar heating of the rocks and that associated with elevated temperatures during or following impact events; the data provide quantitative constraints on the durations and temperatures of each process. From sequentially degassed 38Ar/ 37Ar ratios can be calculated a spectrum of apparent 38Ar exposure ages versus the cumulativemore » release fraction of 37Ar, which is particularly sensitive to conditions at the lunar surface typically over ~106–108 year timescales. Due to variable proportions of K- and Ca-bearing glass, plagioclase and pyroxene, with variability in the grain sizes of these phases, each sample will have distinct sensitivity to, and therefore different resolving power on, past near-surface thermal conditions. Furthermore, we present the underlying assumptions, and the analytical and numerical methods used to quantify the Ar diffusion kinetics in multi-phase whole-rock analyses that provide these constraints.« less

Splicing Factor Prp8 Interacts With NES(AR) and Regulates Androgen Receptor in Prostate Cancer Cells.

PubMed

Wang, Dan; Nguyen, Minh M; Masoodi, Khalid Z; Singh, Prabhpreet; Jing, Yifeng; O'Malley, Katherine; Dar, Javid A; Dhir, Rajiv; Wang, Zhou

2015-12-01

Androgen receptor (AR) plays a pivotal role in the development of primary as well as advanced castration-resistant prostate cancer. Previous work in our lab identified a novel nuclear export signal (NES) (NES(AR)) in AR ligand-binding domain essential for AR nucleocytoplasmic trafficking. By characterizing the localization of green fluorescence protein (GFP)-tagged NES(AR), we designed and executed a yeast mutagenesis screen and isolated 7 yeast mutants that failed to display the NES(AR) export function. One of those mutants was identified as the splicing factor pre-mRNA processing factor 8 (Prp8). We further showed that Prp8 could regulate NES(AR) function using short hairpin RNA knockdown of Prp8 coupled with a rapamycin export assay in mammalian cells and knockdown of Prp8 could induce nuclear accumulation of GFP-tagged AR in PC3 cells. Prp8 expression was decreased in castration-resistant LuCaP35 xenograft tumors as compared with androgen-sensitive xenografts. Laser capture microdissection and quantitative PCR showed Prp8 mRNA levels were decreased in human prostate cancer specimens with high Gleason scores. In prostate cancer cells, coimmunoprecipitation and deletion mutagenesis revealed a physical interaction between Prp8 and AR mainly mediated by NES(AR). Luciferase assay with prostate specific antigen promoter-driven reporter demonstrated that Prp8 regulated AR transcription activity in prostate cancer cells. Interestingly, Prp8 knockdown also increased polyubiquitination of endogenous AR. This may be 1 possible mechanism by which it modulates AR activity. These results show that Prp8 is a novel AR cofactor that interacts with NES(AR) and regulates AR function in prostate cancer cells.

Roles of steroid receptor coactivator (SRC)-1 and transcriptional intermediary factor (TIF) 2 in androgen receptor activity in mice.

PubMed

Ye, Xiangcang; Han, Sang Jun; Tsai, Sophia Y; DeMayo, Francesco J; Xu, Jianming; Tsai, Ming-Jer; O'Malley, Bert W

2005-07-05

Genetic disruption of the steroid receptor coactivator (SRC)-1 and transcriptional intermediary factor (TIF)2/SRC-2 in mouse resulted in distinctive mutant phenotypes. To quantify their roles in the function of androgen receptor (AR) transcriptional activity in vivo, we generated a unique transgenic AR-reporter mouse and analyzed the cell-specific contributions of SRC-1 and TIF2 to the activity of AR in mouse testis. Transgenic AR-luciferase and transgenic AR-lacZ mice harbor a recombinant mouse AR gene, AR(GAL4DBD), which is functionally coupled with a upstream activation sequence-mediated reporter gene (AR activity indicator). After characterization of these mice in terms of AR function, we further derived bigenic mice by crossing AR activity indicator mice with the SRC-1-/- or TIF2+/- mutant mice. Analyses of the resultant bigenic mice by in vivo imaging and luciferase assays showed that testicular AR activity was decreased significantly in those with the TIF2+/- mutation but not in the SRC-1+/- background, suggesting that TIF2 serves as the preferential coactivator for AR in testis. Immunohistological analysis confirmed that AR and TIF2 coexist in mouse testicular Sertoli cell nuclei under normal conditions. Although SRC-1 concentrates in Sertoli cell nuclei in the absence of TIF2, nuclear SRC-1 is not able to rescue AR activity in the TIF2 mutant background. Interestingly, SRC-1 appears to negatively influence AR activity, thereby counterbalancing the TIF2-stimulated AR activity. Our results provide unique in vivo insights to the multidimensional cell-type-specific interactions between AR and coregulators.

40Ar/39Ar Ages of Carbonaceous Xenoliths in 2 HED Meteorites

NASA Technical Reports Server (NTRS)

Turrin, B.; Lindsay, F. N.; Park, J.; Herzog, G. F.; Delaney, J. S.; Swisher, C. C., III; Johnson, J.; Zolensky, M.

2016-01-01

The generally young K/Ar and 40Ar/39Ar ages of CM chondrites made us wonder whether carbonaceous xenoliths (CMX) entombed in Howardite–Eucrite–Diogenite (HED) meteorites might retain more radiogenic 40Ar than do ‘free-range’ CM-chondrites. To find out, we selected two HED breccias with carbonaceous inclusions in order to compare the 40Ar/39Ar release patterns and ages of the inclusions with those of nearby HED material. Carbonaceous inclusions (CMXs) in two HED meteorites lost a greater fraction of radiogenic 40Ar than did surrounding host material, but a smaller fraction of it than did free-range CM-chondrites such as Murchison or more heavily altered ones. Importantly, however, the siting of the CMXs in HED matrix did not prevent the 40Ar loss of about 40 percent of the radiogenic 40Ar, even from phases that degas at high laboratory temperatures. We infer that carbonaceous asteroids with perihelia of 1 astronomical unit probably experience losses of at least this size. The usefulness of 40Ar/39Ar dating for samples returned from C-type asteroids may hinge, therefore, on identifying and analyzing separately small quantities of the most retentive phases of carbonaceous chondrites.

Chromosomal context and replication properties of ARS plasmids in Schizosaccharomyces pombe.

PubMed

Pratihar, Aditya S; Tripathi, Vishnu P; Yadav, Mukesh P; Dubey, Dharani D

2015-12-01

Short, specific DNA sequences called as Autonomously Replicating Sequence (ARS) elements function as plasmid as well as chromosomal replication origins in yeasts. As compared to ARSs, different chromosomal origins vary greatly in their efficiency and timing of replication probably due to their wider chromosomal context. The two Schizosaccharomyces pombe ARS elements, ars727 and ars2004, represent two extremities in their chromosomal origin activity - ars727 is inactive and late replicating, while ars2004 is a highly active, early-firing origin. To determine the effect of chromosomal context on the activity of these ARS elements, we have cloned them with their extended chromosomal context as well as in the context of each other in both orientations and analysed their replication efficiency by ARS and plasmid stability assays. We found that these ARS elements retain their origin activity in their extended/altered context. However, deletion of a 133-bp region of the previously reported ars727- associated late replication enforcing element (LRE) caused advancement in replication timing of the resulting plasmid. These results confirm the role of LRE in directing plasmid replication timing and suggest that the plasmid origin efficiency of ars2004 or ars727 remains unaltered by the extended chromosomal context.

High-Content Screening Identifies Src Family Kinases as Potential Regulators of AR-V7 Expression and Androgen-Independent Cell Growth.

PubMed

Szafran, Adam T; Stephan, Cliff; Bolt, Michael; Mancini, Maureen G; Marcelli, Marco; Mancini, Michael A

2017-01-01

AR-V7 is an androgen receptor (AR) splice variant that lacks the ligand-binding domain and is isolated from prostate cancer cell lines. Increased expression of AR-V7 is associated with the transition from hormone-sensitive prostate cancer to more advanced castration-resistant prostate cancer (CRPC). Due to the loss of the ligand-binding domain, AR-V7 is not responsive to traditional AR-targeted therapies, and the mechanisms that regulate AR-V7 are still incompletely understood. Therefore, we aimed to explore existing classes of small molecules that may regulate AR-V7 expression and intracellular localization and their potential therapeutic role in CRPC. We used AR high-content analysis (AR-HCA) to characterize the effects of a focused library of well-characterized clinical compounds on AR-V7 expression at the single-cell level in PC3 prostate cancer cells stably expressing green fluorescent protein (GFP)-AR-V7 (GFP-AR-V7:PC3). In parallel, an orthogonal AR-HCA screen of a small interfering (si)RNA library targeting 635 protein kinases was performed in GFP-AR-V7:PC3. The effect of the Src-Abl inhibitor PD 180970 was further characterized using cell-proliferation assays, quantitative PCR, and western blot analysis in multiple hormone-sensitive and CRPC cell lines. Compounds that tended to target Akt, Abl, and Src family kinases (SFKs) decreased overall AR-V7 expression, nuclear translocation, absolute nuclear level, and/or altered nuclear distribution. We identified 20 protein kinases that, when knocked down, either decreased nuclear GFP-AR-V7 levels or altered AR-V7 nuclear distribution, a set that included the SFKs Src and Fyn. The Src-Abl dual kinase inhibitor PD180970 decreased expression of AR-V7 by greater than 46% and decreased ligand-independent transcription of AR target genes in the 22RV1 human prostate carcinoma cell line. Further, PD180970 inhibited androgen-independent cell proliferation in endogenous-AR-V7-expressing prostate cancer cell lines and also overcame bicalutamide resistance observed in the 22RV1 cell line. SFKs, especially Src and Fyn, may be important upstream regulators of AR-V7 expression and represent promising targets in a subset of CRPCs expressing high levels of AR-V7. Prostate 77:82-93, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

In situ dating on Mars: A new approach to the K-Ar method utilizing cosmogenic argon

NASA Astrophysics Data System (ADS)

Cassata, William S.

2014-01-01

Cosmogenic argon isotopes are produced in feldspars via nuclear reactions between cosmic rays and Ca and K atoms within the lattice. These cosmogenic isotopes can be used as proxies for K and Ca, much like nuclear reactor-derived 39Ar and 37Ar are used as proxies for K and Ca, respectively, in 40Ar/39Ar geochronology. If Ca and K are uniformly distributed, then the ratio of radiogenic 40Ar (40Ar*) to cosmogenic 38Ar or 36Ar (38Arcos or 36Arcos) is proportional to the difference between the radioisotopic and exposure ages, as well as the K/Ca ratio of the degassing phase. Thus cosmogenic, radiogenic, and trapped Ar isotopes, all of which can be measured remotely and are stable over geologic time, are sufficient to generate an isochron-like diagram from which the isotopic composition of the trapped component may be inferred. Such data also provide a means to assess the extent to which the system has remained closed with respect to 40Ar*, thereby mitigating otherwise unquantifiable uncertainties that complicate the conventional K-Ar dating method.

Ar-40/Ar-39 ages and cosmic ray exposure ages of Apollo 14 samples.

NASA Technical Reports Server (NTRS)

Turner, G.; Huneke, J. C.; Podosek, F. A.; Wasserburg, G. J.

1971-01-01

We have used the Ar-40/Ar-39 dating technique on eight samples of Apollo 14 rocks (14053, 14310), breccia fragments (14321), and soil fragments (14001, 14167). The large basalt fragments give reasonable Ar-40/Ar-39 release patterns and yield well defined crystallization ages of 3.89-3.95 aeons. Correlation of the Ar-40/Ar-39 release patterns with Ar-39/Ar-37 patterns showed that the low temperature fractions with high radiogenic argon loss came from K-rich phases. A highly shocked sample and fragments included in the breccia yield complex release patterns with a low temperature peak. The total argon age of these fragments is 3.95 aeons. Cosmic ray exposure ages on these samples are obtained from the ratio of spallogenic Ar-38 to reactor induced Ar-37 and show a distinct grouping of low exposure ages of 26 m.y. correlated with Cone crater. Other samples have exposure ages of more than 260 m.y. and identify material with a more complex integrated cosmic age exposure history.

The inverse problem of argon diffusion from minerals: Determination of kinetic parameters from stepwise-heating experiments

USGS Publications Warehouse

Brandt, Stephen B.; Rasskazov, S.V.; Brandt, I.S.; Ivanov, A.V.; Kunk, Michael J.

1997-01-01

Results of two routine 40Ar/39Ar stepwise heating experiments on a biotite and a basanite are interpreted in terms of Fick's and Arrhenius' laws. Both patterns represent a saddle-shaped 39Ar release. Argon isotope spectra are suggested to be controlled by the activation energy of diffusion E and the frequency factor D(o). The activation energy of 39Ar is lower than the one of 40Ar. This results in a preferable release of 40Ar relatively to 39Ar at high-temperature steps and an increasing high-temperature wing in the saddle-shaped age spectrum. At low temperatures, considerable losses and irregularities in release of mainly 39Ar are observed, which cause the decreasing low-temperature wing in the 'saddle'. The suggestion of argon losses (mainly of 39Ar) from a loose, 'unstable' zone of the mineral structures becomes justified. The n-irradiation of the samples and the shift of E of 39Ar towards lower values seems to explain the saddle-shaped age-spectra often encountered in 40Ar/39Ar-geochronometry.

40Ar ∗ loss in experimentally deformed muscovite and biotite with implications for 40Ar/ 39Ar geochronology of naturally deformed rocks

NASA Astrophysics Data System (ADS)

Cosca, Michael; Stunitz, Holger; Bourgeix, Anne-Lise; Lee, John P.

2011-12-01

The effects of deformation on radiogenic argon ( 40Ar ∗) retentivity in mica are described from high pressure experiments performed on rock samples of peraluminous granite containing euhedral muscovite and biotite. Cylindrical cores, ˜15 mm in length and 6.25 mm in diameter, were drilled from granite collected from the South Armorican Massif in northwestern France, loaded into gold capsules, and weld-sealed in the presence of excess water. The samples were deformed at a pressure of 10 kb and a temperature of 600 °C over a period 29 of hours within a solid medium assembly in a Griggs-type triaxial hydraulic deformation apparatus. Overall shortening in the experiments was approximately 10%. Transmitted light and secondary and backscattered electron imaging of the deformed granite samples reveals evidence of induced defects and for significant physical grain size reduction by kinking, cracking, and grain segmentation of the micas. Infrared (IR) laser (CO 2) heating of individual 1.5-2.5 mm diameter grains of muscovite and biotite separated from the undeformed granite yield well-defined 40Ar/ 39Ar plateau ages of 311 ± 2 Ma (2σ). Identical experiments on single grains separated from the experimentally deformed granite yield results indicating 40Ar ∗ loss of 0-35% in muscovite and 2-3% 40Ar ∗ loss in biotite. Intragrain in situ ultraviolet (UV) laser ablation 40Ar/ 39Ar ages (±4-10%, 1σ) of deformed muscovites range from 309 ± 13 to 264 ± 7 Ma, consistent with 0-16% 40Ar ∗ loss relative to the undeformed muscovite. The in situ UV laser ablation 40Ar/ 39Ar ages of deformed biotite vary from 301 to 217 Ma, consistent with up to 32% 40Ar ∗ loss. No spatial correlation is observed between in situ40Ar/ 39Ar age and position within individual grains. Using available argon diffusion data for muscovite the observed 40Ar ∗ loss in the experimentally treated muscovite can be utilized to predict average 40Ar ∗ diffusion dimensions. Maximum 40Ar/ 39Ar ages obtained by UV laser ablation overlap those of the undeformed muscovite, indicating argon loss of <1% and an average effective grain radius for 40Ar ∗ diffusion ⩾700 μm. The UV laser ablation and IR laser incremental 40Ar/ 39Ar ages indicating 40Ar ∗ loss of 16% and 35%, respectively, are consistent with an average diffusion radius ≪100 μm. These results support a hypothesis of grain-scale 40Ar ∗ diffusion distances in undeformed mica and a heterogeneous mechanical reduction in the intragrain effective diffusion length scale for 40Ar ∗ in deformed mica. Reduction in the effective diffusion length scale in naturally deformed samples occurs most probably through production of mesoscopic and submicroscopic defects such as, e.g., stacking faults. A network of interconnected defects, continuously forming and annealing during dynamic deformation likely plays an important role in controlling both 40Ar ∗ retention and intragrain distribution in deformed mica. Intragrain 40Ar/ 39Ar ages, when combined with estimates of diffusion kinetics and distances, may provide a means of establishing thermochronological histories from individual micas.

Prognostic Significance of Anti-Aminoacyl-tRNA Synthetase Antibodies in Polymyositis/Dermatomyositis-Associated Interstitial Lung Disease: A Retrospective Case Control Study

PubMed Central

Hozumi, Hironao; Enomoto, Noriyuki; Kono, Masato; Fujisawa, Tomoyuki; Inui, Naoki; Nakamura, Yutaro; Sumikawa, Hiromitsu; Johkoh, Takeshi; Nakashima, Ran; Imura, Yoshitaka; Mimori, Tsuneyo; Suda, Takafumi

2015-01-01

Background In polymyositis/dermatomyositis (PM/DM), anti-aminoacyl-tRNA synthetase (ARS) antibodies are closely associated with interstitial lung disease (ILD), a frequent pulmonary complication. However, the clinical significance of anti-ARS antibodies is not well established. Objective We aimed to evaluate the clinical significance of anti-ARS antibodies in PM/DM-ILD patients. Methods Forty-eight consecutive PM/DM-ILD patients were studied retrospectively. Anti-ARS antibodies were screened by ELISA and confirmed by RNA immunoprecipitation test. Medical records, high-resolution computed tomography images, and surgical lung biopsy specimens were compared between ARS-positive (ARS group) and ARS-negative patients (non-ARS group). Results Anti-ARS antibodies were detected in 23 of 48 patients (48%). Radiologically, nonspecific interstitial pneumonia (NSIP) pattern was observed more frequently in the ARS group than in the non-ARS group (73.9% vs. 40%, P = 0.02). Pathologically, NSIP was the most frequent in both groups. Ten-year survival rate was also significantly higher in the ARS group than in the non-ARS group (91.6% vs. 58.7%, P = 0.02). Univariate Cox hazards analysis revealed that the presence of anti-ARS antibodies was associated with better prognosis (HR = 0.34, 95% CI 0.08–0.80; P = 0.01). Conclusions The presence of anti-ARS antibodies is a possible prognostic marker in patients with PM/DM-ILD. PMID:25789468

Impact of Age at Diagnosis and Hypothalamic Involvement on Body Mass Index Z-Score Change in Pediatric Brain Tumor Survivors.

PubMed

Strobel, Katie; Simpson, Pippa; Donohoue, Patricia A; Firat, Selim; Jogal, Sachin

2016-01-01

Obesity risk is increased for pediatric central nervous system tumor survivors. Hypothalamic involvement (HI) by tumor or treatment increases the risk. In healthy children, body mass index (BMI) normally declines until adiposity rebound (AR). We hypothesized that HI and diagnosis before AR would lead to increased BMI at follow-up. A chart review of 114 brain tumor survivors diagnosed between 2001-2011 at the Children's Hospital of Wisconsin extracted tumor location, treatment and BMI z-scores at diagnosis and 2-year follow-up. Children were categorized based on age at diagnosis relative to AR and presence/absence of HI. Children diagnosed pre-AR and post-AR with HI had higher BMI z-scores at 2-year follow-up (pre-AR: 1.6, post-AR: 1.3) than at diagnosis (0.5, 0.6). All groups without HI showed no increase in BMI z-score from diagnosis to 2-year follow-up (pre-AR: 0.7-0.6, during AR: 0.7-0.8, post-AR: 0.7-0.8). The pre-AR and during-AR cohorts with HI had a higher BMI z-score at 2-year follow-up relative to those without HI, while the post-AR group did not. Except for the post-AR group, patients with HI have increased BMI at 2 years after diagnosis compared to those without HI. Diagnosis pre-AR is associated with greater follow-up BMI z-score. © 2016 S. Karger AG, Basel.

Mobile Audience Response Systems at a Continuing Medical Education Conference.

PubMed

Beaumont, Alexandra; Gousseau, Michael; Sommerfeld, Connor; Leitao, Darren; Gooi, Adrian

2017-01-01

Mobile audience response systems (mARS) are electronic systems allowing speakers to ask questions and audience members to respond anonymously and immediately on a screen which enables learners to view their peers' responses as well as their own. mARS encourages increased interaction and active learning. This study aims to examine the perceptions of audience members and speakers towards the implementation of mARS at a national medical conference. mARS was implemented at the CSO Annual Meeting in Winnipeg 2015. Eleven presenters agreed to participate in the mARS trial. Both audience and presenters received instructions. Five-point Likert questions and short answer questions were emailed to all conference attendees and the data was evaluated. Twenty-seven participants responded, 23 audience members and 4 instructors. Overall, responders indicated improved attention, involvement, engagement and recognition of audience's understanding of topics with the use of mARS. mARS was perceived as easy to use, with clear instructions, and the majority of respondents expressed an interest in using mARS in more presentations and in future national medical conferences. Most respondents preferred lectures with mARS over lectures without mARS. Some negative feedback on mARS involved dissatisfaction with how some presenters implemented mARS into the workshops. Overall mARS was perceived positively with the majority of respondents wanting mARS implemented in more national medical conferences. Future studies should look at how mARS can be used as an educational tool to help improve patient outcomes.

Synthesis and reactivity of dimeric Ar'TlTlAr' and trimeric (Ar"T1)3 (Ar', Ar" = bulky terphenyl group) thallium(I) derivatives: Tl(I)-Tl(I) bonding in species ligated by monodentate ligands.

PubMed

Wright, Robert J; Phillips, Andrew D; Hino, Shirley; Power, Philip P

2005-04-06

The synthesis and characterization of three new organothallium(I) compounds are reported. Reaction of (Ar'Li)(2) (Ar' = C(6)H(3)-2,6-(C(6)H(3)-2,6-Pr(i)(2))(2)) and Ar"Li (Ar" = C(6)H(3)-2,6-(C(6)H(3)-2,6-Me(2))(2)) with TlCl in Et(2)O afforded (Ar'Tl)(2) (1) and (Ar' 'Tl)(3) (2). The "dithallene" 1 is the heaviest group 13 dimetallene and features a planar, trans-bent structure with Ar'Tl-Tl = 119.74(14) degrees and Tl-Tl = 3.0936(8) A. Compound 2 is the first structurally characterized neutral, three-membered ring species of formula c-(MR)(3) (M = Al-Tl; R = organo group). The Tl(3) ring has Tl-Tl distances in the range ca. 3.21-3.37 A as well as pyramidal Tl geometries. The Tl-Tl bonds in 1 and 2 are outside the range (2.88-2.97 A) of Tl-Tl single bonds in R(2)TlTlR(2) compounds. The weak Tl-Tl bonding in 1 and 2 leads to their dissociation into Ar'Tl and Ar' 'Tl monomers in hexane. The Ar'Tl monomer behaves as a Lewis base and readily forms a 1:1 donor-acceptor complex with B(C(6)F(5))(3) to give Ar'TlB(C(6)F(5))(3), 3. Adduct 3 features an almost linear thallium C(ipso)-Tl-B angle of 174.358(7) degrees and a Tl-B distance of 2.311(2) A, which indicates strong association. Treatment of 1 with a variety of reagents resulted in no reactions. The lower reactivity of 1 is in accord with the reluctance of Tl(I) to undergo oxidation to Tl(III) due to the unreactive character of the 6s(2) electrons.

Glycogen synthase kinase-3 inhibitors suppress the AR-V7-mediated transcription and selectively inhibit cell growth in AR-V7-positive prostate cancer cells.

PubMed

Nakata, Daisuke; Koyama, Ryokichi; Nakayama, Kazuhide; Kitazawa, Satoshi; Watanabe, Tatsuya; Hara, Takahito

2017-06-01

Recent evidence suggests that androgen receptor (AR) splice variants, including AR-V7, play a pivotal role in resistance to androgen blockade in prostate cancer treatment. The development of new therapeutic agents that can suppress the transcriptional activities of AR splice variants has been anticipated as the next generation treatment of castration-resistant prostate cancer. High-throughput screening of AR-V7 signaling inhibitors was performed using an AR-V7 reporter system. The effects of a glycogen synthase kinase-3 (GSK3) inhibitor, LY-2090314, on endogenous AR-V7 signaling were evaluated in an AR-V7-positive cell line, JDCaP-hr, by quantitative reverse transcription polymerase chain reaction. The relationship between AR-V7 signaling and β-catenin signaling was assessed using RNA interference. The effect of LY-2090314 on cell growth in various prostate cancer cell lines was also evaluated. We identified GSK3 inhibitors as transcriptional suppressors of AR-V7 using a high-throughput screen with an AR-V7 reporter system. LY-2090314 suppressed the reporter activity and endogenous AR-V7 activity in JDCaP-hr cells. Because silencing of β-catenin partly rescued the suppression, it was evident that the suppression was mediated, at least partially, via the activation of β-catenin signaling. AR-V7 signaling and β-catenin signaling reciprocally regulate each other in JDCaP-hr cells, and therefore, GSK3 inhibition can repress AR-V7 transcriptional activity by accumulating intracellular β-catenin. Notably, LY-2090314 selectively inhibited the growth of AR-V7-positive prostate cancer cells in vitro. Our findings demonstrate the potential of GSK3 inhibitors in treating advanced prostate cancer driven by AR splice variants. In vivo evaluation of AR splice variant-positive prostate cancer models will help illustrate the overall significance of GSK3 inhibitors in treating prostate cancer. © 2017 Wiley Periodicals, Inc.

Genome-wide analysis of AR binding and comparison with transcript expression in primary human fetal prostate fibroblasts and cancer associated fibroblasts.

PubMed

Nash, Claire; Boufaied, Nadia; Mills, Ian G; Franco, Omar E; Hayward, Simon W; Thomson, Axel A

2017-05-05

The androgen receptor (AR) is a transcription factor, and key regulator of prostate development and cancer, which has discrete functions in stromal versus epithelial cells. AR expressed in mesenchyme is necessary and sufficient for prostate development while loss of stromal AR is predictive of prostate cancer progression. Many studies have characterized genome-wide binding of AR in prostate tumour cells but none have used primary mesenchyme or stroma. We applied ChIPseq to identify genomic AR binding sites in primary human fetal prostate fibroblasts and patient derived cancer associated fibroblasts, as well as the WPMY1 cell line overexpressing AR. We identified AR binding sites that were specific to fetal prostate fibroblasts (7534), cancer fibroblasts (629), WPMY1-AR (2561) as well as those common among all (783). Primary fibroblasts had a distinct AR binding profile versus prostate cancer cell lines and tissue, and showed a localisation to gene promoter binding sites 1 kb upstream of the transcriptional start site, as well as non-classical AR binding sequence motifs. We used RNAseq to define transcribed genes associated with AR binding sites and derived cistromes for embryonic and cancer fibroblasts as well as a cistrome common to both. These were compared to several in vivo ChIPseq and transcript expression datasets; which identified subsets of AR targets that were expressed in vivo and regulated by androgens. This analysis enabled us to deconvolute stromal AR targets active in stroma within tumour samples. Taken together, our data suggest that the AR shows significantly different genomic binding site locations in primary prostate fibroblasts compared to that observed in tumour cells. Validation of our AR binding site data with transcript expression in vitro and in vivo suggests that the AR target genes we have identified in primary fibroblasts may contribute to clinically significant and biologically important AR-regulated changes in prostate tissue. Copyright © 2017. Published by Elsevier B.V.

Reconfiguring the AR-TIF2 Protein–Protein Interaction HCS Assay in Prostate Cancer Cells and Characterizing the Hits from a LOPAC Screen

PubMed Central

Fancher, Ashley T.; Hua, Yun; Camarco, Daniel P.; Close, David A.; Strock, Christopher J.

2016-01-01

Abstract The continued activation of androgen receptor (AR) transcription and elevated expression of AR and transcriptional intermediary factor 2 (TIF2) coactivator observed in prostate cancer (CaP) recurrence and the development of castration-resistant CaP (CRPC) support a screening strategy for small-molecule inhibitors of AR-TIF2 protein–protein interactions (PPIs) to find new drug candidates. Small molecules can elicit tissue selective effects, because the cells of distinct tissues express different levels and cohorts of coregulatory proteins. We reconfigured the AR-TIF2 PPI biosensor (PPIB) assay in the PC-3 CaP cell line to determine whether AR modulators and hits from an AR-TIF2 PPIB screen conducted in U-2 OS cells would behave differently in the CaP cell background. Although we did not observe any significant differences in the compound responses between the assay performed in osteosarcoma and CaP cells, the U-2 OS AR-TIF2 PPIB assay would be more amenable to screening, because both the virus and cell culture demands are lower. We implemented a testing paradigm of counter-screens and secondary hit characterization assays that allowed us to identify and deprioritize hits that inhibited/disrupted AR-TIF2 PPIs and AR transcriptional activation (AR-TA) through antagonism of AR ligand binding or by non-specifically blocking nuclear receptor trafficking. Since AR-TIF2 PPI inhibitor/disruptor molecules act distally to AR ligand binding, they have the potential to modulate AR-TA in a cell-specific manner that is distinct from existing anti-androgen drugs, and to overcome the development of resistance to AR antagonism. We anticipate that the application of this testing paradigm to characterize the hits from an AR-TIF2 PPI high-content screening campaign will enable us to prioritize the AR-TIF2 PPI inhibitor/disruptor leads that have potential to be developed into novel therapeutics for CaP and CRPC. PMID:27606620

MISSE Scattered Atomic Oxygen Characterization Experiment

NASA Technical Reports Server (NTRS)

Banks, Bruce A.; deGroh, Kim K.; Miller, Sharon K.

2006-01-01

An experiment designed to measure the atomic oxygen (AO) erosion profile of scattered AO was exposed to Low Earth Orbital (LEO) AO for almost four years as part of the Materials International Space Station Experiment 1 and 2 (MISSE 1 and 2). The experiment was flown in MISSE Passive Experiment Carrier 2 (PEC 2), Tray 1, attached to the exterior of the International Space Station (ISS) Quest Airlock. The experiment consisted of an aperture disk lid of Kapton H (DuPont) polyimide coated on the space exposed surface with a thin AO durable silicon dioxide film. The aperture lid had a small hole in its center to allow AO to enter into a chamber and impact a base disk of aluminum. The AO that scattered from the aluminum base could react with the under side of the aperture lid which was coated sporadically with microscopic sodium chloride particles. Scattered AO erosion can occur to materials within a spacecraft that are protected from direct AO attack but because of apertures in the spacecraft the AO can attack the interior materials after scattering. The erosion of the underside of the Kapton lid was sufficient to be able to use profilometry to measure the height of the buttes that remained after washing off the salt particles. The erosion pattern indicated that peak flux of scattered AO occurred at and angle of approximately 45 from the incoming normal incidence on the aluminum base unlike the erosion pattern predicted for scattering based on Monte Carlo computational predictions for AO scattering from Kapton H polyimide. The effective erosion yield for the scattered AO was found to be a factor of 0.214 of that for direct impingement on Kapton H polyimide.

Sonographic aorta/IVC cross-sectional area index for evaluation of dehydration in children.

PubMed

Kwon, Hyuksool; Jung, Jae Yun; Lee, Jin Hee; Kwak, Young Ho; Kim, Do Kyun; Jung, Jin Hee; Chang, Ik Wan; Kim, Kyuseok

2016-09-01

Current studies have not found sufficient evidence to encourage the use of ultrasound for assessing dehydration in children. We introduce a new sonographic parameter, the "aorta/inferior vena cava (IVC) cross-sectional area index" (Ao/IVCA) measured just inferior to the xiphoid process, for the effective evaluation of dehydration in children. This is a prospective, observational study. We enrolled children who presented to the pediatric emergency department (PED) between May 2014 and January 2015. We measured the maximum diameter of the aorta from inner wall to inner wall, and the long and short axis diameters of IVC using a convex array transducer. Ao/IVCA was calculated and compared with aorta/IVC maximal diameter index (Ao/IVCD) and the clinical dehydration scale (CDS). A total of 34 children were enrolled. We found a statistically significant correlation between Ao/IVCA and CDS (R(2) = 0.30; P <.001). Ao/IVCD did not correlate significantly with CDS (R(2) = 0.08; P =.11). The ability of Ao/IVCA and Ao/IVCD to predict CDS ≥1 was assessed using the receiver operating characteristic analysis. The area under the receiver operating characteristic curve for Ao/IVCA was larger than that for Ao/IVCD (0.87 vs 0.75, P= .04). The cut-off value of Ao/IVCA that yielded the maximum value of Youden index was 1.81 (sensitivity: 72%, specificity: 89%). Ao/IVCA might be a promising index for the assessment of dehydration. The diagnostic performance of Ao/IVCA for dehydration might be higher than that of the method that uses the maximum diameter of IVC and the aorta. Copyright © 2016 Elsevier Inc. All rights reserved.

Formulation of polylactide-co-glycolic acid nanospheres for encapsulation and sustained release of poly(ethylene imine)-poly(ethylene glycol) copolymers complexed to oligonucleotides

PubMed Central

Sirsi, Shashank R; Schray, Rebecca C; Wheatley, Margaret A; Lutz, Gordon J

2009-01-01

Antisense oligonucleotides (AOs) have been shown to induce dystrophin expression in muscles cells of patients with Duchenne Muscular Dystrophy (DMD) and in the mdx mouse, the murine model of DMD. However, ineffective delivery of AOs limits their therapeutic potential. Copolymers of cationic poly(ethylene imine) (PEI) and non-ionic poly(ethylene glycol) (PEG) form stable nanoparticles when complexed with AOs, but the positive surface charge on the resultant PEG-PEI-AO nanoparticles limits their biodistribution. We adapted a modified double emulsion procedure for encapsulating PEG-PEI-AO polyplexes into degradable polylactide-co-glycolic acid (PLGA) nanospheres. Formulation parameters were varied including PLGA molecular weight, ester end-capping, and sonication energy/volume. Our results showed successful encapsulation of PEG-PEI-AO within PLGA nanospheres with average diameters ranging from 215 to 240 nm. Encapsulation efficiency ranged from 60 to 100%, and zeta potential measurements confirmed shielding of the PEG-PEI-AO cationic charge. Kinetic measurements of 17 kDa PLGA showed a rapid burst release of about 20% of the PEG-PEI-AO, followed by sustained release of up to 65% over three weeks. To evaluate functionality, PEG-PEI-AO polyplexes were loaded into PLGA nanospheres using an AO that is known to induce dystrophin expression in dystrophic mdx mice. Intramuscular injections of this compound into mdx mice resulted in over 300 dystrophin-positive muscle fibers distributed throughout the muscle cross-sections, approximately 3.4 times greater than for injections of AO alone. We conclude that PLGA nanospheres are effective compounds for the sustained release of PEG-PEI-AO polyplexes in skeletal muscle and concomitant expression of dystrophin, and may have translational potential in treating DMD. PMID:19351396

Importance of SERCA2a on early isolated diastolic dysfunction induced by supravalvular aortic stenosis in rats

PubMed Central

Silveira, C.F.S.M.P.; Campos, D.H.S.; Freire, P.P.; Deus, A.F.; Okoshi, K.; Padovani, C.R.; Cicogna, A.C.

2017-01-01

Cardiac remodeling is defined as changes in shape and function of the heart in response to aggression (pressure overload). The sarcoplasmic reticulum calcium ATPase cardiac isoform 2a (SERCA2a) is a known factor that influences function. A wide spectrum of studies report a decrease in SERCA2a in heart failure, but none evaluate it's the role in early isolated diastolic dysfunction in supravalvular aortic stenosis (AoS). Our hypothesis was that SERCA2a participates in such dysfunction. Thirty-day-old male Wistar rats (60-80 g) were divided into AoS and Sham groups, which were submitted to surgery with or without aorta clipping, respectively. After 6 weeks, the animals were submitted to echocardiogram and functional analysis by isolated papillary muscle (IPM) in basal condition, hypoxia, and SERCA2a blockage with cyclopiazonic acid at calcium concentrations of 0.5, 1.5, and 2.5 mM. Western-blot analyses were used for SERCA2a and phospholamban detection. Data analysis was carried out with Student's t-test and ANOVA. AoS enhanced left atrium and E and A wave ratio, with preserved ejection fraction. Basal condition in IPM showed similar increases in developed tension (DT) and resting tension (RT) in AoS, and hypoxia was similar between groups. After cyclopiazonic acid blockage, final DT was equally decreased and RT was similar between groups, but the speed of relaxation was decreased in the AoS group. Western-blot was uniform in all evaluations. The hypothesis was confirmed, since functional parameters regarding SERCA2a were changed in the AoS group. PMID:28423119

Wavefront sensorless adaptive optics versus sensor-based adaptive optics for in vivo fluorescence retinal imaging (Conference Presentation)

NASA Astrophysics Data System (ADS)

Wahl, Daniel J.; Zhang, Pengfei; Jian, Yifan; Bonora, Stefano; Sarunic, Marinko V.; Zawadzki, Robert J.

2017-02-01

Adaptive optics (AO) is essential for achieving diffraction limited resolution in large numerical aperture (NA) in-vivo retinal imaging in small animals. Cellular-resolution in-vivo imaging of fluorescently labeled cells is highly desirable for studying pathophysiology in animal models of retina diseases in pre-clinical vision research. Currently, wavefront sensor-based (WFS-based) AO is widely used for retinal imaging and has demonstrated great success. However, the performance can be limited by several factors including common path errors, wavefront reconstruction errors and an ill-defined reference plane on the retina. Wavefront sensorless (WFS-less) AO has the advantage of avoiding these issues at the cost of algorithmic execution time. We have investigated WFS-less AO on a fluorescence scanning laser ophthalmoscopy (fSLO) system that was originally designed for WFS-based AO. The WFS-based AO uses a Shack-Hartmann WFS and a continuous surface deformable mirror in a closed-loop control system to measure and correct for aberrations induced by the mouse eye. The WFS-less AO performs an open-loop modal optimization with an image quality metric. After WFS-less AO aberration correction, the WFS was used as a control of the closed-loop WFS-less AO operation. We can easily switch between WFS-based and WFS-less control of the deformable mirror multiple times within an imaging session for the same mouse. This allows for a direct comparison between these two types of AO correction for fSLO. Our results demonstrate volumetric AO-fSLO imaging of mouse retinal cells labeled with GFP. Most significantly, we have analyzed and compared the aberration correction results for WFS-based and WFS-less AO imaging.

Expression of alpha-AR subtypes in T lymphocytes and role of the alpha-ARs in mediating modulation of T cell function.

PubMed

Bao, Jing-Yin; Huang, Yan; Wang, Feng; Peng, Yu-Ping; Qiu, Yi-Hua

2007-01-01

Previous work in our laboratory has shown that alpha-adrenoreceptors (alpha-ARs) and beta-ARs exist on lymphocytes from functional profile, and that the receptors mediate the regulation of lymphocyte function by catecholamines. In the present study, we directly examined the expression of alpha-AR subtypes, alpha(1)-AR and alpha(2)-AR mRNAs, in T lymphocytes and explored the roles of the alpha-AR subtypes and intracellular signal transduction mechanisms linked to the receptors in mediating the modulation of T lymphocyte function. T lymphocytes from mesenteric lymph nodes of rats were purified by using a nylon wool column. Reverse transcription polymerase chain reaction was used to detect the expression of alpha(1)-AR and alpha(2)-AR mRNAs in the freshly isolated T cells and the mitogen concanavalin A (Con A)-activated lymphocytes. Colorimetric methylthiazoletetrazolium assay was employed to measure lymphocyte proliferation induced by Con A. Interferon-gamma (IFN-gamma) and interleukin-4 (IL-4) levels in the Con A-stimulated lymphocyte culture supernatants were examined by enzyme-linked immunosorbent assay. T cells expressed both alpha(1)-AR and alpha(2)-AR mRNAs. The expression of both alpha(1)-AR and alpha(2)-AR mRNAs was significantly higher in the Con A-activated lymphocytes than in the resting lymphocytes. Phenylephrine, a selective alpha(1)-AR agonist, had no evident effect on lymphocyte proliferation nor on IFN-gamma and IL-4 production induced by Con A. However, the selective alpha(2)-AR agonist clonidine attenuated Con A-induced lymphocyte proliferation as well as IFN-gamma and IL-4 production. The inhibited lymphocyte proliferation and IFN-gamma and IL-4 production by clonidine were blocked by yohimbine, an alpha(2)-AR antagonist. Either phospholipase C inhibitor U-73122 or protein kinase C inhibitor chelerythrine partially prevented the suppressive effect of clonidine on Con A-stimulated lymphocyte proliferation and IL-4 production. T lymphocytes express both alpha(1)-ARs and alpha(2)-ARs, but only the alpha(2)-ARs participate in the suppressive modulation of lymphocyte proliferation and cytokine production in vitro. The inhibitory effect of alpha(2)-AR stimulation on lymphocyte function is partially mediated via the phospholipase C-protein kinase C pathway. (c) 2008 S. Karger AG, Basel.

Novel Junction-specific and Quantifiable In Situ Detection of AR-V7 and its Clinical Correlates in Metastatic Castration-resistant Prostate Cancer.

PubMed

Zhu, Yezi; Sharp, Adam; Anderson, Courtney M; Silberstein, John L; Taylor, Maritza; Lu, Changxue; Zhao, Pei; De Marzo, Angelo M; Antonarakis, Emmanuel S; Wang, Mindy; Wu, Xingyong; Luo, Yuling; Su, Nan; Nava Rodrigues, Daniel; Figueiredo, Ines; Welti, Jonathan; Park, Emily; Ma, Xiao-Jun; Coleman, Ilsa; Morrissey, Colm; Plymate, Stephen R; Nelson, Peter S; de Bono, Johann S; Luo, Jun

2018-05-01

Androgen receptor splice variant 7 (AR-V7) has been implicated in resistance to abiraterone and enzalutamide treatment in men with metastatic castration-resistant prostate cancer (mCRPC). Tissue- or cell-based in situ detection of AR-V7, however, has been limited by lack of specificity. To address current limitations in precision measurement of AR-V7 by developing a novel junction-specific AR-V7 RNA in situ hybridization (RISH) assay compatible with automated quantification. We designed a RISH method to visualize single splice junctions in cells and tissue. Using the validated assay for junction-specific detection of the full-length AR (AR-FL) and AR-V7, we generated quantitative data, blinded to clinical data, for 63 prostate tumor biopsies. We evaluated clinical correlates of AR-FL/AR-V7 measurements, including association with prostate-specific antigen progression-free survival (PSA-PFS) and clinical and radiographic progression-free survival (PFS), in a subset of patients starting treatment with abiraterone or enzalutamide following biopsy. Quantitative AR-FL/AR-V7 data were generated from 56 of the 63 (88.9%) biopsy specimens examined, of which 44 were mCRPC biopsies. Positive AR-V7 signals were detected in 34.1% (15/44) mCRPC specimens, all of which also co-expressed AR-FL. The median AR-V7/AR-FL ratio was 11.9% (range 2.7-30.3%). Positive detection of AR-V7 was correlated with indicators of high disease burden at baseline. Among the 25 CRPC biopsies collected before treatment with abiraterone or enzalutamide, positive AR-V7 detection, but not higher AR-FL, was significantly associated with shorter PSA-PFS (hazard ratio 2.789, 95% confidence interval 1.12-6.95; p=0.0081). We report for the first time a RISH method for highly specific and quantifiable detection of splice junctions, allowing further characterization of AR-V7 and its clinical significance. Higher AR-V7 levels detected and quantified using a novel method were associated with poorer response to abiraterone or enzalutamide in prostate cancer. Copyright © 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Aurora A regulates expression of AR-V7 in models of castrate resistant prostate cancer.

PubMed

Jones, Dominic; Noble, Martin; Wedge, Steve R; Robson, Craig N; Gaughan, Luke

2017-02-16

Androgen receptor variants (AR-Vs) provide a mechanism of therapy evasion in castrate-resistant prostate cancer (CRPC), yet mechanisms of regulation remain largely unknown. Here we investigate the role of Aurora A kinase on AR-Vs in models of CRPC and show depletion of Aurora A reduces AR-V target gene expression. Importantly, knockdown of Aurora A reconfigures splicing of AR pre-mRNA to discriminately down-regulate synthesis of AR-V transcripts, including AR-V7, without effecting full-length AR mRNA; and as a consequence, AR-V-driven proliferation and survival of CRPC cells is markedly reduced. Critically, these effects are reproduced by Aurora A inhibition. We show that Aurora A levels increase in advanced disease and AURKA is an AR-V target gene demonstrating a positive feedback mechanism of androgenic signalling in CRPC. In all, our data suggests that Aurora A plays a pivotal role in regulation of AR-V7 expression and represents a new therapeutic target in CRPC.

Aurora A regulates expression of AR-V7 in models of castrate resistant prostate cancer

PubMed Central

Jones, Dominic; Noble, Martin; Wedge, Steve R.; Robson, Craig N.; Gaughan, Luke

2017-01-01

Androgen receptor variants (AR-Vs) provide a mechanism of therapy evasion in castrate-resistant prostate cancer (CRPC), yet mechanisms of regulation remain largely unknown. Here we investigate the role of Aurora A kinase on AR-Vs in models of CRPC and show depletion of Aurora A reduces AR-V target gene expression. Importantly, knockdown of Aurora A reconfigures splicing of AR pre-mRNA to discriminately down-regulate synthesis of AR-V transcripts, including AR-V7, without effecting full-length AR mRNA; and as a consequence, AR-V-driven proliferation and survival of CRPC cells is markedly reduced. Critically, these effects are reproduced by Aurora A inhibition. We show that Aurora A levels increase in advanced disease and AURKA is an AR-V target gene demonstrating a positive feedback mechanism of androgenic signalling in CRPC. In all, our data suggests that Aurora A plays a pivotal role in regulation of AR-V7 expression and represents a new therapeutic target in CRPC. PMID:28205582

Achievements of the Armenian Astronomy and the Present Activities of the Armenian Astronomical Society

NASA Astrophysics Data System (ADS)

Mickaelian, A. M.

2014-10-01

A report is given on the achievements of the Armenian astronomy during the last years and on the present activities of the Armenian Astronomical Society (ArAS). ArAS membership, ArAS electronic newsletters (ArASNews), ArAS webpage, international collaboration, Armenian Virtual Observatory (ArVO), membership in international organizations, grants, prizes, meetings, summer schools, astronomical Olympiads, other matters related to astronomical education, archaeoastronomy, astronomy outreach and ArAS further projects are discussed.

Evaluating Burning Mouth Syndrome as a Comorbidity of Atypical Odontalgia: The Impact on Pain Experiences.

PubMed

Tu, Trang T H; Miura, Anna; Shinohara, Yukiko; Mikuzuki, Lou; Kawasaki, Kaoru; Sugawara, Shiori; Suga, Takayuki; Watanabe, Takeshi; Watanabe, Motoko; Umezaki, Yojiro; Yoshikawa, Tatsuya; Motomura, Haruhiko; Takenoshita, Miho; Toyofuku, Akira

2018-06-01

This study aimed (1) to investigate the differences in clinical characteristics of patients between 2 groups, those who have atypical odontalgia (AO) only and those who have AO with burning mouth syndrome (BMS), and (2) to assess the influence of psychiatric comorbidity factors on patients' experiences. Medical records and psychiatric referral forms of patients visiting the Psychosomatic Dentistry Clinic of Tokyo Medical and Dental University between 2013 and 2016 were reviewed. The final sample included 2 groups of 355 patients: those who have AO only (n = 272) and those who have AO with BMS (AO-BMS; n = 83). Clinicodemographic variables (gender, age, comorbid psychiatric disorders, and history of headache or sleep disturbances) and pain variables (duration of illness, pain intensity, and severity of accompanying depression) were collected. Initial pain assessment was done using the Short-Form McGill Pain Questionnaire, and depressive state was determined using the Zung Self-Rating Depression Scale. The average age, female ratio, and sleep disturbance prevalence in the AO-only group were significantly lower than those in AO-BMS group. AO-BMS patients rated overall pain score and present pain intensity significantly higher than did the AO-only patients (P = 0.033 and P = 0.034, respectively), emphasizing sharp (P = 0.049), hot-burning (P = 0.000), and splitting (P = 0.003) characteristics of pain. Patients having comorbid psychiatric disorders had a higher proportion of sleep disturbance in both groups and a higher proportion of depressive state in the AO-only group. AO-BMS patients have different epidemiological characteristics, sleep quality, and pain experiences compared to AO-only patients. The presence of psychiatric comorbidities in both groups may exacerbate sleep quality. We suggest that BMS as a comorbid oral disorder in AO patients contributes to a more intensively painful experience. © 2017 The Authors. Pain Practice published by Wiley Periodicals, Inc. on behalf of World Institute of Pain.

Myofibroblast androgen receptor expression determines cell survival in co-cultures of myofibroblasts and prostate cancer cells in vitro.

PubMed

Palethorpe, Helen M; Leach, Damien A; Need, Eleanor F; Drew, Paul A; Smith, Eric

2018-04-10

Fibroblasts express androgen receptor (AR) in the normal prostate and during prostate cancer development. We have reported that loss of AR expression in prostate cancer-associated fibroblasts is a poor prognostic indicator. Here we report outcomes of direct and indirect co-cultures of immortalised AR-positive (PShTert-AR) or AR-negative (PShTert) myofibroblasts with prostate cancer cells. In the initial co-cultures the AR-negative PC3 cell line was used so AR expression and signalling were restricted to the myofibroblasts. In both direct and indirect co-culture with PShTert-AR myofibroblasts, paracrine signalling to the PC3 cells slowed proliferation and induced apoptosis. In contrast, PC3 cells proliferated with PShTert myofibroblasts irrespective of the co-culture method. In direct co-culture PC3 cells induced apoptosis in and destroyed PShTerts by direct signalling. Similar results were seen in direct co-cultures with AR-negative DU145 and AR-positive LNCaP and C4-2B prostate cancer cell lines. The AR ligand 5α-dihydrotestosterone (DHT) inhibited the proliferation of the PShTert-AR myofibroblasts, thereby reducing the extent of their inhibitory effect on cancer cell growth. These results suggest loss of stromal AR would favour prostate cancer cell growth in vivo , providing an explanation for the clinical observation that reduced stromal AR is associated with a poorer outcome.

Synergic role of the two ars operons in arsenic tolerance in Pseudomonas putida KT2440.

PubMed

Fernández, Matilde; Udaondo, Zulema; Niqui, José-Luis; Duque, Estrella; Ramos, Juan-Luis

2014-10-01

The chromosome of Pseudomonas putida KT2440 carries two clusters of genes, denoted ars1 and ars2, that are annotated as putative arsenic resistance operons. In this work, we present evidence that both operons encode functional arsenic-response regulatory genes as well as arsenic extrusion systems that confer resistance to both arsenite [As(III)] and arsenate [As(V)]. Transcriptional fusions of P(ars1) and P(ars2) to lacZ revealed that expression of both operons was induced by arsenite and arsenate. We generated single mutants in ars1 and ars2, which showed lower resistance to arsenic than the wild-type strain. A double ars1/ars2 was found to be highly sensitive to arsenic. Minimum inhibitory concentrations (MICs) for single mutants decreased two- to fourfold with respect to the parental strain, while in the double mutant the MIC decreased 128-fold for arsenite and 32-fold for arsenate. Bioinformatic analysis revealed that the ars2 resistance operon is part of the core genome of P. putida, while the ars1 operon appears to only occur in the KT2440 strain, suggesting that ars1 was acquired by horizontal gene transfer. The presence of ars1 in KT2440 may explain why it exhibits higher resistance to arsenic than other P. putida strains, which bear only the ars2 operon.

Ar/Ar Dating Independent of Monitor Standard Ages

NASA Astrophysics Data System (ADS)

Boswell, S.; Hemming, S. R.

2015-12-01

Because the reported age of an analyzed sample is dependent on the age of the co-irradiated monitor standard(s), Ar/Ar dating is a relative dating technique. There is disagreement at the 1% scale in the age of commonly used monitor standards, and there is a great need to improve the inter-laboratory calibrations. Additionally, new approaches and insights are needed to meet the challenge of bringing the Ar/Ar chronometer to the highest possible precision and accuracy. In this spirit, we present a conceptual framework for Ar/Ar dating that does not depend on the age of monitor standards, but only on the K content of a solid standard. The concept is demonstrated by introducing a re-expressed irradiation parameter (JK) that depends on the ratio of 39ArK to 40Ar* rather than the 40Ar*/39ArK ratio. JK is equivalent to the traditional irradiation parameter J and is defined as JK = (39Ar/40K) • (λ/λe). The ultimate precision and accuracy of the method will depend on how precisely and accurately the 39Ar and 40K can be estimated, and will require isotope dilution measurements of both from the same aliquot. We are testing the workability of our technique at the 1% level by measuring weighed and irradiated hornblende and biotite monitor standards using GLO-1 glauconite to define a calibration curve for argon signals versus abundance.

The celecoxib derivatives AR-12 and AR-14 induce autophagy and clear prion-infected cells from prions.

PubMed

Abdulrahman, Basant A; Abdelaziz, Dalia; Thapa, Simrika; Lu, Li; Jain, Shubha; Gilch, Sabine; Proniuk, Stefan; Zukiwski, Alexander; Schatzl, Hermann M

2017-12-14

Prion diseases are fatal infectious neurodegenerative disorders that affect both humans and animals. The autocatalytic conversion of the cellular prion protein (PrP C ) into the pathologic isoform PrP Sc is a key feature in prion pathogenesis. AR-12 is an IND-approved derivative of celecoxib that demonstrated preclinical activity against several microbial diseases. Recently, AR-12 has been shown to facilitate clearance of misfolded proteins. The latter proposes AR-12 to be a potential therapeutic agent for neurodegenerative disorders. In this study, we investigated the role of AR-12 and its derivatives in controlling prion infection. We tested AR-12 in prion infected neuronal and non-neuronal cell lines. Immunoblotting and confocal microscopy results showed that AR-12 and its analogue AR-14 reduced PrP Sc levels after only 72 hours of treatment. Furthermore, infected cells were cured of PrP Sc after exposure of AR-12 or AR-14 for only two weeks. We partially attribute the influence of the AR compounds on prion propagation to autophagy stimulation, in line with our previous findings that drug-induced stimulation of autophagy has anti-prion effects in vitro and in vivo. Taken together, this study demonstrates that AR-12 and the AR-14 analogue are potential new therapeutic agents for prion diseases and possibly protein misfolding disorders involving prion-like mechanisms.

Characterization of a novel androgen receptor (AR) coregulator RIPK1 and related chemicals that suppress AR-mediated prostate cancer growth via peptide and chemical screening.

PubMed

Hsu, Cheng-Lung; Liu, Jai-Shin; Lin, Ting-Wei; Chang, Ying-Hsu; Kuo, Yung-Chia; Lin, An-Chi; Ting, Huei-Ju; Pang, See-Tong; Lee, Li-Yu; Ma, Wen-Lung; Lin, Chun-Cheng; Wu, Wen-Guey

2017-09-19

Using bicalutamide-androgen receptor (AR) DNA binding domain-ligand binding domain as bait, we observed enrichment of FxxFY motif-containing peptides. Protein database searches revealed the presence of receptor-interacting protein kinase 1 (RIPK1) harboring one FxxFY motif. RIPK1 interacted directly with AR and suppressed AR transactivation in a dose-dependent manner. Domain mapping experiments showed that the FxxFY motif in RIPK1 is critical for interactions with AR and the death domain of RIPK1 plays a crucial role in its inhibitory effect on transactivation. In terms of tissue expression, RIPK1 levels were markedly higher in benign prostate hyperplasia and non-cancerous tissue regions relative to the tumor area. With the aid of computer modeling for screening of chemicals targeting activation function 2 (AF-2) of AR, we identified oxadiazole derivatives as good candidates and subsequently generated a small library of these compounds. A number of candidates could effectively suppress AR transactivation and AR-related functions in vitro and in vivo with tolerable toxicity via inhibiting AR-peptide, AR-coregulator and AR N-C interactions. Combination of these chemicals with antiandrogen had an additive suppressive effect on AR transcriptional activity. Our collective findings may pave the way in creating new strategies for the development and design of anti-AR drugs.

DBC1 promotes castration-resistant prostate cancer by positively regulating DNA binding and stability of AR-V7.

PubMed

Moon, Sue Jin; Jeong, Byong Chang; Kim, Hwa Jin; Lim, Joung Eun; Kwon, Ghee Young; Kim, Jeong Hoon

2018-03-01

Constitutively active AR-V7, one of the major androgen receptor (AR) splice variants lacking the ligand-binding domain, plays a key role in the development of castration-resistant prostate cancer (CRPC) and anti-androgen resistance. However, our understanding of the regulatory mechanisms of AR-V7-driven transcription is limited. Here we report DBC1 as a key regulator of AR-V7 transcriptional activity and stability in CRPC cells. DBC1 functions as a coactivator for AR-V7 and is required for the expression of AR-V7 target genes including CDH2, a mesenchymal marker linked to CRPC progression. DBC1 is required for recruitment of AR-V7 to its target enhancers and for long-range chromatin looping between the CDH2 enhancer and promoter. Mechanistically, DBC1 enhances DNA-binding activity of AR-V7 by direct interaction and inhibits CHIP E3 ligase-mediated ubiquitination and degradation of AR-V7 by competing with CHIP for AR-V7 binding, thereby stabilizing and activating AR-V7. Importantly, DBC1 depletion suppresses the tumorigenic and metastatic properties of CRPC cells. Our results firmly establish DBC1 as a critical AR-V7 coactivator that plays a key role in the regulation of DNA binding and stability of AR-V7 and has an important physiological role in CRPC progression.

Myofibroblast androgen receptor expression determines cell survival in co-cultures of myofibroblasts and prostate cancer cells in vitro

PubMed Central

Palethorpe, Helen M.; Leach, Damien A.; Need, Eleanor F.; Drew, Paul A.; Smith, Eric

2018-01-01

Fibroblasts express androgen receptor (AR) in the normal prostate and during prostate cancer development. We have reported that loss of AR expression in prostate cancer-associated fibroblasts is a poor prognostic indicator. Here we report outcomes of direct and indirect co-cultures of immortalised AR-positive (PShTert-AR) or AR-negative (PShTert) myofibroblasts with prostate cancer cells. In the initial co-cultures the AR-negative PC3 cell line was used so AR expression and signalling were restricted to the myofibroblasts. In both direct and indirect co-culture with PShTert-AR myofibroblasts, paracrine signalling to the PC3 cells slowed proliferation and induced apoptosis. In contrast, PC3 cells proliferated with PShTert myofibroblasts irrespective of the co-culture method. In direct co-culture PC3 cells induced apoptosis in and destroyed PShTerts by direct signalling. Similar results were seen in direct co-cultures with AR-negative DU145 and AR-positive LNCaP and C4-2B prostate cancer cell lines. The AR ligand 5α-dihydrotestosterone (DHT) inhibited the proliferation of the PShTert-AR myofibroblasts, thereby reducing the extent of their inhibitory effect on cancer cell growth. These results suggest loss of stromal AR would favour prostate cancer cell growth in vivo, providing an explanation for the clinical observation that reduced stromal AR is associated with a poorer outcome. PMID:29721186

Exploring exposure to Agent Orange and increased mortality due to bladder cancer.

PubMed

Mossanen, Matthew; Kibel, Adam S; Goldman, Rose H

2017-11-01

During the Vietnam War, many veterans were exposed to Agent Orange (AO), a chemical defoliant containing varying levels of the carcinogen dioxin. The health effects of AO exposure have been widely studied in the VA population. Here we review and interpret data regarding the association between AO exposure and bladder cancer (BC) mortality. Data evaluating the association between AO and BC is limited. Methods characterizing exposure have become more sophisticated over time. Several studies support the link between AO exposure and increased mortality due to BC, including the Korean Veterans Health Study. Available data suggest an association with exposure to AO and increased mortality due to BC. In patients exposed to AO, increased frequency of cystoscopic surveillance and potentially more aggressive therapy for those with BC may be warranted but utility of these strategies remains to be proven. Additional research is required to better understand the relationship between AO and BC. Copyright © 2017 Elsevier Inc. All rights reserved.

Compact MEMS-based Adaptive Optics Optical Coherence Tomography for Clinical Use

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chen, D; Olivier, S; Jones, S

2008-02-04

We describe a compact MEMS-based adaptive optics (AO) optical coherence tomography system with improved AO performance and ease of clinical use. A typical AO system consists of a Shack-Hartmann wavefront sensor and a deformable mirror that measures and corrects the ocular and system aberrations. Because of the limitation on the current deformable mirror technologies, the amount of real-time ocular-aberration compensation is restricted and small in the previous AO-OCT instruments. In this instrument, we proposed to add an optical apparatus to correct the spectacle aberrations of the patients such as myopia, hyperopia and astigmatism. This eliminated the tedious process of themore » trial lenses in clinical imaging. Different amount of spectacle aberration compensation was achieved by motorized stages and automated with the AO computer for ease of clinical use. In addition, the compact AO-OCT was optimized to have minimum system aberrations to reduce AO registration errors and improve AO performance.« less

Preparation of high-content hexagonal boron nitride composite film and characterization of atomic oxygen erosion resistance

NASA Astrophysics Data System (ADS)

Zhang, Yu; Li, Min; Gu, Yizhuo; Wang, Shaokai; Zhang, Zuoguang

2017-04-01

Space aircrafts circling in low earth orbit are suffered from highly reactive atomic oxygen (AO). To shield AO, a flexible thin film with 80 wt.% hexagonal boron nitride (h-BN) and h-BN/epoxy film were fabricated through vacuum filtration and adding nanofibrillated cellulose fibers. H-BN nanosheets were hydroxylated for enhancing interaction in the films. Mass loss and erosion yield at accumulated AO fluence about 3.04 × 1020 atoms/cm2 were adopted to evaluate the AO resistance properties of the films. A carpet-like rough surface, chemical oxidations and change in crystal structure of h-BN were found after AO treatment, and the degrading mechanism was proposed. The mass loss and erosion yield under AO attack were compared between h-BN film and h-BN/epoxy film, and the comparison was also done for various types of shielding AO materials. Excellent AO resistance property of h-BN film is shown, and the reasons are analyzed.

32 CFR Appendix A to Part 584 - Reference

Code of Federal Regulations, 2011 CFR

2011-07-01

... Certain Other Units of the Army. AR 340-18 The Army Functional Files System AR 600-240 Marriage in Oversea...-17 Release of Information and Records from Army Files. (Cited in § 584.1(f)(2).) AR 340-21 The Army... regulation. AR 11-2 Internal Control Systems AR 20-1 Inspector General Activities and Procedures AR 140-1...

32 CFR Appendix A to Part 584 - Reference

Code of Federal Regulations, 2013 CFR

2013-07-01

... Certain Other Units of the Army. AR 340-18 The Army Functional Files System AR 600-240 Marriage in Oversea...-17 Release of Information and Records from Army Files. (Cited in § 584.1(f)(2).) AR 340-21 The Army... regulation. AR 11-2 Internal Control Systems AR 20-1 Inspector General Activities and Procedures AR 140-1...

32 CFR Appendix A to Part 584 - Reference

Code of Federal Regulations, 2012 CFR

2012-07-01

... Certain Other Units of the Army. AR 340-18 The Army Functional Files System AR 600-240 Marriage in Oversea...-17 Release of Information and Records from Army Files. (Cited in § 584.1(f)(2).) AR 340-21 The Army... regulation. AR 11-2 Internal Control Systems AR 20-1 Inspector General Activities and Procedures AR 140-1...

32 CFR Appendix A to Part 584 - Reference

Code of Federal Regulations, 2014 CFR

2014-07-01

... Certain Other Units of the Army. AR 340-18 The Army Functional Files System AR 600-240 Marriage in Oversea...-17 Release of Information and Records from Army Files. (Cited in § 584.1(f)(2).) AR 340-21 The Army... regulation. AR 11-2 Internal Control Systems AR 20-1 Inspector General Activities and Procedures AR 140-1...

Positive family history of aortic dissection dramatically increases dissection risk in family members.

PubMed

Ma, Wei-Guo; Chou, Alan S; Mok, Salvior C M; Ziganshin, Bulat A; Charilaou, Paris; Zafar, Mohammad A; Sieller, Richard S; Tranquilli, Maryann; Rizzo, John A; Elefteriades, John A

2017-08-01

Although family members of patients with aortic dissection (AoD) are believed to be at higher risk of AoD, the prognostic value of family history (FH) of aortic dissection (FHAD) in family members of patients with AoD has not been studied rigorously. We seek examine how much a positive FHAD increases the risk of developing new aortic dissection (AoD) among first-degree relatives. Patients with AoD at our institution were analyzed for information of FHAD. Positive FHAD referred to that AoD occurred in index patient and one or more first-degree relatives. Negative FHAD was defined as the condition in which only one case of AoD (the index patient) occurred in the family. The age at AoD, exposure years in adulthood before AoD, and annual probability of AoD among first-degree relatives were compared between patients with negative and positive FHADs. FHAD was positive in 32 and negative in 68 among the 100 AoD patients with detailed family history information. Mean age at dissection was 59.9±14.7years. Compared to negative FHAD, patients with positive FHAD dissected at significantly younger age (54.7±16.8 vs 62.4±13.0years, p=0.013), had more AoD events in first-degree relatives (2.3±0.6 vs 1.0±0.0, p<0.001), and shorter exposure years per AoD event (18.3±6.7 vs 43.1±8.5, p<0.001). Annual probability of AoD per first-degree relative was 2.77 times higher in patients with positive than negative FHADs (0.0100±0.0057 vs 0.0036±0.0014, p<0.001). A positive FHAD confers a significantly increased risk of developing aortic dissection on family members, with a higher annual probability of aortic dissection, a shorter duration of "exposure time" before dissection occurs and a lower mean age at time of dissection. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

[Effect of acidic oligosaccharides on P-selectin of pulmonary hypertensive rats induced by monocrotaline].

PubMed

Feng, Z; Hu, Y; An, N N; Feng, W J; Hu, T; Mao, Y J

2018-02-12

Objective: To observe the effects of acidic oligosaccharides (AOS) on P-selectin levels in the serum and the pulmonary arteries of pulmonary hypertensive rats induced by monocrotaline. Methods: Sixty healthy adult male Sprague-Dawley rats were randomly divided into control group ( n =10), model group ( n =10), Alprostadil group ( n =10), low-dose AOS group (AOS-L, n =10), medium-dose AOS group (AOS-M, n =10) and high-dose AOS group (AOS-H, n =10). The rat model of pulmonary arterial hypertension was made by a single intraperitoneal injection of monocrotaline(60 mg/kg). Five weeks after injection, pulmonary arterial (PA) acceleration time (PAT) and ejection time (ET) were measured by color Doppler ultrasound. Then, the Alprostadil group was treated by Alprostadil 5 μg·kg(-1)·d(-1)intraperitoneally. Acidic oligosaccharides was administered by intraperitoneal injection to rats in the AOS-L group(5 kg(-1)·d(-1)), AOS-M group (10 mg·kg(-1)·d(-1))and AOS-H group (20 mg·kg(-1)·d(-1)). Control group and model group were given normal saline instead. At the end of experiments, the death rate was recorded and PAT/ET was measured. We calculated the right ventricular hypertrophy index (RVHI) of all rats sacrificed under anesthesia. Precision-cut lung slices were stained with HE for observation of the structure of middle and small arteries. The expression level of P-selectin in serum and pulmonary arterial tissues were detected by ELISA and Western blot respectively. Results: AOS significantly increased the level of PAT/ET ( P <0.01), and attenuated RVHI ( P <0.01). AOS significantly improved intima-media proliferation in small-to medium-sized pulmonary arteries, and attenuated perivascular inflammation. AOS and Alprostadil significantly down-regulated the protein expression of P-selectin in serum and pulmonary arteries ( P <0.01). Conclusion: In this rat model of monocrotaline-induced pulmonary hypertension, AOS decreased the expressions of P-selectin in serum and pulmonary arteries in a dose-dependent manner.

Prevalence of abdominal obesity in Spanish children and adolescents. Do we need waist circumference measurements in pediatric practice?

PubMed

Schröder, Helmut; Ribas, Lourdes; Koebnick, Corinna; Funtikova, Anna; Gomez, Santiago F; Fíto, Montserat; Perez-Rodrigo, Carmen; Serra-Majem, Lluis

2014-01-01

Evidence indicates that central adiposity has increased to a higher degree than general adiposity in children and adolescents in recent decades. However, waist circumference is not a routine measurement in clinical practice. This study aimed to determine the prevalence of abdominal obesity based on waist circumferences (WC) and waist to height ratio (WHtR) in Spanish children and adolescents aged 6 to 17 years. Further, the prevalence of abdominal obesity (AO) among normal and overweight individuals was analyzed. Data were obtained from a study conducted from 1998 to 2000 in a representative national sample of 1521 children and adolescents aged 6 to 17 years (50.0% female) in Spain. WC and WHtR measurements were obtained in addition to BMI. AO was defined as WHtR ≥0.50 (WHtR-AO), sex and age specific WC≥90(th) percentile (WC-AO1), and sex and age specific WC cut-off values associated with high trunk fat measured by by dual-energy X-ray absorptiometry (WC-AO2). IOTF- based overweight and obsity prevalence was 21.5% and 6.6% in children and 17.4% and 5.2% in adolescents, respectively. Abdominal obesity (AO) was defined as WHtR≥0.50 (WHtR-AO), sex- and age-specific WC≥90th percentile (WC-AO1), and sex- and age-specific WC cut-off values associated with high trunk fat measured by dual-energy X-ray absorptiometry (WC-AO2). The respective prevalence of WHtR-AO, WC-AO1, and WC-AO2 was 21.3% (24.6% boys; 17.9% girls), 9.4% (9.1% boys; 9.7% girls), and 26.8% (30.6% boys;22.9% girls) in children and 14.3% (20.0% boys; 8.7% girls), 9.6% (9.8% boys; 9.5% girls), and 21.1% (28.8% boys; 13.7% girls) in adolescents. The prevalence of AO in Spanish children and adolescents is of concern. The high proportion of AO observed in young patients who are normal weight or overweight indicates a need to include waist circumference measurements in routine clinical practice.

Prevalence of Abdominal Obesity in Spanish Children and Adolescents. Do We Need Waist Circumference Measurements in Pediatric Practice?

PubMed Central

Schröder, Helmut; Ribas, Lourdes; Koebnick, Corinna; Funtikova, Anna; Gomez, Santiago F.; Fíto, Montserat; Perez-Rodrigo, Carmen; Serra-Majem, Lluis

2014-01-01

Background Evidence indicates that central adiposity has increased to a higher degree than general adiposity in children and adolescents in recent decades. However, waist circumference is not a routine measurement in clinical practice. Objective This study aimed to determine the prevalence of abdominal obesity based on waist circumferences (WC) and waist to height ratio (WHtR) in Spanish children and adolescents aged 6 to 17 years. Further, the prevalence of abdominal obesity (AO) among normal and overweight individuals was analyzed. Design Data were obtained from a study conducted from 1998 to 2000 in a representative national sample of 1521 children and adolescents aged 6 to 17 years (50.0% female) in Spain. WC and WHtR measurements were obtained in addition to BMI. AO was defined as WHtR ≥0.50 (WHtR-AO), sex and age specific WC≥90th percentile (WC-AO1), and sex and age specific WC cut-off values associated with high trunk fat measured by by dual-energy X-ray absorptiometry (WC-AO2). Results IOTF- based overweight and obsity prevalence was 21.5% and 6.6% in children and 17.4% and 5.2% in adolescents, respectively. Abdominal obesity (AO) was defined as WHtR≥0.50 (WHtR-AO), sex- and age-specific WC≥90th percentile (WC-AO1), and sex- and age-specific WC cut-off values associated with high trunk fat measured by dual-energy X-ray absorptiometry (WC-AO2). The respective prevalence of WHtR-AO, WC-AO1, and WC-AO2 was 21.3% (24.6% boys; 17.9% girls), 9.4% (9.1% boys; 9.7% girls), and 26.8% (30.6% boys;22.9% girls) in children and 14.3% (20.0% boys; 8.7% girls), 9.6% (9.8% boys; 9.5% girls), and 21.1% (28.8% boys; 13.7% girls) in adolescents. Conclusion The prevalence of AO in Spanish children and adolescents is of concern. The high proportion of AO observed in young patients who are normal weight or overweight indicates a need to include waist circumference measurements in routine clinical practice. PMID:24475305

Meat quality and rigor mortis development in broiler chickens with gas-induced anoxia and postmortem electrical stimulation.

PubMed

Sams, A R; Dzuik, C S

1999-10-01

This study was conducted to evaluate the combined rigor-accelerating effects of postmortem electrical stimulation (ES) and argon-induced anoxia (Ar) of broiler chickens. One hundred broilers were processed in the following treatments: untreated controls, ES, Ar, or Ar with ES (Ar + ES). Breast fillets were harvested at 1 h postmortem for all treatments or at 1 and 6 h postmortem for the control carcasses. Fillets were sampled for pH and ratio of inosine to adenosine (R-value) and were then individually quick frozen (IQF) or aged on ice (AOI) until 24 h postmortem. Color was measured in the AOI fillets at 24 h postmortem. All fillets were then cooked and evaluated for Allo-Kramer shear value. The Ar treatment accelerated the normal pH decline, whereas the ES and AR + ES treatments yielded even lower pH values at 1 h postmortem. The Ar + ES treatment had a greater R-value than the ES treatment, which was greater than either the Ar or 1-h controls, which, in turn, were not different from each other. The ES treatment had the lowest L* value, and ES, Ar, and Ar + ES produced significantly higher a* values than the 1-h controls. For the IQF fillets, the ES and Ar + ES treatments were not different in shear value but were lower than Ar, which was lower than the 1-h controls. The same was true for the AOI fillets except that the ES and the Ar treatments were not different. These results indicated that although ES and Ar had rigor-accelerating and tenderizing effects, ES seemed to be more effective than Ar; there was little enhancement when Ar was added to the ES treatment and fillets were deboned at 1 h postmortem.

Structural Changes Due to Antagonist Binding in Ligand Binding Pocket of Androgen Receptor Elucidated Through Molecular Dynamics Simulations.

PubMed

Sakkiah, Sugunadevi; Kusko, Rebecca; Pan, Bohu; Guo, Wenjing; Ge, Weigong; Tong, Weida; Hong, Huixiao

2018-01-01

When a small molecule binds to the androgen receptor (AR), a conformational change can occur which impacts subsequent binding of co-regulator proteins and DNA. In order to accurately study this mechanism, the scientific community needs a crystal structure of the Wild type AR (WT-AR) ligand binding domain, bound with antagonist. To address this open need, we leveraged molecular docking and molecular dynamics (MD) simulations to construct a structure of the WT-AR ligand binding domain bound with antagonist bicalutamide. The structure of mutant AR (Mut-AR) bound with this same antagonist informed this study. After molecular docking analysis pinpointed the suitable binding orientation of a ligand in AR, the model was further optimized through 1 μs of MD simulations. Using this approach, three molecular systems were studied: (1) WT-AR bound with agonist R1881, (2) WT-AR bound with antagonist bicalutamide, and (3) Mut-AR bound with bicalutamide. Our structures were very similar to the experimentally determined structures of both WT-AR with R1881 and Mut-AR with bicalutamide, demonstrating the trustworthiness of this approach. In our model, when WT-AR is bound with bicalutamide, Val716/Lys720/Gln733, or Met734/Gln738/Glu897 move and thus disturb the positive and negative charge clumps of the AF2 site. This disruption of the AF2 site is key for understanding the impact of antagonist binding on subsequent co-regulator binding. In conclusion, the antagonist induced structural changes in WT-AR detailed in this study will enable further AR research and will facilitate AR targeting drug discovery.

Allergic rhinitis and associated risk of migraine among children: a nationwide population-based cohort study.

PubMed

Wang, I-Chung; Tsai, Jeng-Dau; Lin, Cheng-Li; Shen, Te-Chun; Li, Tsai-Chung; Wei, Chang-Ching

2016-03-01

Increased frequency of migraine was reported in adults with allergic rhinitis (AR). Although migraine is less common in children than in adults, it can begin in early childhood and persist into adulthood. We conducted this population-based cohort study to investigate the incidence and subsequent risk of migraine in children with AR. From 2000 to 2007, 461,850 children with recently diagnosed AR and 460,718 non-AR controls were included in the study. By the end of 2008, incidences of migraine in both cohorts, the AR to non-AR cohort hazard ratios (HRs), and confidence intervals (CIs) were measured. The incidence of migraine during the study period was 3.2-fold higher in the AR cohort (95% CI, 2.97 to 3.46) than in the non-AR cohort (11.4 vs 3.49 per 10000 person-years). The risk was greater for boys than for girls, and for children aged <6 years. The HR for migraine in children with AR was 1.44 (95% CI, 1.31 to 1.58) for those with ≤2 annual AR-related medical visits, whereas, 14.8 (95% CI, 13.6 to 16.2) for those with >4 visits (p < 0.0001, the trend test). The risk of migraine development in the AR cohort was highest within the first year after AR diagnosis (HR 4.89; 95% CI, 3.98 to 6.00). Children with AR were more likely to have migraine without aura than migraine with aura. Children with AR had a higher incidence and subsequent risk of migraine. Physicians should be more aware of migraine in children with AR who complain of headache. © 2015 ARS-AAOA, LLC.

Coronal Heating and the Magnetic Field in Solar Active Regions

NASA Astrophysics Data System (ADS)

Falconer, D. A.; Tiwari, S. K.; Winebarger, A. R.; Moore, R. L.

2017-12-01

A strong dependence of active-region (AR) coronal heating on the magnetic field is demonstrated by the strong correlation of AR X-ray luminosity with AR total magnetic flux (Fisher et al 1998 ApJ). AR X-ray luminosity is also correlated with AR length of strong-shear neutral line in the photospheric magnetic field (Falconer 1997). These two whole-AR magnetic parameters are also correlated with each other. From 150 ARs observed within 30 heliocentric degrees from disk center by AIA and HMI on SDO, using AR luminosity measured from the hot component of the AIA 94 Å band (Warren et al 2012, ApJ) near the time of each of 3600 measured HMI vector magnetograms of these ARs and a wide selection of whole-AR magnetic parameters from each vector magnetogram after it was deprojected to disk center, we find: (1) The single magnetic parameter having the strongest correlation with AR 94-hot luminosity is the length of strong-field neutral line. (2) The two-parameter combination having the strongest still-stronger correlation with AR 94-hot luminosity is a combination of AR total magnetic flux and AR neutral-line length weighted by the vertical-field gradient across the neutral line. We interpret these results to be consistent with the results of both Fisher et al (1998) and Falconer (1997), and with the correlation of AR coronal loop heating with loop field strength recently found by Tiwari et al (2017, ApJ Letters). Our interpretation is that, in addition to depending strongly on coronal loop field strength, AR coronal heating has a strong secondary positive dependence on the rate of flux cancelation at neutral lines at coronal loop feet. This work was funded by the Living With a Star Science and Heliophysics Guest Investigators programs of NASA's Heliophysics Division.

Roles of steroid receptor coactivator (SRC)-1 and transcriptional intermediary factor (TIF) 2 in androgen receptor activity in mice

PubMed Central

Ye, Xiangcang; Han, Sang Jun; Tsai, Sophia Y.; DeMayo, Francesco J.; Xu, Jianming; Tsai, Ming-Jer; O'Malley, Bert W.

2005-01-01

Genetic disruption of the steroid receptor coactivator (SRC)-1 and transcriptional intermediary factor (TIF)2/SRC-2 in mouse resulted in distinctive mutant phenotypes. To quantify their roles in the function of androgen receptor (AR) transcriptional activity in vivo, we generated a unique transgenic AR-reporter mouse and analyzed the cell-specific contributions of SRC-1 and TIF2 to the activity of AR in mouse testis. Transgenic AR-luciferase and transgenic AR-lacZ mice harbor a recombinant mouse AR gene, ARGAL4DBD, which is functionally coupled with a upstream activation sequence-mediated reporter gene (AR activity indicator). After characterization of these mice in terms of AR function, we further derived bigenic mice by crossing AR activity indicator mice with the SRC-1-/- or TIF2+/- mutant mice. Analyses of the resultant bigenic mice by in vivo imaging and luciferase assays showed that testicular AR activity was decreased significantly in those with the TIF2+/- mutation but not in the SRC-1+/- background, suggesting that TIF2 serves as the preferential coactivator for AR in testis. Immunohistological analysis confirmed that AR and TIF2 coexist in mouse testicular Sertoli cell nuclei under normal conditions. Although SRC-1 concentrates in Sertoli cell nuclei in the absence of TIF2, nuclear SRC-1 is not able to rescue AR activity in the TIF2 mutant background. Interestingly, SRC-1 appears to negatively influence AR activity, thereby counterbalancing the TIF2-stimulated AR activity. Our results provide unique in vivo insights to the multidimensional cell-type-specific interactions between AR and coregulators. PMID:15983373

SMILES/AOS: acousto-optical spectrometer for high resolution submillimeter-wave spectroscopy

NASA Astrophysics Data System (ADS)

Mazuray, L.; Barthès, J.-C.; Bayle, F.; Castel, D.; Claviere, P.; Delbru, F.; Doittau, P.-O.; Gladin, L.; Guilleux, P.; Halbout, S.; Lavielle, D.; Varin, J.-L.; de Zotti, S.; Rosolen, C.; Ozeki, H.

2017-11-01

An acousto-optical spectrometer (AOS) is employed in order to meet scientific mission objectives of submillimeter-wave limb-emission sounder (SMILES) to be aboard the Japanese Experiment Module (JEM) of International space station (ISS). AOS is developed by ASTRIUM for the Japanese space agency (NASDA). The capability of multi channel detection with AOS is suitable for observing multi-chemical species in a wide frequency region. Low noise of the AOS enables us to obtain the spectra with a very high sensitivity. Several technical concerns relating to important instrumental characteristics of AOS are discussed and expected performance of the design are overviewed.

MagAO: status and science

NASA Astrophysics Data System (ADS)

Morzinski, Katie M.; Close, Laird M.; Males, Jared R.; Hinz, Phil M.; Esposito, Simone; Riccardi, Armando; Briguglio, Runa; Follette, Katherine B.; Pinna, Enrico; Puglisi, Alfio; Vezilj, Jennifer; Xompero, Marco; Wu, Ya-Lin

2016-07-01

"MagAO" is the adaptive optics instrument at the Magellan Clay telescope at Las Campanas Observatory, Chile. MagAO has a 585-actuator adaptive secondary mirror and 1000-Hz pyramid wavefront sensor, operating on natural guide stars from R-magnitudes of -1 to 15. MagAO has been in on-sky operation for 166 nights since installation in 2012. MagAO's unique capabilities are simultaneous imaging in the visible and infrared with VisAO and Clio, excellent performance at an excellent site, and a lean operations model. Science results from MagAO include the first ground-based CCD image of an exoplanet, demonstration of the first accreting protoplanets, discovery of a new wide-orbit exoplanet, and the first empirical bolometric luminosity of an exoplanet. We describe the status, report the AO performance, and summarize the science results. New developments reported here include color corrections on red guide stars for the wavefront sensor; a new field stop stage to facilitate VisAO imaging of extended sources; and eyepiece observing at the visible-light diffraction limit of a 6.5-m telescope. We also discuss a recent hose failure that led to a glycol coolant leak, and the recovery of the adaptive secondary mirror (ASM) after this recent (Feb. 2016) incident.

Characterization of mechanical properties and electrochemical behaviour in a Hank´s solution of 316L/Cr1- xAlxN system

NASA Astrophysics Data System (ADS)

Osorio, D. M.; Caicedo, J. C.; Aperador, W.; Benitez-Castro, A. M.; Giraldo-Betancur, A. L.; Muñoz-Saldaña, J.; Yañez-Limón, J. M.; Sanchez, O.; Zambrano, G.

2017-01-01

Cr1-xAlxN hard coatings were successfully deposited by R.F. reactive magnetron co-sputtering in an Ar/N2 gas mixture using chromium and aluminium targets on 316L stainless steel substrates. Crystallographic orientations associated to the Cr1-xAlxN FCC based in the conjugate complex of CrN and w-AlN phases, with ao=4.18Å lattice parameter for the ternary Cr1-xAlxN compound were identified by X-Ray diffraction. The thickness and roughness of the deposited coatings are 1.00±0.05nm and 2.65±0.6nm, respectively. The mechanical properties were determined by nanoindentation leading to a hardness of 27.8±2.6GPa and elastic modulus of 346GPa. The corrosion resistance of the coated 316L/Cr1-xAlxN system under simulated body fluid (SBF, Hank’s solution) was determined via electrochemical impedance spectroscopy. A reduction in the corrosion rate of 99% in relation to uncoated 316L stainless steel substrate was found by Tafel. Thus, these coatings seem to be excellent candidates to be used in biomedical applications.

Ethylene and 1-MCP regulate major volatile biosynthetic pathways in apple fruit.

PubMed

Yang, Xiaotang; Song, Jun; Du, Lina; Forney, Charles; Campbell-Palmer, Leslie; Fillmore, Sherry; Wismer, Paul; Zhang, Zhaoqi

2016-03-01

The effects of ethylene and 1-methylcyclopropene (1-MCP) on apple fruit volatile biosynthesis and gene expression were investigated. Statistical analysis identified 17 genes that changed significantly in response to ethylene and 1-MCP treatments. Genes encoding branched-chain amino acid aminotransferase (BCAT), aromatic amino acid aminotransferase (ArAT) and amino acid decarboxylases (AADC) were up-regulated during ripening and further enhanced by ethylene treatment. Genes related to fatty acid synthesis and metabolism, including acyl-carrier-proteins (ACPs), malonyl-CoA:ACP transacylase (MCAT), acyl-ACP-desaturase (ACPD), lipoxygenase (LOX), hydroperoxide lyase (HPL), alcohol dehydrogenase (ADH), pyruvate decarboxylase (PDC2), β-oxidation, acyl-CoA synthetase (ACS), enoyl-CoA hydratase (ECHD), acyl-CoA dehydrogenase (ACAD), and alcohol acyltransferases (AATs) also increased during ripening and in response to ethylene treatment. Allene oxide synthase (AOS), alcohol dehydrogenase 1 (ADH1), 3-ketoacyl-CoA thiolase and branched-chain amino acid aminotransferase 2 (BCAT2) decreased in ethylene-treated fruit. Treatment with 1-MCP and ethylene generally produced opposite effects on related genes, which provides evidence that regulation of these genes is ethylene dependent. Crown Copyright © 2015. Published by Elsevier Ltd. All rights reserved.

Armenian Astronomical Society (ArAS) activities

NASA Astrophysics Data System (ADS)

Mickaelian, A. M.

2016-09-01

A review on the activities and achievements of Armenian Astronomical Society (ArAS) and Armenian astronomy in general during the last years is given. ArAS membership, ArAS electronic newsletters (ArASNews), ArAS webpage, Annual Meetings, Annual Prize for Young Astronomers (Yervant Terzian Prize) and other awards, international relations, presence in international organizations, local and international summer schools, science camps, astronomical Olympiads and other events, matters related to astronomical education, astronomical heritage, amateur astronomy, astronomy outreach and ArAS further projects are described and discussed.

Targeting Ligand-Dependent and Ligand-Independent Androgen Receptor Signaling in Prostate Cancer

DTIC Science & Technology

2013-10-01

that disrupt more selective classes of LxxLL motifs: for example, we have compounds that can block AR-PELP1 and AR- hsp27 interaction through the LxxLL...motif as well as compounds that only block AR-PELP1 (and not AR- hsp27 ). We believe that these compounds will be critical for ascertaining the...IP: AR Input PELP1 PELP1 AR AR Hsp27 hsp27 10 Planned structural modifications of D2-derived peptidomimetics by docking

Advanced orbiting systems test-bedding and protocol verification

NASA Technical Reports Server (NTRS)

Noles, James; De Gree, Melvin

1989-01-01

The Consultative Committee for Space Data Systems (CCSDS) has begun the development of a set of protocol recommendations for Advanced Orbiting Systems (SOS). The AOS validation program and formal definition of AOS protocols are reviewed, and the configuration control of the AOS formal specifications is summarized. Independent implementations of the AOS protocols by NASA and ESA are discussed, and cross-support/interoperability tests which will allow the space agencies of various countries to share AOS communication facilities are addressed.

First closed-loop visible AO test results for the advanced adaptive secondary AO system for the Magellan Telescope: MagAO's performance and status

NASA Astrophysics Data System (ADS)

Close, Laird M.; Males, Jared R.; Kopon, Derek A.; Gasho, Victor; Follette, Katherine B.; Hinz, Phil; Morzinski, Katie; Uomoto, Alan; Hare, Tyson; Riccardi, Armando; Esposito, Simone; Puglisi, Alfio; Pinna, Enrico; Busoni, Lorenzo; Arcidiacono, Carmelo; Xompero, Marco; Briguglio, Runa; Quiros-Pacheco, Fernando; Argomedo, Javier

2012-07-01

The heart of the 6.5 Magellan AO system (MagAO) is a 585 actuator adaptive secondary mirror (ASM) with <1 msec response times (0.7 ms typically). This adaptive secondary will allow low emissivity and high-contrast AO science. We fabricated a high order (561 mode) pyramid wavefront sensor (similar to that now successfully used at the Large Binocular Telescope). The relatively high actuator count (and small projected ~23 cm pitch) allows moderate Strehls to be obtained by MagAO in the “visible” (0.63-1.05 μm). To take advantage of this we have fabricated an AO CCD science camera called "VisAO". Complete “end-to-end” closed-loop lab tests of MagAO achieve a solid, broad-band, 37% Strehl (122 nm rms) at 0.76 μm (i’) with the VisAO camera in 0.8” simulated seeing (13 cm ro at V) with fast 33 mph winds and a 40 m Lo locked on R=8 mag artificial star. These relatively high visible wavelength Strehls are enabled by our powerful combination of a next generation ASM and a Pyramid WFS with 400 controlled modes and 1000 Hz sample speeds (similar to that used successfully on-sky at the LBT). Currently only the VisAO science camera is used for lab testing of MagAO, but this high level of measured performance (122 nm rms) promises even higher Strehls with our IR science cameras. On bright (R=8 mag) stars we should achieve very high Strehls (>70% at H) in the IR with the existing MagAO Clio2 (λ=1-5.3 μm) science camera/coronagraph or even higher (~98% Strehl) the Mid-IR (8-26 microns) with the existing BLINC/MIRAC4 science camera in the future. To eliminate non-common path vibrations, dispersions, and optical errors the VisAO science camera is fed by a common path advanced triplet ADC and is piggy-backed on the Pyramid WFS optical board itself. Also a high-speed shutter can be used to block periods of poor correction. The entire system passed CDR in June 2009, and we finished the closed-loop system level testing phase in December 2011. Final system acceptance (“pre-ship” review) was passed in February 2012. In May 2012 the entire AO system is was successfully shipped to Chile and fully tested/aligned. It is now in storage in the Magellan telescope clean room in anticipation of “First Light” scheduled for December 2012. An overview of the design, attributes, performance, and schedule for the Magellan AO system and its two science cameras are briefly presented here.

Characterization of the cod (Gadus morhua) steroidogenic acute regulatory protein (StAR) sheds light on StAR gene structure in fish.

PubMed

Goetz, Frederick W; Norberg, Birgitta; McCauley, Linda A R; Iliev, Dimitar B

2004-03-01

The full-length cDNA for the cod (Gadus morhua) StAR was cloned by RT-PCR and library screening using ovarian RNA. From the library screening, 2 size classes of cDNA were obtained; a 1577 bp cDNA (cStAR1) and a 2851 bp cDNA (cStAR2). The cStAR1 cDNA presumably encodes a protein of 286 amino acids. The cStAR2 cDNA was composed of 6 separated sequences that contained all of the coding regions of cStAR1 when added together, but also contained 5 noncoding regions not observed in cStAR1. Polymerase chain reactions of cod genomic DNA produced products slightly larger than cStAR2. The sequence of these products were the same as cStAR2 but revealed one additional noncoding region (intron). Thus, the fish StAR gene contains the same number of exons (7) and introns (6) as observed in mammals, but is approximately half the size of the mammalian gene. Using Northern analysis and RT-PCR, cStAR1 expression was observed only in testes, ovaries and head kidneys. Polymerase chain reaction products were also observed using cDNA from steroidogenic tissues and primers designed to regions specific for cStAR2, indicating that cStAR2 is expressed in tissues and may account for the presence of larger transcripts observed on Northern blots.

Interaction with beta-arrestin determines the difference in internalization behavor between beta1- and beta2-adrenergic receptors.

PubMed

Shiina, T; Kawasaki, A; Nagao, T; Kurose, H

2000-09-15

The beta(1)-adrenergic receptor (beta(1)AR) shows the resistance to agonist-induced internalization. As beta-arrestin is important for internalization, we examine the interaction of beta-arrestin with beta(1)AR with three different methods: intracellular trafficking of beta-arrestin, binding of in vitro translated beta-arrestin to intracellular domains of beta(1)- and beta(2)ARs, and inhibition of betaAR-stimulated adenylyl cyclase activities by beta-arrestin. The green fluorescent protein-tagged beta-arrestin 2 translocates to and stays at the plasma membrane by beta(2)AR stimulation. Although green fluorescent protein-tagged beta-arrestin 2 also translocates to the plasma membrane, it returns to the cytoplasm 10-30 min after beta(1)AR stimulation. The binding of in vitro translated beta-arrestin 1 and beta-arrestin 2 to the third intracellular loop and the carboxyl tail of beta(1)AR is lower than that of beta(2)AR. The fusion protein of beta-arrestin 1 with glutathione S-transferase inhibits the beta(1)- and beta(2)AR-stimulated adenylyl cyclase activities, although inhibition of the beta(1)AR-stimulated activity requires a higher concentration of the fusion protein than that of the beta(2)AR-stimulated activity. These results suggest that weak interaction of beta(1)AR with beta-arrestins explains the resistance to agonist-induced internalization. This is further supported by the finding that beta-arrestin can induce internalization of beta(1)AR when beta-arrestin 1 does not dissociate from beta(1)AR by fusing to the carboxyl tail of beta(1)AR.

Risk factors for allergic rhinitis in Costa Rican children with asthma.

PubMed

Bunyavanich, S; Soto-Quiros, M E; Avila, L; Laskey, D; Senter, J M; Celedón, J C

2010-02-01

Risk factors for allergic rhinitis (AR) in asthmatics are likely distinct from those for AR or asthma alone. We sought to identify clinical and environmental risk factors for AR in children with asthma. We performed a cross-sectional study of 616 Costa Rican children aged 6-14 years with asthma. Candidate risk factors were drawn from questionnaire data, spirometry, methacholine challenge testing, skin testing, and serology. Two outcome measures, skin test reaction (STR)-positive AR and physician-diagnosed AR, were examined by logistic regression. STR-positive AR had high prevalence (80%) in Costa Rican children with asthma, and its independent risk factors were nasal symptoms after exposure to dust or mold, parental history of AR, older age at asthma onset, oral steroid use in the past year, eosinophilia, and positive IgEs to dust mite and cockroach. Physician-diagnosed AR had lower prevalence (27%), and its independent risk factors were nasal symptoms after pollen exposure, STR to tree pollens, a parental history of AR, inhaled steroid and short-acting beta2 agonist use in the past year, household mold/mildew, and fewer older siblings. A physician's diagnosis was only 29.5% sensitive for STR-positive AR. Risk factors for AR in children with asthma depend on the definition of AR. Indoor allergens drive risk for STR-positive AR. Outdoor allergens and home environmental conditions are risk factors for physician-diagnosed AR. We propose that children with asthma in Costa Rica and other Latin American nations undergo limited skin testing or specific IgE measurements to reduce the current under-diagnosis of AR.

Polyclonal antibody against a complement-activating pectin from the roots of Angelica acutiloba.

PubMed

Wang, N L; Kiyohara, H; Matsumoto, T; Otsuka, H; Hirano, M; Yamada, H

1994-10-01

Anti-sera against a complement-activating pectin (AR-2IIb), which was purified from the roots of Angelica acutiloba Kitagawa, were obtained by immunization of rabbits, and a polyclonal anti-AR-2IIb antibody of the IgG class was purified by affinity chromatography on AR-2IIb-immobilized Sepharose and Protein G-Sepharose. Periodate oxidation of AR-2IIb significantly reduced its inhibitory activity on the reactivity of AR-2IIb to anti-AR-2IIb-IgG, but pronase digestion of AR-2IIb did not affect its inhibitory activity. Other pharmacologically active pectins from A. autiloba, Bupleurum falcatum, and Glycyrrhiza uralensis and the complement-activating pectic arabinogalactan from A. autiloba also showed significant inhibitory activities on the reactivity of AR-2IIb to anti-AR-2IIb-IgG, but these inhibitory activities were lower than that of AR-2IIb. Other pectins, polygalacturonic acid, arabinogalactan, galactan, and araban tested had negligible inhibitory activity. Endo-a-(1-->4)-polygalacturonase digestion of AR-2IIb indicated that its "ramified" region (rhamnogalacturonan core possessing neutral oligosaccharide side-chains) contained epitopes for anti-AR-2IIb-IgG, but that 2-keto-3-deoxyoctulosonic acid (KDO)-containing regions and oligogalacturonides obtained from AR-2IIb were not recognized by anti-AR-2IIb-IgG. Although carboxyl-reduction of galacturonic acid in the "ramified" region decreased the inhibitory activity of the "ramified" on its reactivity to anti-AR-2IIb, an acidic tetrasaccharide unit in the rhamnogalacturonan core had negligible inhibitory activity.

Regulation of Androgen Receptor-Mediated Transcription by RPB5 Binding Protein URI/RMP ▿

PubMed Central

Mita, Paolo; Savas, Jeffrey N.; Djouder, Nabil; Yates, John R.; Ha, Susan; Ruoff, Rachel; Schafler, Eric D.; Nwachukwu, Jerome C.; Tanese, Naoko; Cowan, Nicholas J.; Zavadil, Jiri; Garabedian, Michael J.; Logan, Susan K.

2011-01-01

Androgen receptor (AR)-mediated transcription is modulated by interaction with coregulatory proteins. We demonstrate that the unconventional prefoldin RPB5 interactor (URI) is a new regulator of AR transcription and is critical for antagonist (bicalutamide) action. URI is phosphorylated upon androgen treatment, suggesting communication between the URI and AR signaling pathways. Whereas depletion of URI enhances AR-mediated gene transcription, overexpression of URI suppresses AR transcriptional activation and anchorage-independent prostate cancer cell growth. Repression of AR-mediated transcription is achieved, in part, by URI binding and regulation of androgen receptor trapped clone 27 (Art-27), a previously characterized AR corepressor. Consistent with this idea, genome-wide expression profiling in prostate cancer cells upon depletion of URI or Art-27 reveals substantially overlapping patterns of gene expression. Further, depletion of URI increases the expression of the AR target gene NKX-3.1, decreases the recruitment of Art-27, and increases AR occupancy at the NKX-3.1 promoter. While Art-27 can bind AR directly, URI is bound to chromatin prior to hormone-dependent recruitment of AR, suggesting a role for URI in modulating AR recruitment to target genes. PMID:21730289

Instrumentation development for In Situ 40Ar/39Ar planetary geochronology

USGS Publications Warehouse

Morgan, Leah; Munk, Madicken; Davidheiser-Kroll, Brett; Warner, Nicholas H.; Gupta, Sanjeev; Slaybaugh, Rachel; Harkness, Patrick; Mark, Darren

2017-01-01

The chronology of the Solar System, particularly the timing of formation of extra-terrestrial bodies and their features, is an outstanding problem in planetary science. Although various chronological methods for in situ geochronology have been proposed (e.g., Rb-Sr, K-Ar), and even applied (K-Ar), the reliability, accuracy, and applicability of the 40Ar/39Ar method makes it by far the most desirable chronometer for dating extra-terrestrial bodies. The method however relies on the neutron irradiation of samples, and thus a neutron source. Herein, we discuss the challenges and feasibility of deploying a passive neutron source to planetary surfaces for the in situ application of the 40Ar/39Ar chronometer. Requirements in generating and shielding neutrons, as well as analysing samples are described, along with an exploration of limitations such as mass, power and cost. Two potential solutions for the in situ extra-terrestrial deployment of the 40Ar/39Ar method are presented. Although this represents a challenging task, developing the technology to apply the 40Ar/39Ar method on planetary surfaces would represent a major advance towards constraining the timescale of solar system formation and evolution.

The cloud-radiative forcing of the U.S. landfalling atmospheric rivers

NASA Astrophysics Data System (ADS)

Luo, Qianwen

Atmospheric rivers (ARs) are narrow channels in the atmosphere that transport an enormous amount of moisture from the tropics to the higher latitudes. Streaks of highly reflective clouds are observed along with the ARs in satellite imagery. These clouds both influence the moisture transport of ARs, as well as modify the Earth-Atmospheric energy budget through pathways such as cloud-radiative forcing (CRF). This dissertation studies the CRF of the U.S. Landfalling ARs in weather and climate scales. Three crucial questions are addressed. First, how do clouds produced by the ARs modulate the moisture and heat balance of the Earth-Atmospheric system? Even though studies of ARs date back to the 90s, past research has been primarily focused on their hydrological impacts. We addressed this research gap by comparing the dominant types of precipitating clouds and convection of two ARs. Through quantifying their effects on the energy balance in the midlatitudes, we found that when deep convection was the dominant cloud types of an AR, impressive CRF cooling was produced. Second, what are the sufficient climate conditions for the extensive CRF in the continental U.S.? We studied 60 ARs that reached the California coast (the Southwest ARs) and 60 ARs that reached Pacific Northwest during Nov-Mar, 2000-2008. It was found that when these West-Coast ARs were followed by the moisture surge from the Gulf of Mexico (the Gulf-Coast AR), it resulted in apparent statewide CRF. Such condition happened more frequently in the Southwest-AR scenario. Third, how does the subgrid-scale-convection-induced CRF influence the moisture transport of ARs?We ran two WRF ARW simulations for a Southwest-AR that was followed by a Gulf-Coast AR. The only difference between the two simulations was one considered the CRF of subgrid-scale clouds while the other did not. By comparing the two simulations, we found that the subgrid-scale-convection-induced CRF helped prolong the lifespan of clouds in an AR, thus enabling moisture to be transported further downstream. In short, this work helps improve our understanding of CRF of the U.S. landfalling ARs from both weather and climate perspectives. Our results are useful for validating the representation of clouds and radiation processes in weather and climate models, thereby help to improve AR predictions.

Isolation and Characterization of an Agaro-Oligosaccharide (AO)-Hydrolyzing Bacterium from the Gut Microflora of Chinese Individuals

PubMed Central

Li, Miaomiao; Li, Guangsheng; Zhu, Liying; Yin, Yeshi; Zhao, Xiaoliang; Xiang, Charlie; Yu, Guangli; Wang, Xin

2014-01-01

Agarose (AP) from red algae has a long history as food ingredients in East Asia. Agaro-oligosaccharides (AO) derived from AP have shown potential prebiotic effects. However, the human gut microbes responsible for the degradation of AO and AP have not yet been fully investigated. Here, we reported that AO and AP can be degraded and utilized at various rates by fecal microbiota obtained from different individuals. Bacteroides uniformis L8 isolated from human feces showed a pronounced ability to degrade AO and generate D-galactose as its final end product. PCR-DGGE analysis showed B. uniformis to be common in the fecal samples, but only B. uniformis L8 had the ability to degrade AO. A synergistic strain, here classified as Escherichia coli B2, was also identified because it could utilize the D-galactose as the growth substrate. The cross-feeding interaction between B. uniformis L8 and E. coli B2 led to exhaustion of the AO supply. Bifidobacterium infantis and Bifidobacterium adolescentis can utilize one of the intermediates of AO hydrolysis, agarotriose. Growth curves indicated that AO was the substrate that most favorably sustained the growth of B. uniformis L8. In contrast, κ-carrageenan oligosaccharides (KCO), guluronic acid oligosaccharides (GO), and mannuronic acid oligosaccharides (MO) were found to be unusable to B. uniformis L8. Current results indicate that B. uniformis L8 is a special degrader of AO in the gut microbiota. Because B. uniformis can mitigate high-fat-diet-induced metabolic disorders, further study is required to determine the potential applications of AO. PMID:24622338

Patterns of Post-Stroke Brain Damage that Predict Speech Production Errors in Apraxia of Speech and Aphasia Dissociate

PubMed Central

Basilakos, Alexandra; Rorden, Chris; Bonilha, Leonardo; Moser, Dana; Fridriksson, Julius

2015-01-01

Background and Purpose Acquired apraxia of speech (AOS) is a motor speech disorder caused by brain damage. AOS often co-occurs with aphasia, a language disorder in which patients may also demonstrate speech production errors. The overlap of speech production deficits in both disorders has raised questions regarding if AOS emerges from a unique pattern of brain damage or as a sub-element of the aphasic syndrome. The purpose of this study was to determine whether speech production errors in AOS and aphasia are associated with distinctive patterns of brain injury. Methods Forty-three patients with history of a single left-hemisphere stroke underwent comprehensive speech and language testing. The Apraxia of Speech Rating Scale was used to rate speech errors specific to AOS versus speech errors that can also be associated with AOS and/or aphasia. Localized brain damage was identified using structural MRI, and voxel-based lesion-impairment mapping was used to evaluate the relationship between speech errors specific to AOS, those that can occur in AOS and/or aphasia, and brain damage. Results The pattern of brain damage associated with AOS was most strongly associated with damage to cortical motor regions, with additional involvement of somatosensory areas. Speech production deficits that could be attributed to AOS and/or aphasia were associated with damage to the temporal lobe and the inferior pre-central frontal regions. Conclusion AOS likely occurs in conjunction with aphasia due to the proximity of the brain areas supporting speech and language, but the neurobiological substrate for each disorder differs. PMID:25908457

Isolation and characterization of an agaro-oligosaccharide (AO)-hydrolyzing bacterium from the gut microflora of Chinese individuals.

PubMed

Li, Miaomiao; Li, Guangsheng; Zhu, Liying; Yin, Yeshi; Zhao, Xiaoliang; Xiang, Charlie; Yu, Guangli; Wang, Xin

2014-01-01

Agarose (AP) from red algae has a long history as food ingredients in East Asia. Agaro-oligosaccharides (AO) derived from AP have shown potential prebiotic effects. However, the human gut microbes responsible for the degradation of AO and AP have not yet been fully investigated. Here, we reported that AO and AP can be degraded and utilized at various rates by fecal microbiota obtained from different individuals. Bacteroides uniformis L8 isolated from human feces showed a pronounced ability to degrade AO and generate D-galactose as its final end product. PCR-DGGE analysis showed B. uniformis to be common in the fecal samples, but only B. uniformis L8 had the ability to degrade AO. A synergistic strain, here classified as Escherichia coli B2, was also identified because it could utilize the D-galactose as the growth substrate. The cross-feeding interaction between B. uniformis L8 and E. coli B2 led to exhaustion of the AO supply. Bifidobacterium infantis and Bifidobacterium adolescentis can utilize one of the intermediates of AO hydrolysis, agarotriose. Growth curves indicated that AO was the substrate that most favorably sustained the growth of B. uniformis L8. In contrast, κ-carrageenan oligosaccharides (KCO), guluronic acid oligosaccharides (GO), and mannuronic acid oligosaccharides (MO) were found to be unusable to B. uniformis L8. Current results indicate that B. uniformis L8 is a special degrader of AO in the gut microbiota. Because B. uniformis can mitigate high-fat-diet-induced metabolic disorders, further study is required to determine the potential applications of AO.

Pig StAR: mRNA expression and alternative splicing in testis and Leydig cells, and association analyses with testicular morphology traits.

PubMed

Zhang, Yanghai; Cui, Yang; Zhang, Xuelian; Wang, Yimin; Gao, Jiayang; Yu, Ting; Lv, Xiaoyan; Pan, Chuanying

2018-05-31

Steroidogenic acute regulatory protein (StAR), primarily expressed in Leydig cells (LCs) in the mammalian testes, is essential for testosterone biosynthesis and male fertility. However, no previous reports have explored the expression profiles, alternative splicing and genetic variations of StAR gene in pig. The aim of current study was to explore the expression profiles in different tissues and different types of testicular cells (LCs; spermatogonial stem cells, SSCs; Sertoli cells, SCs), to identify different splice variants and their expression levels, as well as to detect the indel polymorphism in pig StAR gene. Expression analysis results revealed that StAR was widely expressed in all tested tissues and the expression level in testis was significantly higher than that in other tissues (P < 0.01); among different types of testicular cells, the StAR mRNA expression level was significantly higher in LCs than others (P < 0.05). Furthermore, three splice variants, StAR-a, StAR-b and StAR-c, were first found in pig. Further study showed StAR-a was highly expressed in both testis and LCs when compared with other variants (P < 0.01), suggesting StAR-a was the primary variant at StAR gene post-transcription and may facilitate the combination and transportation of cholesterol with StAR. In addition, a 5-bp duplicated deletion (NC_010457.5:g.5524-5528 delACTTG) was verified in the porcine StAR gene, which was closely related to male testicular morphology traits (P < 0.05), and we speculated that the allele "D" of StAR gene might be a positive allele. Briefly, the current findings suggest that StAR and StAR-a play imperative roles in male fertility and the 5-bp indel can be a potential DNA marker for the marker-assisted selection in boar. Copyright © 2018 Elsevier Inc. All rights reserved.

Observed Trends in West Coast Atmospheric River Temperatures

NASA Astrophysics Data System (ADS)

Gonzales, K. R.; Swain, D. L.; Barnes, E. A.; Diffenbaugh, N. S.

2017-12-01

Understanding the changing characteristics of atmospheric rivers (ARs) in a warming climate is critical in light of their importance in generating precipitation and creating the potential for flood and geophysical hazards. Numerous changes to the characteristics of ARs under the influence of a changing climate have been documented or hypothesized; one simple hypothesis is that AR precipitation will occur at increasingly warm temperatures, potentially altering the critical rain/snow balance in snowpack-dependent watersheds and causing precipitation at higher elevations to fall as rain rather than snow. Not only would warmer, primarily rain-producing ARs greatly affect snow accumulation, but they might also increase the intensity of runoff, the potential for flooding, and the occurrence of rain-on-snow events. Since the West Coast of North America relies heavily on ARs as a source of precipitation and snowpack accumulation, these regions may be profoundly affected by changes in AR temperatures and associated impacts. Using a catalog of ARs encompassing 1979-2014 and ERA-Interim reanalysis, we assess whether detectable trends exist in cool season AR temperatures over the Pacific Coast states of California, Oregon, and Washington. We define AR temperature by the mean temperature of the air mass between 1000 hPa and 750 hPa, and compare AR temperature trends to background temperature trends over the same period. We find overall AR warming over this period and particularly robust warming in March ARs coincident with an apparent poleward shift in March AR frequency. Further analysis suggests that warmer ARs have higher rates of warming than cooler ARs. AR temperature trends generally scale with background temperature trends, although some regions exhibit a near one-to-one relationship while others are largely uncorrelated. The observed warming of ARs making landfall on the West Coast may have potentially significant implications for rain vs. snow at higher elevations, the rain/snow balance, and rain-on-snow flood hazards (particularly in March).

Characterization of a C3a receptor in rainbow trout and Xenopus: the first identification of C3a receptors in nonmammalian species

USGS Publications Warehouse

Boshra, Hani; Wang, Tiehui; Hove-Madsen, Leif; Hansen, John D.; Li, Jun; Matlapudi, Anjun; Secombes, Christopher J.; Tort, Lluis; Sunyer, J. Oriol

2005-01-01

Virtually nothing is known about the structure, function, and evolutionary origins of the C3aR in nonmammalian species. Because C3aR and C5aR are thought to have arisen from the same common ancestor, the recent characterization of a C5aR in teleost fish implied the presence of a C3aR in this animal group. In this study we report the cloning of a trout cDNA encoding a 364-aa molecule (TC3aR) that shows a high degree of sequence homology and a strong phylogenetic relationship with mammalian C3aRs. Northern blotting demonstrated that TC3aR was expressed primarily in blood leukocytes. Flow cytometric analysis and immunofluorescence microscopy showed that Abs raised against TC3aR stained to a high degree all blood B lymphocytes and, to a lesser extent, all granulocytes. More importantly, these Abs inhibited trout C3a-mediated intracellular calcium mobilization in trout leukocytes. A fascinating structural feature of TC3aR is the lack of a significant portion of the second extracellular loop (ECL2). In all C3aR molecules characterized to date, the ECL2 is exceptionally large when compared with the same region of C5aR. However, the exact function of the extra portion of ECL2 is unknown. The lack of this segment in TC3aR suggests that the extra piece of ECL2 was not necessary for the interaction of the ancestral C3aR with its ligand. Our findings represent the first C3aR characterized in nonmammalian species and support the hypothesis that if C3aR and C5aR diverged from a common ancestor, this event occurred before the emergence of teleost fish.

Revised error propagation of 40Ar/39Ar data, including covariances

NASA Astrophysics Data System (ADS)

Vermeesch, Pieter

2015-12-01

The main advantage of the 40Ar/39Ar method over conventional K-Ar dating is that it does not depend on any absolute abundance or concentration measurements, but only uses the relative ratios between five isotopes of the same element -argon- which can be measured with great precision on a noble gas mass spectrometer. The relative abundances of the argon isotopes are subject to a constant sum constraint, which imposes a covariant structure on the data: the relative amount of any of the five isotopes can always be obtained from that of the other four. Thus, the 40Ar/39Ar method is a classic example of a 'compositional data problem'. In addition to the constant sum constraint, covariances are introduced by a host of other processes, including data acquisition, blank correction, detector calibration, mass fractionation, decay correction, interference correction, atmospheric argon correction, interpolation of the irradiation parameter, and age calculation. The myriad of correlated errors arising during the data reduction are best handled by casting the 40Ar/39Ar data reduction protocol in a matrix form. The completely revised workflow presented in this paper is implemented in a new software platform, Ar-Ar_Redux, which takes raw mass spectrometer data as input and generates accurate 40Ar/39Ar ages and their (co-)variances as output. Ar-Ar_Redux accounts for all sources of analytical uncertainty, including those associated with decay constants and the air ratio. Knowing the covariance matrix of the ages removes the need to consider 'internal' and 'external' uncertainties separately when calculating (weighted) mean ages. Ar-Ar_Redux is built on the same principles as its sibling program in the U-Pb community (U-Pb_Redux), thus improving the intercomparability of the two methods with tangible benefits to the accuracy of the geologic time scale. The program can be downloaded free of charge from http://redux.london-geochron.com.

Significance of the cosmogenic argon correction in deciphering the 40Ar/39Ar ages of the Nakhlite (Martian) meteorites

NASA Astrophysics Data System (ADS)

Cohen, B. E.; Cassata, W.; Mark, D. F.; Tomkinson, T.; Lee, M. R.; Smith, C. L.

2015-12-01

All meteorites contain variable amounts of cosmogenic 38Ar and 36Ar produced during extraterrestrial exposure, and in order to calculate reliable 40Ar/39Ar ages this cosmogenic Ar must be removed from the total Ar budget. The amount of cosmogenic Ar has usually been calculated from the step-wise 38Ar/36Ar, minimum 36Ar/37Ar, or average 38Arcosmogenic/37Ar from the irradiated meteorite fragment. However, if Cl is present in the meteorite, then these values will be disturbed by Ar produced during laboratory neutron irradiation of Cl. Chlorine is likely to be a particular issue for the Nakhlite group of Martian meteorites, which can contain over 1000 ppm Cl [1]. An alternative method for the cosmogenic Ar correction uses the meteorite's exposure age as calculated from an un-irradiated fragment and step-wise production rates based on the measured Ca/K [2]. This calculation is independent of the Cl concentration. We applied this correction method to seven Nakhlites, analyzed in duplicate or triplicate. Selected samples were analyzed at both Lawrence Livermore National Laboratory and SUERC to ensure inter-laboratory reproducibility. We find that the cosmogenic argon correction of [2] has a significant influence on the ages calculated for individual steps, particularly for those at lower temperatures (i.e., differences of several tens of million years for some steps). The lower-temperature steps are more influenced by the alternate cosmogenic correction method of [2], as these analyses yielded higher concentrations of Cl-derived 38Ar. As a result, the Nakhlite data corrected using [2] yields step-heating spectra that are flat or nearly so across >70% of the release spectra (in contrast to downward-stepping spectra often reported for Nakhlite samples), allowing for the calculation of precise emplacement ages for these meteorites. [1] Cartwright J. A. et al. (2013) GCA, 105, 255-293. [2] Cassata W. S., and Borg L. E. (2015) 46th LPSC, Abstract #2742.

The immunohistochemical expression and potential prognostic value of HDAC6 and AR in invasive breast cancer.

PubMed

Li, Congying; Cao, Lu; Xu, Cong; Liu, Fang; Xiang, Guomin; Liu, Xiaozhen; Jiao, Jiao; Niu, Yun

2018-05-01

Previous studies have investigated the role of histone deacetylase 6 (HDAC6) in the regulation of androgen receptor (AR) in prostate cancer; however, the role of HDAC6 has not yet been clearly identified in breast cancer. The aim of this study was to examine the expression of HDAC6 and AR, determine the correlation between HDAC6 and AR, and assess the prognostic value of HDAC6 and AR in breast cancer. A total of 228 cases of invasive breast cancer were randomly selected. The expression of HDAC6 and AR was analyzed by immunohistochemistry. χ 2 Tests were performed to determine the association between conventional clinicopathological factors and HDAC6, AR, and HDAC6/AR co-expression. Spearman correlation methods were performed to determine the correlation between HDAC6 and AR, and Kaplan-Meier analyses were performed to determine the prognostic impact of HDAC6, AR and HDAC6/AR co-expression; 58.8% (134/228) patients exhibited high expression of HDAC6. High HDAC6 expression was significantly associated with high histologic grade (G3) (P<.001) and p53 overexpression (P=.002). HDAC6 and AR expression levels were significantly associated (r=0.382, P<.01). In estrogen receptor (ER)-negative samples, high expression of HDAC6 was more common in the AR+ groups (P<.001) and correlated with high histologic grade (G3) (P=.009), as well as higher HER2 (P=.006) and p53 levels (P=.012). Higher expression of AR and HDAC6 and HDAC6/AR co-expression had a worse clinical prognosis. The expression levels of HDAC6 and AR are correlated in breast cancer; moreover, HDAC6 and AR have prognostic value in predicting the overall survival (OS) of ER-negative breast cancer patients. Copyright © 2017 Elsevier Inc. All rights reserved.

Targeting AR Variant-Coactivator Interactions to Exploit Prostate Cancer Vulnerabilities.

PubMed

Magani, Fiorella; Peacock, Stephanie O; Rice, Meghan A; Martinez, Maria J; Greene, Ann M; Magani, Pablo S; Lyles, Rolando; Weitz, Jonathan R; Burnstein, Kerry L

2017-11-01

Castration-resistant prostate cancer (CRPC) progresses rapidly and is incurable. Constitutively active androgen receptor splice variants (AR-Vs) represent a well-established mechanism of therapeutic resistance and disease progression. These variants lack the AR ligand-binding domain and, as such, are not inhibited by androgen deprivation therapy (ADT), which is the standard systemic approach for advanced prostate cancer. Signaling by AR-Vs, including the clinically relevant AR-V7, is augmented by Vav3, an established AR coactivator in CRPC. Using mutational and biochemical studies, we demonstrated that the Vav3 Diffuse B-cell lymphoma homology (DH) domain interacted with the N-terminal region of AR-V7 (and full length AR). Expression of the Vav3 DH domain disrupted Vav3 interaction with and enhancement of AR-V7 activity. The Vav3 DH domain also disrupted AR-V7 interaction with other AR coactivators: Src1 and Vav2, which are overexpressed in PC. This Vav3 domain was used in proof-of-concept studies to evaluate the effects of disrupting the interaction between AR-V7 and its coactivators on CRPC cells. This disruption decreased CRPC cell proliferation and anchorage-independent growth, caused increased apoptosis, decreased migration, and resulted in the acquisition of morphological changes associated with a less aggressive phenotype. While disrupting the interaction between FL-AR and its coactivators decreased N-C terminal interaction, disrupting the interaction of AR-V7 with its coactivators decreased AR-V7 nuclear levels. Implications: This study demonstrates the potential therapeutic utility of inhibiting constitutively active AR-V signaling by disrupting coactivator binding. Such an approach is significant, as AR-Vs are emerging as important drivers of CRPC that are particularly recalcitrant to current therapies. Mol Cancer Res; 15(11); 1469-80. ©2017 AACR . ©2017 American Association for Cancer Research.

Partial agonist clonidine mediates alpha(2)-AR subtypes specific regulation of cAMP accumulation in adenylyl cyclase II transfected DDT1-MF2 cells.

PubMed

Limon-Boulez, I; Bouet-Alard, R; Gettys, T W; Lanier, S M; Maltier, J P; Legrand, C

2001-02-01

alpha2-Adrenergic receptor (alpha(2)-AR) activation in the pregnant rat myometrium at midterm potentiates beta(2)-AR stimulation of adenylyl cyclase (AC) via Gbetagamma regulation of the type II isoform of adenylyl cyclase. However, at term, alpha(2)-AR activation inhibits beta(2)-AR stimulation of AC. This phenomenon is associated with changes in alpha(2)-AR subtype expression (midterm alpha(2A/D)-AR > alpha(2B)-AR; term alpha(2B) >or =alpha(2A/D)-AR), without any change in ACII mRNA, suggesting that alpha(2A/D)- and alpha(2B)-AR differentially regulate beta(2)-cAMP production. To address this issue, we have stably expressed the same density of alpha(2A/D)- or alpha(2B)-AR with AC II in DDT1-MF2 cells. Clonidine (partial agonist) increased beta(2)-AR-stimulated cAMP production in alpha(2A/D)-AR-ACII transfectants but inhibited it in alpha(2B)-AR-ACII transfectants. In contrast, epinephrine (full agonist) enhanced beta(2)-stimulated ACII in both alpha(2A)- and alpha(2B)-ACII clonal cell lines. 4-Azidoanilido-[alpha-(32)P]GTP-labeling of activated G proteins indicated that, in alpha(2B)-AR transfectants, clonidine activated only Gi(2), whereas epinephrine, the full agonist, effectively coupled to Gi(2) and Gi(3). Thus, partial and full agonists selectively activate G proteins that lead to drug specific effects on effectors. Moreover, these data indicate that Gi(3) activation is required for potentiation of beta(2)-AR stimulation of AC by alpha(2A/D) and alpha(2B)-AR in DDT1-MF2 cells. This may reflect an issue of the amount of Gbetagamma released upon receptor activation and/or betagamma composition of Gi(3) versus Gi(2).

A possible cause of the AO polarity reversal from winter to summer in 2010 and its relation to hemispheric extreme summer weather

NASA Astrophysics Data System (ADS)

Otomi, Y.; Tachibana, Y.; Nakamura, T.

2012-12-01

In 2010, the Northern Hemisphere, in particular Russia, Europe and Japan, experienced an abnormally hot summer characterized by record-breaking warm temperatures and associated with a strongly positive Arctic Oscillation (AO). In contrast, in winter 2009/2010, the continent suffered from anomalously cold weather associated with a record-breaking negative AO. The winter-to-summer of the AO index during 2009/2010 evolved as follows: a strongly negative wintertime AO index continued until May, after which it abruptly changed, becoming strongly positive in July and continuing so until the beginning of August. The abrupt change of the AO index from strongly negative to strongly positive in 2010 thus corresponded to the change from the abnormally cold winter of 2009/2010 to the abnormally hot summer of 2010, which shows that the AO index is a good indicator of abnormal weather on a planetary-scale, and that extra-seasonal prediction of the AO is a key to long-term forecasting. In this study, we therefore aimed to examine the cause of the 2010 change in the AO index from strongly negative to strongly positive. We suggest that an oceanic memory of the strongly negative wintertime AO may have influenced the strongly positive summertime AO. The winter sea surface temperatures (SST) in the North Atlantic Ocean showed a tripolar anomaly pattern which is warm SST anomalies over the tropics and high latitudes and cold SST anomalies over the midlatitudes. The strongly negative wintertime AO would cause the warm SST anomaly in this region. The warm SST anomalies continued into summer 2010 because of the large oceanic heat capacity. In May and June, the heat flux anomaly changed from downward to upward in the tropics, and in July and August, the center of the upward anomaly moved westward. The area of the upward heat flux anomaly coincided with the area of the warm SST anomaly from May to August. The numerical model experiment showed that the tripolar SST pattern resulted in an anomalous height and wind pattern that caused a blocking high over Europe. The observed wave activity flux also seems to emanate from Europe. This midlatitude atmospheric response implies that strengthening of the positive geopotential anomalies over Europe was associated with the Atlantic tripolar SST anomaly. The positive geopotential anomaly in the area of the polar jet stream caused eastward propagation of Rossby waves, and the exceeding amplification of Rossby waves might have led to the formation of blocking anticyclones. As a consequence of these interactions, the positive AO pressure pattern can continue for a long time. Thus, a possible cause of the AO polarity reversal might be the "memory" of the negative winter AO in the North Atlantic Ocean, suggesting an interseasonal linkage of the AO in which the oceanic memory of a wintertime negative AO induces a positive AO in the following summer. Understanding of this interseasonal linkage may aid in the long-term prediction of such abnormal summer events. If this reversal pattern recurs, it might be possible to predict the summertime AO from the wintertime AO. Main parts of this study were published in Climatic Dynamics by Otomi et al, (2012).

[The impact of the androgen receptor splice variant AR-V7 on the prognosis and treatment of advanced prostate cancer].

PubMed

Thelen, P; Taubert, H; Duensing, S; Kristiansen, G; Merseburger, A S; Cronauer, M V

2018-01-25

A recently discovered mechanism enabling prostate cancer cells to escape the effects of endocrine therapies consists in the synthesis of C-terminally truncated, constitutively active androgen receptor (AR) splice variants (AR-V). Devoid of a functional C-terminal hormone/ligand binding domain, various AR-Vs are insensitive to therapies targeting the androgen/AR signalling axis. Preliminary studies suggest that AR-V7, the most common AR-V, is a promising predictive tumour marker and a relevant selection marker for the treatment of advanced prostate cancer. This review critically outlines recent advances in AR-V7 diagnostics and presents an overview of current AR-V7 targeted therapies. © Georg Thieme Verlag KG Stuttgart · New York.

Enhanced expression of EGFP gene in CHSE-214 cells by an ARS element from mud loach (Misgurnus mizolepis).

PubMed

Kim, Moo-Sang; Lim, Hak-Seob; Ahn, Sang Jung; Jeong, Yong-Kee; Kim, Chul Geun; Lee, Hyung Ho

2007-11-01

The origins of replication are associated with nuclear matrices or are found in close proximity to matrix attachment regions (MARs). In this report, fish MARs were cloned into an autonomously replicating sequence (ARS) cloning vector and were screened for ARS elements in Saccharomyces cerevisiae. Sixteen clones were isolated that were able to grow on the selective plates. In particular, an ARS905 that shows high efficiency among them was selected for this study. Southern hybridization indicated the autonomous replication of the transformation vector containing the ARS905 element. DNA sequences analysis showed that the ARS905 contained two ARS consensus sequences as well as MAR motifs, such as AT tracts, ORI patterns, and ATC tracts. In vitro matrix binding analysis, major matrix binding activity and ARS function coincided in a subfragment of the ARS905. To analyze the effects of ARS905 on expression of a reporter gene, an ARS905(E1158) with ARS activity was inserted into pBaEGFP(+) containing mud loach beta-actin promoter, EGFP as a reporter gene, and SV40 poly(A) signal. The pBaEGFP(+)-ARS905(E1158) was transfected into a fish cell line, CHSE-214. The intensity of EGFP transfected cells was a 7-fold of the control at 11days post-transfection. These results indicate that ARS905 enhances the expression of the EGFP gene and that it should be as a component of expression vectors in further fish biotechnological studies.

The androgen receptor malignancy shift in prostate cancer.

PubMed

Copeland, Ben T; Pal, Sumanta K; Bolton, Eric C; Jones, Jeremy O

2018-05-01

Androgens and the androgen receptor (AR) are necessary for the development, function, and homeostatic growth regulation of the prostate gland. However, once prostate cells are transformed, the AR is necessary for the proliferation and survival of the malignant cells. This change in AR function appears to occur in nearly every prostate cancer. We have termed this the AR malignancy shift. In this review, we summarize the current knowledge of the AR malignancy shift, including the DNA-binding patterns that define the shift, the transcriptome changes associated with the shift, the putative drivers of the shift, and its clinical implications. In benign prostate epithelial cells, the AR primarily binds consensus AR binding sites. In carcinoma cells, the AR cistrome is dramatically altered, as the AR associates with FOXA1 and HOXB13 motifs, among others. This shift leads to the transcription of genes associated with a malignant phenotype. In model systems, some mutations commonly found in localized prostate cancer can alter the AR cistrome, consistent with the AR malignancy shift. Current evidence suggests that the AR malignancy shift is necessary but not sufficient for transformation of prostate epithelial cells. Reinterpretation of prostate cancer genomic classification systems in light of the AR malignancy shift may improve our ability to predict clinical outcomes and treat patients appropriately. Identifying and targeting the molecular factors that contribute to the AR malignancy shift is not trivial but by doing so, we may be able to develop new strategies for the treatment or prevention of prostate cancer. © 2018 Wiley Periodicals, Inc.

Novel galeterone analogs act independently of AR and AR-V7 for the activation of the unfolded protein response and induction of apoptosis in the CWR22Rv1 prostate cancer cell model.

PubMed

McCarty, David J; Huang, Weiliang; Kane, Maureen A; Purushottamachar, Puranik; Gediya, Lalji K; Njar, Vincent C O

2017-10-24

The androgen receptor (AR) has long been the primary target for the treatment of prostate cancer (PC). Despite continuous efforts to block AR activity through ligand depletion, AR antagonism, AR depletion and combinations thereof, advanced PC tumors remain resilient. Herein, we evaluate two galeterone analogs, VNPT-178 and VNLG-74A, in PC cell models of diverse androgen and AR dependence attempting to delineate their mechanisms of action and potential clinical utility. Employing basic biochemical techniques, we determined that both analogs have improved antiproliferative and anti-AR activities compared to FDA-approved abiraterone and enzalutamide. However, induction of apoptosis in these models is independent of the AR and its truncated variant, AR-V7, and instead likely results from sustained endoplasmic reticulum stress and deregulated calcium homeostasis. Using in silico molecular docking, we predict VNPT-178 and VNLG-74A bind the ATPase domain of BiP/Grp78 and Hsp70-1A with greater affinity than the AR. Disruption of 70 kDa heat shock protein function may be the underlying mechanism of action for these galeterone analogs. Therefore, despite simultaneously antagonizing AR activity, AR and/or AR-V7 expression alone may inadequately predict a patient's response to treatment with VNPT-178 or VNLG-74A. Future studies evaluating the context-specific limitations of these compounds may provide clarity for their clinical application.

Cell cycle-coupled expansion of AR activity promotes cancer progression.

PubMed

McNair, C; Urbanucci, A; Comstock, C E S; Augello, M A; Goodwin, J F; Launchbury, R; Zhao, S G; Schiewer, M J; Ertel, A; Karnes, J; Davicioni, E; Wang, L; Wang, Q; Mills, I G; Feng, F Y; Li, W; Carroll, J S; Knudsen, K E

2017-03-23

The androgen receptor (AR) is required for prostate cancer (PCa) survival and progression, and ablation of AR activity is the first line of therapeutic intervention for disseminated disease. While initially effective, recurrent tumors ultimately arise for which there is no durable cure. Despite the dependence of PCa on AR activity throughout the course of disease, delineation of the AR-dependent transcriptional network that governs disease progression remains elusive, and the function of AR in mitotically active cells is not well understood. Analyzing AR activity as a function of cell cycle revealed an unexpected and highly expanded repertoire of AR-regulated gene networks in actively cycling cells. New AR functions segregated into two major clusters: those that are specific to cycling cells and retained throughout the mitotic cell cycle ('Cell Cycle Common'), versus those that were specifically enriched in a subset of cell cycle phases ('Phase Restricted'). Further analyses identified previously unrecognized AR functions in major pathways associated with clinical PCa progression. Illustrating the impact of these unmasked AR-driven pathways, dihydroceramide desaturase 1 was identified as an AR-regulated gene in mitotically active cells that promoted pro-metastatic phenotypes, and in advanced PCa proved to be highly associated with development of metastases, recurrence after therapeutic intervention and reduced overall survival. Taken together, these findings delineate AR function in mitotically active tumor cells, thus providing critical insight into the molecular basis by which AR promotes development of lethal PCa and nominate new avenues for therapeutic intervention.

Experience of health professionals in care of the homeless population with tuberculosis.

PubMed

Alecrim, Tatiana Ferraz de Araújo; Mitano, Fernando; Reis, Amanda Alessandra Dos; Roos, Cristine Moraes; Palha, Pedro Fredemir; Protti-Zanatta, Simone Teresinha

2016-01-01

Analyzing statements of health professionals from a Street Clinic regarding care of a homeless population with tuberculosis. This is a qualitative research, conducted in the central region of São Paulo at three basic health units in the period of November to December 2014. A semi-structured interview guideline was implemented for data collection and all interviews were recorded using a digital recorder. Six health professionals were interviewed. According to the Discourse Analysis perspective, three discursive segments emerged: experiences on care in the streets; weaknesses inherent to the treatment process; and incentives as a means of maintaining sick people in treatment. Caring for a the homeless population with tuberculosis constitutes a new and challenging experience. It involves difficulties in dealing with the reality of a miserable social context, a lack and inadequacy of services, as well as care limitations for treatment and treatment dropout, which reinforces multiresistance. However, the investigated Street Clinic teams seek to expand access to health and social care services to this population. Analisar os discursos dos profissionais de saúde do Consultório na Rua em relação ao cuidado à pessoa em situação de rua com tuberculose. Trata-se de uma pesquisa qualitativa, realizada na região central do município de São Paulo, em três Unidades Básicas de Saúde, no período de novembro a dezembro de 2014. Utilizou-se de um roteiro de entrevista semiestruturada para a coleta de dados e todas as entrevistas foram gravadas com recurso a um gravador digital. Foram entrevistados seis profissionais de saúde. Segundo a perspectiva da Análise de Discurso, emergiram três blocos discursivos: experiência sobre o cuidar na rua; fragilidades inerentes ao processo de tratamento e incentivos como meio para a permanência do sujeito doente no tratamento. Cuidar da pessoa com tuberculose e em situação de rua constitui uma experiência nova e desafiadora, implica dificuldades em lidar com a realidade de um contexto social miserável, falta e inadequação de serviços, bem como limitações do cuidado para a cura e abandono do tratamento, podendo reforçar a multirresistência. Contudo, as equipes de Consultório na Rua investigadas buscam ampliar o acesso aos serviços de saúde e assistência social a essa população.

High-Content Positional Biosensor Screening Assay for Compounds to Prevent or Disrupt Androgen Receptor and Transcriptional Intermediary Factor 2 Protein–Protein Interactions

PubMed Central

Hua, Yun; Shun, Tong Ying; Strock, Christopher J.

2014-01-01

Abstract The androgen receptor–transcriptional intermediary factor 2 (AR-TIF2) positional protein–protein interaction (PPI) biosensor assay described herein combines physiologically relevant cell-based assays with the specificity of binding assays by incorporating structural information of AR and TIF2 functional domains along with intracellular targeting sequences and fluorescent reporters. Expression of the AR-red fluorescent protein (RFP) “prey” and TIF2-green fluorescent protein (GFP) “bait” components of the biosensor was directed by recombinant adenovirus constructs that expressed the ligand binding and activation function 2 surface domains of AR fused to RFP with nuclear localization and nuclear export sequences, and three α-helical LXXLL motifs from TIF2 fused to GFP and an HIV Rev nucleolar targeting sequence. In unstimulated cells, AR-RFP was localized predominantly to the cytoplasm and TIF2-GFP was localized to nucleoli. Dihydrotestosterone (DHT) treatment induced AR-RFP translocation into the nucleus where the PPIs between AR and TIF2 resulted in the colocalization of both biosensors within the nucleolus. We adapted the translocation enhanced image analysis module to quantify the colocalization of the AR-RFP and TIF2-GFP biosensors in images acquired on the ImageXpress platform. DHT induced a concentration-dependent AR-TIF2 colocalization and produced a characteristic condensed punctate AR-RFP PPI nucleolar distribution pattern. The heat-shock protein 90 inhibitor 17-N-allylamino-17-demethoxygeldanamycin (17-AAG) and antiandrogens flutamide and bicalutamide inhibited DHT-induced AR-TIF2 PPI formation with 50% inhibition concentrations (IC50s) of 88.5±12.5 nM, 7.6±2.4 μM, and 1.6±0.4 μM, respectively. Images of the AR-RFP distribution phenotype allowed us to distinguish between 17-AAG and flutamide, which prevented AR translocation, and bicalutamide, which blocked AR-TIF2 PPIs. We screened the Library of Pharmacologically Active Compounds (LOPAC) set for compounds that inhibited AR-TIF2 PPI formation or disrupted preexisting complexes. Eleven modulators of steroid family nuclear receptors (NRs) and 6 non-NR ligands inhibited AR-TIF2 PPI formation, and 10 disrupted preexisting complexes. The hits appear to be either AR antagonists or nonspecific inhibitors of NR activation and trafficking. Given that the LOPAC set represents such a small and restricted biological and chemical diversity, it is anticipated that screening a much larger and more diverse compound library will be required to find AR-TIF2 PPI inhibitors/disruptors. The AR-TIF2 protein–protein interaction biosensor (PPIB) approach offers significant promise for identifying molecules with potential to modulate AR transcriptional activity in a cell-specific manner that is distinct from the existing antiandrogen drugs that target AR binding or production. Small molecules that disrupt AR signaling at the level of AR-TIF2 PPIs may also overcome the development of resistance and progression to castration-resistant prostate cancer. PMID:25181412

Evidence for shock heating and constraints on Martian surface temperatures revealed by 40Ar/ 39Ar thermochronometry of Martian meteorites

NASA Astrophysics Data System (ADS)

Cassata, William S.; Shuster, David L.; Renne, Paul R.; Weiss, Benjamin P.

2010-12-01

The thermal histories of Martian meteorite are important for the interpretation of petrologic, geochemical, geochronological, and paleomagnetic constraints that they provide on the evolution of Mars. In this paper, we quantify 40Ar/ 39Ar ages and Ar diffusion kinetics of Martian meteorites Allan Hills (ALH) 84001, Nakhla, and Miller Range (MIL) 03346. We constrain the thermal history of each meteorite and discuss the resulting implications for their petrology, paleomagnetism, and geochronology. Maskelynite in ALH 84001 yields a 40Ar/ 39Ar isochron age of 4163 ± 35 Ma, which is indistinguishable from recent Pb-Pb ( Bouvier et al., 2009a) and Lu-Hf ages ( Lapen et al., 2010). The high precision of this result arises from clear resolution of a reproducible trapped 40Ar/ 36Ar component in maskelynite in ALH 84001 ( 40Ar/ 36Ar = 632 ± 90). The maskelynite 40Ar/ 39Ar age predates the Late Heavy Bombardment and likely represents the time at which the original natural remanent magnetization (NRM) component observed in ALH 84001 was acquired. Nakhla and MIL 03346 yield 40Ar/ 39Ar isochron ages of 1332 ± 24 and 1339 ± 8 Ma, respectively, which we interpret to date crystallization. Multi-phase, multi-domain diffusion models constrained by the observed Ar diffusion kinetics and 40Ar/ 39Ar age spectra suggest that localized regions within both ALH 84001 and Nakhla were intensely heated for brief durations during shock events at 1158 ± 110 and 913 ± 9 Ma, respectively. These ages may date the marginal melting of pyroxene in each rock, mobilization of carbonates and maskelynite in ALH 84001, and NRM overprints observed in ALH 84001. The inferred peak temperatures of the shock heating events (>1400 °C) are sufficient to mobilize Ar, Sr, and Pb in constituent minerals, which may explain some of the dispersion observed in 40Ar/ 39Ar, Rb-Sr, and U-Th-Pb data toward ages younger than ˜4.1 Ga. The data also place conservative upper bounds on the long-duration residence temperatures of the ALH 84001 and Nakhla protolith to be 22-∞+8 °C and 81-∞+9 °C over the last ˜4.16 Ga and ˜1.35 Ga, respectively. MIL 03346 has apparently not experienced significant shock-heating since it crystallized, consistent with the fact that various chronometers yield concordant ages.

AR-v7 protein expression is regulated by protein kinase and phosphatase

PubMed Central

Li, Yinan; Xie, Ning; Gleave, Martin E.; Rennie, Paul S.; Dong, Xuesen

2015-01-01

Failure of androgen-targeted therapy and progression of castration-resistant prostate cancer (CRPC) are often attributed to sustained expression of the androgen receptor (AR) and its major splice variant, AR-v7. Although the new generation of anti-androgens such as enzalutamide effectively inhibits AR activity, accumulating pre-clinical and clinical evidence indicates that AR-v7 remains constitutively active in driving CRPC progression. However, molecular mechanisms which control AR-v7 protein expression remain unclear. We apply multiple prostate cancer cell models to demonstrate that enzalutamide induces differential activation of protein phosphatase-1 (PP-1) and Akt kinase depending on the gene context of cancer cells. The balance between PP-1 and Akt activation governs AR phosphorylation status and activation of the Mdm2 ubiquitin ligase. Mdm2 recognizes phosphorylated serine 213 of AR-v7, and induces AR-v7 ubiquitination and protein degradation. These findings highlight the decisive roles of PP-1 and Akt for AR-v7 protein expression and activities when AR is functionally blocked. PMID:26378044

Early Thermal History of Eucrites by Ar-39-Ar-40

NASA Technical Reports Server (NTRS)

Bogard, D. D.; Garrison, D. H.

2001-01-01

Ar-39-Ar-40 ages for Piplia Kalan (3.58 +/- 0.02 Ga) and two other eucrites indicate later impact resetting. Older Ar-39-Ar-40 ages exist for the Moama cumulate eucrite (4.42 +/- 0.01 Ga) and the PCA82502 (4.506 +/- 0.009 Ga) and PCA91007 non-brecciated eucrites. Additional information is contained in the original extended abstract.

Growth Inhibition by Testosterone in an Androgen Receptor Splice Variant-Driven Prostate Cancer Model.

PubMed

Nakata, Daisuke; Nakayama, Kazuhide; Masaki, Tsuneo; Tanaka, Akira; Kusaka, Masami; Watanabe, Tatsuya

2016-12-01

Castration resistance creates a significant problem in the treatment of prostate cancer. Constitutively active splice variants of androgen receptor (AR) have emerged as drivers for resistance to androgen deprivation therapy, including the next-generation androgen-AR axis inhibitors abiraterone and enzalutamide. In this study, we describe the characteristics of a novel castration-resistant prostate cancer (CRPC) model, designated JDCaP-hr (hormone refractory). JDCaP-hr was established from an androgen-dependent JDCaP xenograft model after surgical castration. The expression of AR and its splice variants in JDCaP-hr was evaluated by immunoblotting and quantitative reverse transcription-polymerase chain reaction. The effects of AR antagonists and testosterone on JDCaP-hr were evaluated in vivo and in vitro. The roles of full-length AR (AR-FL) and AR-V7 in JDCaP-hr cell growth were evaluated using RNA interference. JDCaP-hr acquired a C-terminally truncated AR protein during progression from the parental JDCaP. The expression of AR-FL and AR-V7 mRNA was upregulated by 10-fold in JDCaP-hr compared with that in JDCaP, indicating that the JDCaP and JDCaP-hr models simulate castration resistance with some clinical features, such as overexpression of AR and its splice variants. The AR antagonist bicalutamide did not affect JDCaP-hr xenograft growth, and importantly, testosterone induced tumor regression. In vitro analysis demonstrated that androgen-independent prostate-specific antigen secretion and cell proliferation of JDCaP-hr were predominantly mediated by AR-V7. JDCaP-hr cell growth displayed a bell-shaped dependence on testosterone, and it was suppressed by physiological concentrations of testosterone. Testosterone induced rapid downregulation of both AR-FL and AR-V7 expression at physiological concentrations and suppressed expression of the AR target gene KLK3. Our findings support the clinical value of testosterone therapy, including bipolar androgen therapy, in the treatment of AR-overexpressed CRPC driven by AR splice variants that are not clinically actionable at present. Prostate 76:1536-1545, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Atmospheric River Development and Effects on Southern California

NASA Astrophysics Data System (ADS)

Harris, S. M.; Carvalho, L. V.

2014-12-01

Throughout most of southern California (SCA) annual precipitation totals occur from relatively few storms per season. Any changes to storm frequency or intensity may dramatically impact the region, as its landscapes are prone to various rainfall-induced hazards including landslides and floods. These hazards become more frequent following drought or fire events, conditions also reliant on precipitation and common in SCA. Rainfall forecasts are especially difficult to determine as regional precipitation is affected by numerous phenomena. On synoptic timescales, atmospheric rivers (ARs) are one such phenomenon known to impact SCA rainfall. ARs are channels of high water vapor content found within the lower atmosphere that transport moisture towards midlatitudes. In areas with varying topography, ARs often produce high-intensity precipitation due to orographic forcing. Although much insight has been gained in understanding AR climatology affecting North America's western coast, the spatiotemporal characteristics and atmospheric forcings driving ARs to SCA need to be further addressed. The goal of this work is to understand the characteristics of ARs that impact SCA and to distinguish them from ARs that impact northern latitudes. We investigate AR characteristics as well as atmospheric features prior to plume initiation for ARs impacting different landfall regions along North America's western coast between 1998-2008. Dates of AR events are organized according to landfall region using total precipitable water (TPW) fields from the National Oceanic and Atmospheric Administration's Climate Forecast System Reanalysis (CFSR). Additional CFSR fields are used to create anomaly composites of moist static energy, geopotential height, as well as upper-level zonal and low-level meridional winds for each landfall region on the day of and prior to AR occurrence. ARs that impact SCA display different TPW plume characteristics as well as wave train patterns throughout the AR lifecycle (prior to plume initiation-AR landfall) compared to ARs that landfall further north. This suggests that ARs impacting SCA differ in initiation mechanisms as well as structural qualities from other ARs. Information from these analyses will assist in creating and validating an automatic tool for identifying AR occurrences.

Functional Characterization of Paralogous Gonadotropin-Releasing Hormone-Type and Corazonin-Type Neuropeptides in an Echinoderm

PubMed Central

Tian, Shi; Egertová, Michaela; Elphick, Maurice R.

2017-01-01

Homologs of the vertebrate neuropeptide gonadotropin-releasing hormone (GnRH) have been identified in invertebrates, including the insect neuropeptide corazonin (CRZ). Recently, we reported the discovery of GnRH-type and CRZ-type signaling systems in an echinoderm, the starfish Asterias rubens, demonstrating that the evolutionary origin of paralogous GnRH-type and CRZ-type neuropeptides can be traced back to the common ancestor of protostomes and deuterostomes. Here, we have investigated the physiological roles of the GnRH-type (ArGnRH) and the CRZ-type (ArCRZ) neuropeptides in A. rubens, using mRNA in situ hybridization, immunohistochemistry and in vitro pharmacology. ArGnRH precursor (ArGnRHP)-expressing cells and ArGnRH-immunoreactive cells and/or processes are present in the radial nerve cords, circumoral nerve ring, digestive system (e.g., cardiac stomach and pyloric stomach), body wall-associated muscle (apical muscle), and appendages (tube feet, terminal tentacle). The general distribution of ArCRZ precursor (ArCRZP)-expressing cells is similar to that of ArGnRHP, but with specific local differences. For example, cells expressing ArGnRHP are present in both the ectoneural and hyponeural regions of the radial nerve cords and circumoral nerve ring, whereas cells expressing ArCRZP were only observed in the ectoneural region. In vitro pharmacological experiments revealed that both ArGnRH and ArCRZ cause contraction of cardiac stomach, apical muscle, and tube foot preparations. However, ArGnRH was more potent/effective than ArCRZ as a contractant of the cardiac stomach, whereas ArCRZ was more potent/effective than ArGnRH as a contractant of the apical muscle. These findings demonstrate that both ArGnRH and ArCRZ are myoexcitatory neuropeptides in starfish, but differences in their expression patterns and pharmacological activities are indicative of distinct physiological roles. This is the first study to investigate the physiological roles of both GnRH-type and CRZ-type neuropeptides in a deuterostome, providing new insights into the evolution and comparative physiology of these paralogous neuropeptide signaling systems in the Bilateria. PMID:29033898

Androgen receptor is overexpressed in boys with severe hypospadias, and ZEB1 regulates androgen receptor expression in human foreskin cells

PubMed Central

Qiao, Liang; Tasian, Gregory E.; Zhang, Haiyang; Cao, Mei; Ferretti, Max; Cunha, Gerald R.; Baskin, Laurence S.

2012-01-01

INTRODUCTION ZEB1 is overexpressed in patients with severe hypospadias. We examined the interaction between ZeB1 and the androgen receptor (AR) in vitro and the expression of AR in boys with hypospadias. RESULTS ZEB1 and AR colocalize to the nucleus. Estrogen upregulated ZEB1 and AR expression. Chromatin immunoprecipitation (ChIP) demonstrated that ZEB1 binds to an E-box sequence in the AR gene promoter. AR expression is higher in subjects with severe hypospadias than those with mild hypospadias and control subjects (P < 0.05). ZEB1 physically interacts with AR in human foreskin cells. DISCUSSION AR is overexpressed in patients with severe hypospadias. Environmental estrogenic compounds may increase the risk of hypospadias by facilitating the interaction between ZEB1 and AR. METHODS Hs68 cells, a fibroblast cell line derived from neonatal human foreskin, were exposed to 0, 10, and 100 nmol/l of estrogen, after which the cellular localization of ZEB1 and AR was assessed using immunocytochemistry. To determine if ZEB1 interacted with the AR gene, ChIP was performed using ZEB1 antibody and polymerase chain reaction (PCR) for AR. Second, AR expression was quantified using real-time PcR and western blot in normal subjects (n = 32), and subjects with mild (n = 16) and severe hypospadia (n = 16). PMID:22391641

Precise K-Ar, 40Ar/39Ar, Rb-Sr and U/Pb mineral ages from the 27.5 Ma fish canyon tuff reference standard

USGS Publications Warehouse

Lanphere, M.A.; Baadsgaard, H.

2001-01-01

The accuracy of ages measured using the 40Ar/39Ar technique is affected by uncertainties in the age of radiation fluence-monitor minerals. At present, there is lack of agreement about the ages of certain minerals used as fluence monitors. The accuracy of the age of a standard may be improved if the age can be measured using different decay schemes. This has been done by measuring ages on minerals from the Oligocene Fish Canyon Tuff (FCT) using the K-Ar, 40Ar/39Ar. Rb-Sr and U/Pb methods. K-Ar and 40Ar/39Ar total fusion ages of sanidine, biotite and hornblende yielded a mean age of 27.57 ?? 0.36 Ma. The weighted mean 40Ar/39Ar plateau age of sanidine and biotite is 27.57 ?? 0.18 Ma. A biotite-feldspar Rb-Sr isochron yielded an age of 27.44 ?? 0.16 Ma. The U-Pb data for zircon are complex because of the presence of Precambrian zircons and inheritance of radiogenic Pb. Zircons with 207Pb/235U < 0.4 yielded a discordia line with a lower concordia intercept of 27.52 ?? 0.09 Ma. Evaluation of the combined data suggests that the best age for FCT is 27.51 Ma. Published by Elsevier Science B.V.

ArsR arsenic-resistance regulatory protein from Cupriavidus metallidurans CH34

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhang, Y.; van der Lelie, D.; Monchy, S.

The Cupriavidus metallidurans CH34 arsR gene, which is part of the arsRIC{sub 2}BC{sub 1}HP operon, and its putative arsenic-resistance regulatory protein were identified and characterized. The arsenic-induced transcriptome of C. metallidurans CH34 showed that the genes most upregulated in the presence of arsenate were all located within the ars operon, with none of the other numerous heavy metal resistance systems present in CH34 being induced. A transcriptional fusion between the luxCDABE operon and the arsR promoter/operator (P/O) region was used to confirm the in vivo induction of the ars operon by arsenite and arsenate. The arsR gene was cloned intomore » expression vectors allowing for the overexpression of the ArsR protein as either his-tagged or untagged protein. The ability of the purified ArsR proteins to bind to the ars P/O region was analyzed in vitro by gel mobility shift assays. ArsR showed an affinity almost exclusively to its own ars P/O region. Dissociation of ArsR and its P/O region was metal dependent, and based on decreasing degrees of dissociation three groups of heavy metals could be distinguished: As(III), Bi(III), Co(II), Cu(II), Ni(II); Cd(II); Pb(II) and Zn(II), while no dissociation was observed in the presence of As(V).« less

Regulation of androgen receptor and histone deacetylase 1 by Mdm2-mediated ubiquitylation.

PubMed

Gaughan, Luke; Logan, Ian R; Neal, David E; Robson, Craig N

2005-01-01

The androgen receptor (AR) is a member of the nuclear hormone receptor family of transcription factors and plays a critical role in regulating the expression of genes involved in androgen-dependent and -independent tumour formation. Regulation of the AR is achieved by alternate binding of either histone acetyltransferase (HAT)-containing co-activator proteins, or histone deacetylase 1 (HDAC1). Factors that control AR stability may also constitute an important regulatory mechanism, a notion that has been confirmed with the finding that the AR is a direct target for Mdm2-mediated ubiquitylation and proteolysis. Using chromatin immunoprecipitation (ChIP) and re-ChIP analyses, we show that Mdm2 associates with AR and HDAC1 at the active androgen-responsive PSA promoter in LNCaP prostate cancer cells. Furthermore, we demonstrate that Mdm2-mediated modification of AR and HDAC1 catalyses protein destabilization and attenuates AR sactivity, suggesting that ubiquitylation of the AR and HDAC1 may constitute an additional mechanism for regulating AR function. We also show that HDAC1 and Mdm2 function co-operatively to reduce AR-mediated transcription that is attenuated by the HAT activity of the AR co-activator Tip60, suggesting interplay between acetylation status and receptor ubiquitylation in AR regulation. In all, our data indicates a novel role for Mdm2 in regulating components of the AR transcriptosome.

Cross Sections of the 36Ar(d,α)34mCl, 40Ar(d,α)38Cl and 40Ar(d,p)41Ar Nuclear Reactions below 8.4 MeV

PubMed Central

Engle, J W; Severin, G W; Barnhart, T E; Knutson, L D; Nickles, R J

2011-01-01

We have measured the cross section for production of the medically interesting isotope 34mCl, along with 38Cl and 41Ar, using deuteron bombardments of 36Ar and 40Ar below 8.4 MeV. ALICE/ASH analytical codes were employed to determine the shape of nuclear excitation functions, and experiments were performed using the University of Wisconsin tandem electrostatic accelerator to irradiate thin targets of argon gas. PMID:22041299

Astronomical calibration of 40Ar/39Ar reference minerals using high-precision, multi-collector (ARGUSVI) mass spectrometry

NASA Astrophysics Data System (ADS)

Phillips, D.; Matchan, E. L.; Honda, M.; Kuiper, K. F.

2017-01-01

The new generation of multi-collector mass spectrometers (e.g. ARGUSVI) permit ultra-high precision (<0.1%) 40Ar/39Ar geochronology of rocks and minerals. At the same time, the 40Ar/39Ar method is limited by relatively large uncertainties (>1%) in 40K decay constants and the ages of natural reference minerals that form the basis of the technique. For example, reported ages for widely used 40Ar/39Ar reference materials, such as the ca. 28 Ma Fish Canyon Tuff sanidine (FCTs) and the ca. 1.2 Ma Alder Creek Rhyolite sanidine (ACRs), vary by >1%. Recent attempts to independently calibrate these reference minerals have focused on K-Ar analyses of the same minerals and inter-comparisons with astronomically tuned tephras in sedimentary sequences and U-Pb zircon ages from volcanic rocks. Most of these studies used older generation (effectively single-collector) mass spectrometers that employed peak-jumping analytical methods to acquire 40Ar/39Ar data. In this study, we reassess the inter-calibration and ages of commonly used 40Ar/39Ar reference minerals Fish Canyon Tuff sanidine (FCTs), Alder Creek Rhyolite sanidine (ACRs) and Mount Dromedary biotite (MD2b; equivalent to GA-1550 biotite), relative to the astronomically tuned age of A1 Tephra sanidine (A1Ts), Faneromeni section, Crete (Rivera et al., 2011), using a multi-collector ARGUSVI mass spectrometer. These analyses confirm the exceptional precision capability (<0.1%) of this system, compared to most previous studies. All sanidine samples (FCTs, ACRs and A1Ts) exhibit discordant 40Ar/39Ar step-heating spectra, with generally monotonically increasing ages (∼1% gradients). The similarity in these patterns, mass-dependent fractionation modeling, and results from step-crushing experiments on FCTs, which yield younger apparent ages, suggest that the discordance may be due to a combination of recoil loss and redistribution of 39ArK and isotope mass fractionation. In contrast to our previous inferences, these results imply that the sanidine samples are suitable 40Ar/39Ar reference materials, provided appropriate corrections are included for differential recoil loss of 39ArK and contributions from xenocrysts/antecrysts can be resolved. Relative to an age of 6.943 ± 0.005 Ma for A1Ts, we calculate astronomically tuned ages for FCTs, ACRs and MD2b of 28.126 ± 0.019 (0.066%) Ma, 1.18144 ± 0.00068 (0.058%) Ma and 99.125 ± 0.076 (0.077%) Ma, respectively (95% internal errors). These results are consistent with recent 238U/206Pb age data from these localities, but are marginally younger (∼0.2%) than previous 40Ar/39Ar ages inter-calibrated with astronomically tuned tephra from the Mediterranean, and distinctly younger (0.6%) than results optimized against a broad array of 238U/206Pb zircon ages. Consideration of published and assumed recoil loss 39ArK proportions (0.18-0.40%), yields recoil-corrected age estimates of 28.187 ± 0.019 Ma, 1.18404 ± 0.00068 Ma and 99.204 ± 0.076 Ma, respectively. This comparison indicates inherent uncertainties of >0.1% in the 40Ar/39Ar ages of reference minerals without consideration of recoil artefacts, thus limiting the benefits of high precision multi-collector analyses. Significant improvement to the accuracy of the 40Ar/39Ar method (<0.1%) will require further inter-laboratory 40Ar/39Ar studies utilizing multi-collector mass spectrometry, additional constraints on recoil 39ArK loss from reference minerals, further resolution of discrepancies between astronomically tuned sedimentary successions and refinement of the 238U/206Pb zircon age cross-calibration approach.

Risk Factors for Allergic Rhinitis in Costa Rican Children with Asthma

PubMed Central

Bunyavanich, Supinda; Soto-Quiros, Manuel E.; Avila, Lydiana; Laskey, Daniel; Senter, Jody M.; Celedón, Juan C.

2009-01-01

Background Risk factors for allergic rhinitis (AR) in asthmatics are likely distinct from those for AR or asthma alone. We sought to identify clinical and environmental risk factors for AR in children with asthma. Methods We performed a cross-sectional study of 616 Costa Rican children aged 6–14 years with asthma. Candidate risk factors were drawn from questionnaire data, spirometry, methacholine challenge testing, skin testing, and serology. Two outcome measures, skin test reaction (STR)-positive AR and physician-diagnosed AR, were examined by logistic regression. Results STR-positive AR had high prevalence (80%) in Costa Rican children with asthma, and its independent risk factors were nasal symptoms after exposure to dust or mold, parental history of AR, older age at asthma onset, oral steroid use in the past year, eosinophilia, and positive IgEs to dust mite and cockroach. Physician-diagnosed AR had lower prevalence (27%), and its independent risk factors were nasal symptoms after pollen exposure, STR to tree pollens, a parental history of AR, inhaled steroid and short-acting β2 agonist use in the past year, household mold/mildew, and fewer older siblings. A physician’s diagnosis was only 29.5% sensitive for STR-positive AR. Conclusions Risk factors for AR in children with asthma depend on the definition of AR. Indoor allergens drive risk for STR-positive AR. Outdoor allergens and home environmental conditions are risk factors for physician-diagnosed AR. We propose that children with asthma in Costa Rica and other Latin American nations undergo limited skin testing or specific IgE measurements to reduce the current under-diagnosis of AR. PMID:19796208

Structural basis for cyclization specificity of two Azotobacter type III polyketide synthases: a single amino acid substitution reverses their cyclization specificity.

PubMed

Satou, Ryutaro; Miyanaga, Akimasa; Ozawa, Hiroki; Funa, Nobutaka; Katsuyama, Yohei; Miyazono, Ken-ichi; Tanokura, Masaru; Ohnishi, Yasuo; Horinouchi, Sueharu

2013-11-22

Type III polyketide synthases (PKSs) show diverse cyclization specificity. We previously characterized two Azotobacter type III PKSs (ArsB and ArsC) with different cyclization specificity. ArsB and ArsC, which share a high sequence identity (71%), produce alkylresorcinols and alkylpyrones through aldol condensation and lactonization of the same polyketomethylene intermediate, respectively. Here we identified a key amino acid residue for the cyclization specificity of each enzyme by site-directed mutagenesis. Trp-281 of ArsB corresponded to Gly-284 of ArsC in the amino acid sequence alignment. The ArsB W281G mutant synthesized alkylpyrone but not alkylresorcinol. In contrast, the ArsC G284W mutant synthesized alkylresorcinol with a small amount of alkylpyrone. These results indicate that this amino acid residue (Trp-281 of ArsB or Gly-284 of ArsC) should occupy a critical position for the cyclization specificity of each enzyme. We then determined crystal structures of the wild-type and G284W ArsC proteins at resolutions of 1.76 and 1.99 Å, respectively. Comparison of these two ArsC structures indicates that the G284W substitution brings a steric wall to the active site cavity, resulting in a significant reduction of the cavity volume. We postulate that the polyketomethylene intermediate can be folded to a suitable form for aldol condensation only in such a relatively narrow cavity of ArsC G284W (and presumably ArsB). This is the first report on the alteration of cyclization specificity from lactonization to aldol condensation for a type III PKS. The ArsC G284W structure is significant as it is the first reported structure of a microbial resorcinol synthase.

Cell-autonomous intracellular androgen receptor signaling drives the growth of human prostate cancer initiating cells.

PubMed

Vander Griend, Donald J; D'Antonio, Jason; Gurel, Bora; Antony, Lizamma; Demarzo, Angelo M; Isaacs, John T

2010-01-01

The lethality of prostate cancer is due to the continuous growth of cancer initiating cells (CICs) which are often stimulated by androgen receptor (AR) signaling. However, the underlying molecular mechanism(s) for such AR-mediated growth stimulation are not fully understood. Such mechanisms may involve cancer cell-dependent induction of tumor stromal cells to produce paracrine growth factors or could involve cancer cell autonomous autocrine and/or intracellular AR signaling pathways. We utilized clinical samples, animal models and a series of AR-positive human prostate cancer cell lines to evaluate AR-mediated growth stimulation of prostate CICs. The present studies document that stromal AR expression is not required for prostate cancer growth, since tumor stroma surrounding AR-positive human prostate cancer metastases (N = 127) are characteristically AR-negative. This lack of a requirement for AR expression in tumor stromal cells is also documented by the fact that human AR-positive prostate cancer cells grow equally well when xenografted in wild-type versus AR-null nude mice. AR-dependent growth stimulation was documented to involve secretion, extracellular binding, and signaling by autocrine growth factors. Orthotopic xenograft animal studies documented that the cellautonomous autocrine growth factors which stimulate prostate CIC growth are not the andromedins secreted by normal prostate stromal cells. Such cell autonomous and extracellular autocrine signaling is necessary but not sufficient for the optimal growth of prostate CICs based upon the response to anti-androgen plus/or minus preconditioned media. AR-induced growth stimulation of human prostate CICs requires AR-dependent intracellular pathways. The identification of such AR-dependent intracellular pathways offers new leads for the development of effective therapies for prostate cancer. (c) 2009 Wiley-Liss, Inc.

Advancements in cosmogenic 38Ar exposure dating of terrestrial rocks

NASA Astrophysics Data System (ADS)

Oostingh, K. F.; Jourdan, F.; Danišík, M.; Evans, N. J.

2017-11-01

Cosmogenic exposure dating of Ca-rich minerals using 38Ar on terrestrial rocks could be a valuable new dating tool to determine timescales of geological surface processes on Earth. Here, we show that advancement in analytical precision, using the new generation multi-collector ARGUSVI mass spectrometer on irradiated pyroxene and apatite samples, allows determination of cosmogenic 38Ar abundances above background values, as well as discrimination of 38Ar/36Ar ratios (1σ absolute precision of ±0.3%) from the non-cosmogenic background value. Four statistically significant cosmochron (38Ar/36Ar vs37Ar/36Ar) diagrams could be constructed for southeast Australian pyroxene samples from the Mt Elephant scoria cone for which a combined apparent exposure age of 313 ± 179 ka (2σ) was obtained when using a 38Ar production rate (Ca) of 250 atoms /g Ca/ yr. This exposure age overlaps within error with the known 40Ar/39Ar eruption age of 184 ± 15 ka (2σ). Although apatite shows much larger 38Ar abundances than pyroxene, our modelling and analyses of unirradiated apatite suggest that apatite suffers from both natural and reactor-derived chlorogenic as well as natural nucleogenic contributions of 38Ar. Hence, we suggest that cosmogenic 38Ar exposure dating on irradiated Ca-rich (and eventually K-rich), but Cl-free, terrestrial minerals is a potential valuable and accessible tool to determine geological surface processes on timescales of a few Ma. Calculations show that with the new generation multi-collector mass spectrometers an analytical uncertainty better than 5% (2σ) can be achieved on samples with expected exposure ages of >4 Ma.

Fulvestrant (ICI 182,780) down-regulates androgen receptor expression and diminishes androgenic responses in LNCaP human prostate cancer cells.

PubMed

Bhattacharyya, Rumi S; Krishnan, Aruna V; Swami, Srilatha; Feldman, David

2006-06-01

The androgen receptor (AR) plays a key role in the development and progression of prostate cancer. Targeting the AR for down-regulation would be a useful strategy for treating prostate cancer, especially hormone-refractory or androgen-independent prostate cancer. In the present study, we showed that the antiestrogen fulvestrant [ICI 182,780 (ICI)] effectively suppressed AR expression in several human prostate cancer cells, including androgen-independent cells. In LNCaP cells, ICI (10 micromol/L) treatment decreased AR mRNA expression by 43% after 24 hours and AR protein expression by approximately 50% after 48 hours. We further examined the mechanism of AR down-regulation by ICI in LNCaP cells. ICI did not bind to the T877A-mutant AR present in the LNCaP cells nor did it promote proteasomal degradation of the AR. ICI did not affect AR mRNA or protein half-life. However, ICI decreased the activity of an AR promoter-luciferase reporter plasmid transfected into LNCaP cells, suggesting a direct repression of AR gene transcription. As a result of AR down-regulation by ICI, androgen induction of prostate-specific antigen mRNA and protein expression were substantially attenuated. Importantly, LNCaP cell proliferation was significantly inhibited by ICI treatment. Following 6 days of ICI treatment, a 70% growth inhibition was seen in androgen-stimulated LNCaP cells. These data show that the antiestrogen ICI is a potent AR down-regulator that causes significant inhibition of prostate cancer cell growth. Our study suggests that AR down-regulation by ICI would be an effective strategy for the treatment of all prostate cancer, especially AR-dependent androgen-independent prostate cancer.

Probing Subsurface Flows in NOAA Active Region 12192: Comparison with NOAA 10486

NASA Astrophysics Data System (ADS)

Jain, Kiran; Tripathy, S. C.; Hill, F.

2017-11-01

NOAA Active Region (AR) 12192 is the biggest AR observed in solar cycle 24 so far. This was a long-lived AR that survived for four Carrington rotations (CRs) and exhibited several unusual phenomena. We measure the horizontal subsurface flows in this AR in multiple rotations using the ring-diagram technique of local helioseismology and the Global Oscillation Network Group (GONG+) Dopplergrams, and we investigate how different was the plasma flow in AR 12192 from that in AR 10486. Both regions produced several high M- and X-class flares, but they had different coronal mass ejection (CME) productivity. Our analysis suggests that these ARs had unusually large horizontal flow amplitude with distinctly different directions. While meridional flow in AR 12192 was poleward that supports the flux transport to poles, it was equatorward in AR 10486. Furthermore, there was a sudden increase in the magnitude of estimated zonal flow in shallow layers in AR 12192 during the X3.1 flare; however, it reversed direction in AR 10486 with the X17.2 flare. These flow patterns produced strong twists in horizontal velocity with depth in AR 10486 that persisted throughout the disk passage, as opposed to AR 12192, which produced a twist only after the eruption of the X3.1 flare that disappeared soon after. Our study indicates that the sunspot rotation combined with the reorganization of magnetic field in AR 10486 was not sufficient to decrease the flow energy even after several large flares that might have triggered CMEs. Furthermore, in the absence of sunspot rotation in AR 12192, this reorganization of magnetic field contributed significantly to the substantial release of flow energy after the X3.1 flare.

Skp2 regulates androgen receptor through ubiquitin-mediated degradation independent of Akt/mTOR pathways in prostate cancer.

PubMed

Li, Bo; Lu, Wenfu; Yang, Qing; Yu, Xiuping; Matusik, Robert J; Chen, Zhenbang

2014-04-01

The intervention of advanced prostate cancer (PCa) in patients has been commonly depending on androgen deprivation therapy. Despite of tremendous research efforts, however, molecular mechanisms on AR regulation remain poorly understood, particularly for castration resistant prostate cancer (CRPC). Targeting AR and associated factors is considered an effective strategy in PCa treatment. Human prostate cancer cells were used in this study. Manipulations of Skp2 expression were achieved by Skp2 shRNA/siRNA or overexpression of plasmids. Dual luciferase reporter assay was applied for AR activity assessment. Western blot, ubiquitination assay, immunoprecipitation, and immunofluorescence were applied to detect the proteins. Our results demonstrated that Skp2 directly involves the regulation of AR expression through ubiquitination-mediated degradation. Skp2 interacted with AR protein in PCa cells, and enforced expression of Skp2 resulted in a decreased level and activity of AR. By contrast, Skp2 knockdown increased the protein accumulation and activity of AR. Importantly, changes of AR contributed by Skp2 led to subsequent alterations of PSA level in PCa cells. AR ubiquitination was significantly increased upon Skp2 overexpression but greatly reduced upon Skp2 knockdown. AR mutant at K847R abrogated Skp2-mediated ubiquitination of AR. NVP-BEZ235, a dual PI3K/mTOR inhibitor, remarkably inhibited Skp2 level with a striking elevation of AR. The results indicate that Skp2 is an E3 ligase for proteasome-dependent AR degradation, and K847 on AR is the recognition site for Skp2-mediated ubiquitination. Our findings reveal an essential role of Skp2 in AR signaling. © 2013 Wiley Periodicals, Inc.

Identification of Novel Transplantable GPCR Recycling Motif for Drug Discovery

PubMed Central

Nooh, Mohammed M.; Mancarella, Salvatore; Bahouth, Suleiman W.

2016-01-01

β1-adrenergic receptor (β1-AR) agonists and antagonists are widely used in the treatment of major cardiovascular diseases such as heart failure and hypertension. The β1-AR like other G protein-couple receptors (GPCR) is endocytosed in response to intense agonist activation. Recycling of the agonist-internalized β1-AR is dependent on its carboxy-terminal type-1 PSD-95/DLG/ZO1 (PDZ) and on phospho-serine312 in the third intracellular loop of the β1-AR. Progressive elongation of the β1-AR at its C-tail inactivated the PDZ-biding domain and inhibited the recycling of the β1-AR. However, fusing a twenty amino acid peptide derived from the multiple cloning region of the mammalian expression vector pCDNA3 to the C-tail of the β1-AR (β1-AR[+20]) produced a chimeric β1-AR that recycled rapidly and efficiently. The β1-AR[+20] recycled in a type-1 PDZ and phospho-Ser312-independent manner, indicating that this peptide provided a general GPCR recycling signal. Fusing the enhanced yellow fluorescent protein (EYFP) down-stream of β1-AR[+20] generated a β1-AR-EYFP chimera that was expressed on the membrane and recycled efficiently after agonist-induced internalization. This construct trafficked in a PDZ-SNX27/retromer-independent manner. We also fused EYFP to the N-terminus of the β1-AR to created EYFP-WT β1-AR. This construct recycled in PDZ and SNX27/retromer dependent manner. These β1-AR-EYFP constructs would be useful for high throughput screening (HTS) programs to identify new entities that would interfere with the recycling of agonist internalized GPCR that traffic in PDZ-dependent vs. PDZ-independent roadmaps. PMID:27645110

Differentially methylated genes and androgen receptor re-expression in small cell prostate carcinomas.

PubMed

Kleb, Brittany; Estécio, Marcos R H; Zhang, Jiexin; Tzelepi, Vassiliki; Chung, Woonbok; Jelinek, Jaroslav; Navone, Nora M; Tahir, Salahaldin; Marquez, Victor E; Issa, Jean-Pierre; Maity, Sankar; Aparicio, Ana

2016-03-03

Small cell prostate carcinoma (SCPC) morphology is rare at initial diagnosis but often emerges during prostate cancer progression and portends a dismal prognosis. It does not express androgen receptor (AR) or respond to hormonal therapies. Clinically applicable markers for its early detection and treatment with effective chemotherapy are needed. Our studies in patient tumor-derived xenografts (PDX) revealed that AR-negative SCPC (AR(-)SCPC) expresses neural development genes instead of the prostate luminal epithelial genes characteristic of AR-positive castration-resistant adenocarcinomas (AR(+)ADENO). We hypothesized that the differences in cellular lineage programs are reflected in distinct epigenetic profiles. To address this hypothesis, we compared the DNA methylation profiles of AR(-) and AR(+) PDX using methylated CpG island amplification and microarray (MCAM) analysis and identified a set of differentially methylated promoters, validated in PDX and corresponding donor patient samples. We used the Illumina 450K platform to examine additional regions of the genome and the correlation between the DNA methylation profiles of the PDX and their corresponding patient tumors. Struck by the low frequency of AR promoter methylation in the AR(-)SCPC, we investigated this region's specific histone modification patterns by chromatin immunoprecipitation. We found that the AR promoter was enriched in silencing histone modifications (H3K27me3 and H3K9me2) and that EZH2 inhibition with 3-deazaneplanocin A (DZNep) resulted in AR expression and growth inhibition in AR(-)SCPC cell lines. We conclude that the epigenome of AR(-) is distinct from that of AR(+) castration-resistant prostate carcinomas, and that the AR(-) phenotype can be reversed with epigenetic drugs.

Objective age of acquisition norms for a set of 286 words in Russian: relationships with other psycholinguistic variables.

PubMed

Grigoriev, Andrei; Oshhepkov, Ivan

2013-12-01

Normative data on the objective age of acquisition (AoA) for 286 Russian words are presented in this article. In addition, correlations between the objective AoA and subjective ratings, name agreement, picture name agreement, imageability, familiarity, word frequency, and word length are provided, as are correlations between the objective AoA and two measures of exemplar dominance (exemplar generation frequency and the number of times an exemplar was named first). The correlations between the aforementioned variables are generally consistent with the correlations reported in other normative studies. The objective AoA data are highly correlated with the subjective AoA ratings, whereas the correlations between the objective AoA and other psycholinguistic variables are moderate. The correlations between the objective AoA of Russian words and similar data for other languages are moderately high. The complete word norms may be downloaded from supplementary material.

Age of acquisition predicts naming and lexical-decision performance above and beyond 22 other predictor variables: an analysis of 2,342 words.

PubMed

Cortese, Michael J; Khanna, Maya M

2007-08-01

Age of acquisition (AoA) ratings were obtained and were used in hierarchical regression analyses to predict naming and lexical-decision performance for 2,342 words (from Balota, Cortese, Sergent-Marshall, Spieler, & Yap, 2004). In the analyses, AoA was included in addition to the set of predictors used by Balota et al. (2004). AoA significantly predicted latency performance on both tasks above and beyond the standard predictor set. However, AoA was more strongly related to lexical-decision performance than to naming performance. Finally, the previously reported effect of imageability on naming latencies by Balota et al. was not significant with AoA included as a factor. These results are consistent with the idea either that AoA has a semantic/lexical locus or that AoA effects emerge primarily in situations in which the input-output mapping is arbitrary.

In-situ Ar isotope, 40Ar/39Ar analysis and mineral chemistry of nosean in the phonolite from Olbrück volcano, East Eifel volcanic field, Germany: Implication for the source of excess 40Ar

NASA Astrophysics Data System (ADS)

Sudo, Masafumi; Altenberger, Uwe; Günter, Christina

2014-05-01

Since the report by Lippolt et al. (1990), hauyne and nosean phenocrysts in certain phonolites from the northwest in the Quaternary East Eifel volcanic field in Germany were known to contain significant amounts of excess 40Ar, thus, show apparent older ages than the other minerals. However, its petrographic meaning have not been well known. Meanwhile, Sumino et al. (2008) has identified the source of the excess 40Ar in the plagioclase phenocrysts from the historic Unzen dacite lava as the melt inclusions in the zones parallely developed to the plagioclase rim by in-situ laser Ar isotope analysis. In order to obtain eruption ages of very young volcanoes as like Quaternary Eifel volcanic field by the K-Ar system, it is quite essential to know about the location of excess 40Ar in volcanic rocks. We have collected phonolites from the Olbrück volcano in East Eifel and investigated its petrography and mineral chemistry and also performed in-situ Ar isotope analyses of unirradiated rock section sample and also in-situ 40Ar/39Ar analysis of neutron irradiated section sample with the UV pulse laser (wavelength 266 nm) and 40Ar/39Ar analytical system of the University of Potsdam. Petrographically, nosean contained fine melt and/or gas inclusions of less than 5 micrometer, which mostly distribute linearly and are relatively enriched in chlorine than the areas without inclusions. Solid inclusions of similar sizes contain CaO and fluorine. In nosean, typically around 5 wt% of sulfur is contained. The 40Ar/39Ar dating was also performed to leucite, sanidine and groundmass in the same section for comparison of those ages with that of nosean. In each analysis, 200 micrometer of beam size was used for making a pit with depth of up to 300 micrometer by laser ablation. As our 40Ar/39Ar analyses were conducted one and half year after the neutron irradiation, thus, short lived 37Ar derived from Ca had decayed very much, we measured Ca and K contents in nosean by SEM-EDS then applied their Ca/K ratios to the Ar analytical results. The in-situ Ar isotopic analysis of nosean and leucite show clearly the different slope of isochron and implied apparent older age for the nosean. The in-situ 40Ar/39Ar analysis of nosean yields three various ages, from 6.86 ± 2.77 Ma to 41.57 ± 11.58 Ma, but clearly older than those of the other minerals and groundmass. However, it was difficult to analyze and compare the 40Ar/39Ar ages between different areas with or without inclusions by the UV-laser because of its less spatial resolution, therefore, was difficult to understand the correlation between ages and the presence of inclusions. Considering the enriched contents of S and Cl in nosean, the excess 40Ar could be derived from the common volatile component separated from the magma which provided S and Cl then be trapped in nosean during or after the formation of nosean. References: Lippolt, H. J., M. Troesch and J. C. Hess (1990) Earth Planet. Sci. Lett., 101, 19-33 Sumino, H., K. Ikehata, A. Shimizu, K. Nagao and S. Nakada (2008) J. Volcanol. Geotherm. Res., 175, 189-207

Ar-39-Ar-40 Ages of Euerites and the Thermal History of Asteroid 4-Vesta

NASA Technical Reports Server (NTRS)

Bogard, Donald D.; Garrison, Daniel H.

2002-01-01

Eucrite meteorites are igneous rocks that derive from a large asteroid, probably 4 Vesta. Prior studies have shown that after eucrites formed, most were subsequently metamorphosed to temperatures up to equal to or greater than 800 C, and much later many were brecciated and heated by large impacts into the parent body surface. The uncommon basaltic, unbrecciated eucrites also formed near the surface but presumably escaped later brecciation, whereas the cumulate eucrites formed at depth where metamorphism may have persisted for a considerable period. To further understand the complex HED parent body thermal history, we determined new Ar-39-Ar-40 ages for nine eucrites classified as basaltic but unbrecciated, six eucrites classified as cumulate, and several basaltic-brecciated eucrites. Relatively precise Ar-Ar ages of two cumulate eucrites (Moama and EET87520) and four unbrecciated eucrites give a tight cluster at 4.48 +/1 0.01 Gyr. Ar-Ar ages of six additional unbrecciated eucrites are consistent with this age, within their larger age uncertainties. In contrast, available literature data on Pb-Pb isochron ages of four cumulate eucrites and one unbrecciated eucrite vary over 4.4-4.515 Gyr, and Sm-147 - Nd-143 isochron ages of four cumulate and three unbrecciated eucrites vary over 4.41-4.55 Gyr. Similar Ar-Ar ages for cumulate and unbrecciated eucrites imply that cumulate eucrites do not have a younger formation age than basaltic eucrites, as previously proposed. Rather, we suggest that these cumulate and unbrecciated eucrites resided at depth where parent body temperatures were sufficiently high to cause the K-Ar and some other chronometers to remain open diffusion systems. From the strong clustering of Ar-Ar ages at approximately 4.48 Gyr, we propose that these meteorites were excavated from depth in a single large impact event approximately 4.48 Gyr ago, which quickly cooled the samples and started the K-Ar chronometer. A large (approximately 460 km) crater postulated to exist on Vesta may be the source of these eucrites and of many smaller asteroids thought to be spectrally or physically associated with Vesta. Some Pb-Pb and Sm-Nd ages of cumulate and unbrecciated eucrites are consistent with the 4.48 Gyr Ar-Ar age, and the few older Pb-Pb and Sm-Nd ages may reflect isotopic closure prior to the large cratering event. One cumulate eucrite gives an Ar-Ar age of 4.25 Gyr; three additional cumulate eucrites give Ar-Ar ages of 3.4-3.7 Gyr; and two unbrecciated eucrites give Ar-Ar ages of approximately 3.55 Gyr. We attribute these younger ages to later impact heating. In addition, we find Ar-Ar impact-reset ages of several brecciated eucrites and eucritic clasts in howardites to fall in the range of 3.5-4.1 Gyr. Among these, Piplia Kalan, the first eucrite to show evidence for extinct 26 Al, was strongly impact heated approximately3.5 Gyr ago. When these data are combined with eucrite Ar-Ar ages in the literature, they confirm the previous suggestion that several large impact heating events occurred on Vesta over the time period approximately 4.1-3.4 Gyr ago. The onset of major impact heating may have occurred at similar times for both Vesta and the Moon, but impact heating appears to have persisted to a somewhat later time on Vesta compared to the Moon.

AATA AOS evaluation : transfer and on-time performance study : before and after AOS implementation, October 1996 - May 1999

DOT National Transportation Integrated Search

1999-01-01

This study develops, using data before AOS in 1996 and 1997 and after AOS in 1998 and 1999, implementation data on AATAs on-time performance and vehicle-to-vehicle timing of transfers at four major transfer location. Systematic evaluation of on-ti...

The Subaru Coronagraphic Extreme AO Project: Progress and Upgrades

NASA Astrophysics Data System (ADS)

Jovanovic, Nemanja; Martinache, F.; Guyon, O.; Clergeon, C.; Garrel, V.

2013-01-01

The Subaru Coronagraphic Extreme AO (SCExAO) instrument consists of a high performance Phase Induced Amplitude Apodisation (PIAA) coronagraph combined with an extreme Adaptive Optics (AO) system operating in the near-infrared (H band). The extreme AO system driven by the 2000 element deformable mirror will allow for Strehl ratios>90% to be achieved in the H-band when it goes closed loop. This makes the SCExAO instrument a powerful platform for high contrast imaging down to angular separations of the order of 1 λ/D. In this paper we report on the recent progress in regards to the development of the instrument, which includes the addition of a visible bench that makes use of the light at shorter wavelengths not currently utilized by SCExAO and closing the loop on the tip/tilt wavefront sensor. We will also discuss two exciting guest instruments which will expand the capabilities of SCExAO over the next few years; namely CHARIS which is a integral field spectrograph as well as VAMPIRES, a visible aperture masking experiment based on polarimetric analysis of circumstellar disks.

Acridine orange as a biosensitive photovoltaic material

NASA Astrophysics Data System (ADS)

Sharifi, Faranak; Bauld, Reg; Fanchini, Giovanni

2013-10-01

Acridine orange (AO), a biosensitive molecule that is customarily used for labeling nucleic acids including DNA and RNA, is here investigated as a cost effective, water soluble, and photoactive material for the fabrication of potentially biosensitive organic photovoltaics. The electronic energy levels of AO are determined using Kelvin Probe Force Microscopy (KPFM) and UV-Visible spectroscopy. The effect of anticrystallization agents, as well as low-temperature annealing, on the work function of AO is investigated: amorphous AO films are shown to possess a significantly higher work function than microcrystalline AO films and the work function also increases by annealing. Photo-induced processes in AO films are investigated by considering the changes of the KPFM signal under illumination. We demonstrate that acridine orange is able to photogenerate electron-hole pairs at rates comparable to the most commonly used solar-grade photovoltaic materials, including polythiophenes. In addition, the effect of the morphology of different types of AO thin films spun from different solvents is studied in bilayer photovoltaic devices fabricated from stacks of AO and phenyl-C61-butyric acid methyl ester thin films.

Discovery and analysis of an active long terminal repeat-retrotransposable element in Aspergillus oryzae.

PubMed

Jie Jin, Feng; Hara, Seiichi; Sato, Atsushi; Koyama, Yasuji

2014-01-01

Wild-type Aspergillus oryzae RIB40 contains two copies of the AO090005001597 gene. We previously constructed A. oryzae RIB40 strain, RKuAF8B, with multiple chromosomal deletions, in which the AO090005001597 copy number was found to be increased significantly. Sequence analysis indicated that AO090005001597 is part of a putative 6,000-bp retrotransposable element, flanked by two long terminal repeats (LTRs) of 669 bp, with characteristics of retroviruses and retrotransposons, and thus designated AoLTR (A. oryzae LTR-retrotransposable element). AoLTR comprised putative reverse transcriptase, RNase H, and integrase domains. The deduced amino acid sequence alignment of AoLTR showed 94% overall identity with AFLAV, an A. flavus Tf1/sushi retrotransposon. Quantitative real-time RT-PCR showed that AoLTR gene expression was significantly increased in the RKuAF8B, in accordance with the increased copy number. Inverse PCR indicated that the full-length retrotransposable element was randomly integrated into multiple genomic locations. However, no obvious phenotypic changes were associated with the increased AoLTR gene copy number.

Determination of the LD50 of acridine orange via intravenous administration in mice in preparation for clinical application to cancer therapy.

PubMed

Nakamura, Tomoki; Kusuzaki, Katsuyuki; Matsubara, Takao; Matsumine, Akihiko; Asanuma, Kunihiro; Satonaka, Haruhiko; Uchida, Atsumasa; Sudo, Akihiro

2014-01-01

We undertook studies to determine the lethal dose 50 (LD50) of acridine orange (AO) using mice in order to confirm the safety of intravenous administration of AO. We used 40 mice and AO was administered once intravenously. General behavior and mortality were continuously observed for 14 days. At the end of the experiment, all animals were sacrificed for subsequent studies. The LD50 for AO in male and female mice was determined to be 32 mg/kg and 36 mg/kg, respectively. Histopathological abnormalities were observed in only one mouse which died three days after the administration of AO. The other nine mice which died immediately after the administration of AO had no pathological findings in major organs. The clinical use of AO can be kept at 1.0 mg/kg or below and, therefore, intravenous administration of AO might be safe for use as cancer therapy. Copyright © 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

The Role of Tropical Moisture Export on Atmospheric River Intensity

NASA Astrophysics Data System (ADS)

Hu, H.; Dominguez, F.

2017-12-01

There has been considerable debate regarding the relative importance of tropical moisture export (TME) and local evapotranspiration on the total moisture associated with atmospheric rivers (ARs). While case studies have related TME signatures with some extreme ARs affecting the U.S. West Coast, no robust relationship between them has been established. In this study, our goal is to quantify the role of TME on AR-related precipitation intensity. From a total of 244 identified ARs that have affected the U.S. Northwest Coast in winters of 1979 to 2016, we are focusing on a subset of 37 ARs with TME features (TME-ARs). These TME-ARs are identified using vapor-weighted wind vectors to back-track ARs 3 days before they reach the Northwest Coast. If their back-trajectories reach latitudes south of 25°N, the AR is labeled as a TME-AR. Compared with the rest of ARs without TME features, TME-ARs are associated with higher vertically integrated vapor transport (IVT) and greater precipitation intensity. At the same time, they also span a wide range of precipitation intensity and thus allow an examination of the TME effect on a full spectrum of AR intensity. To quantify the effect of TME on AR-related precipitable water and precipitation, we simulate the 37 TME-ARs using the tool of water vapor tracer in WRF model (WRF-WVT) to tag the moisture evaporated from latitudes lower than 25°N. Consequently, the total moisture can be separated into that from TME and that from midlatitude evaporation. Our analysis shows that as the AR gets stronger in terms of total precipitable water and precipitation, there is a significant increase of the contribution from TME to total precipitable water. Similarly, the contribution from TME to AR precipitation also increases but with a weaker correlation. Both of them suggest an increasing role of TME on more intense ARs. We also find a higher efficiency of TME moisture being converted to precipitation than that from local sources. However, this efficiency decreases when AR precipitation intensity increases, suggesting an increasing role of local (midlatitude) evaporation in generating precipitation. This is probably due to the thermodynamic changes associated with TME, which enhances local circulation and thus local moisture recycling.

Androgen receptor status is highly conserved during tumor progression of breast cancer.

PubMed

Grogg, André; Trippel, Mafalda; Pfaltz, Katrin; Lädrach, Claudia; Droeser, Raoul A; Cihoric, Nikola; Salhia, Bodour; Zweifel, Martin; Tapia, Coya

2015-11-09

With the advent of new and more efficient anti-androgen drugs targeting androgen receptor (AR) in breast cancer (BC) is becoming an increasingly important area of investigation. This would potentially be most useful in triple negative BC (TNBC), where better therapies are still needed. The assessment of AR status is generally performed on the primary tumor even if the tumor has already metastasized. Very little is known regarding discrepancies of AR status during tumor progression. To determine the prevalence of AR positivity, with emphasis on TNBCs, and to investigate AR status during tumor progression, we evaluated a large series of primary BCs and matching metastases and recurrences. AR status was performed on 356 primary BCs, 135 matching metastases, and 12 recurrences using a next-generation Tissue Microarray (ngTMA). A commercially available AR antibody was used to determine AR-status by immunohistochemistry. AR positivity was defined as any nuclear staining in tumor cells ≥1 %. AR expression was correlated with pathological tumor features of the primary tumor. Additionally, the concordance rate of AR expression between the different tumor sites was determined. AR status was positive in: 87 % (307/353) of primary tumors, 86.1 % (105/122) of metastases, and in 66.7 % (8/12) of recurrences. TNBC tested positive in 11.4 %, (4/35) of BCs. A discrepant result was seen in 4.3 % (5/117) of primary BC and matching lymph node (LN) metastases. Three AR negative primary BCs were positive in the matching LN metastasis, representing 17.6 % of all negative BCs with lymph node metastases (3/17). Two AR positive primary BCs were negative in the matching LN metastasis, representing 2.0 % of all AR positive BCs with LN metastases (2/100). No discrepancies were seen between primary BC and distant metastases or recurrence (n = 17). Most primary (87 %) and metastasized (86.1 %) BCs are AR positive including a significant fraction of TNBCs (11.4 %). Further, AR status is highly conserved during tumor progression and a change only occurs in a small fraction (4.1 %). Our study supports the notion that targeting AR could be effective for many BC patients and that re-testing of AR status in formerly negative or mixed type BC's is recommended.

32 CFR 552.107 - References.

Code of Federal Regulations, 2010 CFR

2010-07-01

... References. (a) AR 190-5 (Motor Vehicle Traffic Supervision) (b) AR 190-52 (Countering Terrorism and Other Major Disruptions on Military Reservations) (c) AR 210-7 (Commercial Solicitation on Army Installations) (d) AR 210-10 (Administration) (e) Fort Lewis Supplement 1 to AR 190-5 (Motor Vehicle Traffic...

Development of Protein Degradation Inducers of Androgen Receptor by Conjugation of Androgen Receptor Ligands and Inhibitor of Apoptosis Protein Ligands.

PubMed

Shibata, Norihito; Nagai, Katsunori; Morita, Yoko; Ujikawa, Osamu; Ohoka, Nobumichi; Hattori, Takayuki; Koyama, Ryokichi; Sano, Osamu; Imaeda, Yasuhiro; Nara, Hiroshi; Cho, Nobuo; Naito, Mikihiko

2018-01-25

Targeted protein degradation using small molecules is a novel strategy for drug development. We have developed hybrid molecules named specific and nongenetic inhibitor of apoptosis protein [IAP]-dependent protein erasers (SNIPERs) that recruit IAP ubiquitin ligases to degrade target proteins. Here, we show novel SNIPERs capable of inducing proteasomal degradation of the androgen receptor (AR). Through derivatization of the SNIPER(AR) molecule at the AR ligand and IAP ligand and linker, we developed 42a (SNIPER(AR)-51), which shows effective protein knockdown activity against AR. Consistent with the degradation of the AR protein, 42a inhibits AR-mediated gene expression and proliferation of androgen-dependent prostate cancer cells. In addition, 42a efficiently induces caspase activation and apoptosis in prostate cancer cells, which was not observed in the cells treated with AR antagonists. These results suggest that SNIPER(AR)s could be leads for an anticancer drug against prostate cancers that exhibit AR-dependent proliferation.

An Interdomain Interaction of the Androgen Receptor Is Required for Its Aggregation and Toxicity in Spinal and Bulbar Muscular Atrophy*

PubMed Central

Orr, Christopher R.; Montie, Heather L.; Liu, Yuhong; Bolzoni, Elena; Jenkins, Shannon C.; Wilson, Elizabeth M.; Joseph, James D.; McDonnell, Donald P.; Merry, Diane E.

2010-01-01

Polyglutamine expansion within the androgen receptor (AR) causes spinal and bulbar muscular atrophy (SBMA) and is associated with misfolded and aggregated species of the mutant AR. We showed previously that nuclear localization of the mutant AR was necessary but not sufficient for SBMA. Here we show that an interdomain interaction of the AR that is central to its function within the nucleus is required for AR aggregation and toxicity. Ligands that prevent the interaction between the amino-terminal FXXLF motif and carboxyl-terminal AF-2 domain (N/C interaction) prevented toxicity and AR aggregation in an SBMA cell model and rescued primary SBMA motor neurons from 5α-dihydrotestosterone-induced toxicity. Moreover, genetic mutation of the FXXLF motif prevented AR aggregation and 5α-dihydrotestosterone toxicity. Finally, selective androgen receptor modulators, which prevent the N/C interaction, ameliorated AR aggregation and toxicity while maintaining AR function, highlighting a novel therapeutic strategy to prevent the SBMA phenotype while retaining AR transcriptional function. PMID:20826791

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

PubMed

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

2016-05-16

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.

SCExAO as a precursor to an ELT exoplanet direct imaging instrument

NASA Astrophysics Data System (ADS)

Jovanovic, Nemanja; Guyon, Olivier; Martinache, Frantz; Clergeon, Christophe; Singh, Garima; Vievard, Sebastien; Kudo, Tomoyuki; Garrel, Vincent; Norris, Barnaby; Tuthill, Peter; Stewart, Paul; Huby, Elsa; Perrin, Guy; Lacour, Sylvestre

2013-12-01

The Subaru Coronagraphic Extreme AO (SCExAO) instrument consists of a high performance Phase Induced Amplitude Apodisation (PIAA) coronagraph combined with an extreme Adaptive Optics (AO) system operating in the near-infrared (H band). The extreme AO system driven by the 2000 element deformable mirror will allow for Strehl ratios>90% to be achieved in the H-band when it goes closed loop. This makes the SCExAO instrument a powerful platform for high contrast imaging down to angular separations of the order of 1 lambda/D and an ideal testbed for exploring coronagraphic techniques for ELTs. In this paper we report on the recent progress in regards to the development of the instrument, which includes the addition of a visible bench that makes use of the light at shorter wavelengths not currently utilized by SCExAO and closing the loop on the tip/tilt wavefront sensor. We will also discuss several exciting guest instruments which will expand the capabilities of SCExAO over the next few years; namely CHARIS which is a integral field spectrograph as well as VAMPIRES, a visible aperture masking experiment based on polarimetric analysis of circumstellar disks. In addition we will elucidate the unique role extreme AO systems will play in enabling high precision radial velocity spectroscopy for the detection of small companions.

MagAO: Status and on-sky performance of the Magellan adaptive optics system

NASA Astrophysics Data System (ADS)

Morzinski, Katie M.; Close, Laird M.; Males, Jared R.; Kopon, Derek; Hinz, Phil M.; Esposito, Simone; Riccardi, Armando; Puglisi, Alfio; Pinna, Enrico; Briguglio, Runa; Xompero, Marco; Quirós-Pacheco, Fernando; Bailey, Vanessa; Follette, Katherine B.; Rodigas, T. J.; Wu, Ya-Lin; Arcidiacono, Carmelo; Argomedo, Javier; Busoni, Lorenzo; Hare, Tyson; Uomoto, Alan; Weinberger, Alycia

2014-07-01

MagAO is the new adaptive optics system with visible-light and infrared science cameras, located on the 6.5-m Magellan "Clay" telescope at Las Campanas Observatory, Chile. The instrument locks on natural guide stars (NGS) from 0th to 16th R-band magnitude, measures turbulence with a modulating pyramid wavefront sensor binnable from 28×28 to 7×7 subapertures, and uses a 585-actuator adaptive secondary mirror (ASM) to provide at wavefronts to the two science cameras. MagAO is a mutated clone of the similar AO systems at the Large Binocular Telescope (LBT) at Mt. Graham, Arizona. The high-level AO loop controls up to 378 modes and operates at frame rates up to 1000 Hz. The instrument has two science cameras: VisAO operating from 0.5-1μm and Clio2 operating from 1-5 μm. MagAO was installed in 2012 and successfully completed two commissioning runs in 2012-2013. In April 2014 we had our first science run that was open to the general Magellan community. Observers from Arizona, Carnegie, Australia, Harvard, MIT, Michigan, and Chile took observations in collaboration with the MagAO instrument team. Here we describe the MagAO instrument, describe our on-sky performance, and report our status as of summer 2014.

Nitric oxide mediates alginate oligosaccharides-induced root development in wheat (Triticum aestivum L.).

PubMed

Zhang, Yunhong; Liu, Hang; Yin, Heng; Wang, Wenxia; Zhao, Xiaoming; Du, Yuguang

2013-10-01

Alginate oligosaccharides (AOS), which are marine oligosaccharides, are involved in regulating plant root growth, but the promotion mechanism for AOS remains unclear. Here, AOS (10-80 mg L(-1)) were found to induce the generation of nitric oxide (NO) in the root system of wheat (Triticum aestivum L.), which promoted the formation and elongation of wheat roots in a dose-dependent manner. NO inhibitors suggested that nitrate reductase (NR), rather than nitric oxide synthase (NOS), was essential for AOS-induced root development. Further studies confirmed that AOS-induced NO generation in wheat roots by up-regulating the gene expression and enzyme activity of NR at the post-transcriptional level. The anatomy and RT-PCR results showed that AOS accelerated the division and growth of stele cells, leading to an increase in the ratio of stele area to root transverse area. This could be inhibited by the NR inhibitor, sodium tungstate, which indicated that NO catalyzed by the NR was involved in AOS regulation of root development. Taken together, in the early stage of AOS-induced root development, NO generation was a novel mechanism by which AOS regulated plant growth. The results also showed that this marine resource could be widely used for crop development. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

Structures, bonding, and reaction chemistry of the neutral organogallium(I) compounds (GaAr)n(n = 1 or 2) (Ar = terphenyl or related ligand): an experimental investigation of Ga-Ga multiple bonding.

PubMed

Hardman, Ned J; Wright, Robert J; Phillips, Andrew D; Power, Philip P

2003-03-05

The synthesis, structure, and properties of several new organogallium(I) compounds are reported. The monovalent compounds GaAr* (Ar* = C(6)H(3)-2,6-Trip(2), Trip = C(6)H(2)-2,4,6-Pr(i)()(3), 1), GaAr# (Ar# = C(6)H(3)-2,6(Bu(t)Dipp)(2), Bu(t)Dipp = C(6)H(2)-2,6-Pr(i)(2)-4-Bu(t)(), 4), and the dimeric (GaAr')(2) (Ar' = C(6)H(3)-2,6-Dipp(2), Dipp = C(6)H(3)-2,6-Pr(i)(2), 6) were synthesized by the reaction of "GaI" with (Et(2)O)LiAr*, (Et(2)O)LiAr# (3), or (LiAr')(2). Compounds 1 and 4 were isolated as green crystals, whereas 6 was obtained as a brown-red crystalline solid. All three compounds dissolved in hydrocarbon solvents to give green solutions and almost identical UV/visible spectra. Cryoscopy of 1 and 6 showed that they were monomeric in cyclohexane. Crystals of 1 and 4 were unsuitable for X-ray crystal structure determinations, but an X-ray data set for 6 showed that it was weakly dimerized in the solid with a long Ga-Ga bond of 2.6268(7) A and a trans-bent CGaGaC core array. The 1,2-diiodo-1,2-diaryldigallane compounds [Ga(Ar*)I](2) (2), [Ga(Ar#)I](2) (5), and [Ga(Ar')I](2) (7) were isolated as byproducts of the synthesis of 1, 4, and 6. The crystal structures of 2 and 7 showed that they had planar ICGaGaCI core arrays with Ga-Ga distances near 2.49 A, consistent with Ga-Ga single bonding. Treatment of 1, 4, and 6 with B(C(6)F(5))(3) immediately afforded the 1:1 donor-acceptor complexes ArGa[B(C(6)F(5))(3)] (Ar = Ar*, 8; Ar#, 9; Ar', 10) that featured almost linear gallium coordination, Ga-B distances near the sum of the covalent radii of gallium and boron, as well as some close Ga...F contacts. Compound 1 also reacted with Fe(CO)(5) under ambient conditions to give Ar*GaFe(CO)(4) (11), which had been previously synthesized by the reaction of GaAr*Cl(2) with Na(2)Fe(CO)(4). Reaction of 1 with 2,3-dimethyl-1,3-butadiene afforded the compound [Ar*GaCH(2)C(Me)C(Me)CH(2)]2 (12) that had a 10-membered 1,5-Ga(2)C(8) ring with no Ga-Ga interaction. Stirring 1 or 6 with sodium readily gave Na(2)[Ar*GaGaAr*] (13) and Na(2)(Ar'GaGaAr') (14). The former species 13 had been synthesized previously by reduction of GaAr*Cl(2) with sodium and was described as having a Ga-Ga triple bond because of the short Ga-Ga distance and the electronic relationship between [Ar*GaGaAr*](2-) and the corresponding neutral group 14 alkyne analogues. Compound 14 has a similar structure featuring a trans-bent CGaGaC core, bridged by sodiums which were also coordinated to the flanking aryl rings of the Ar' ligands. The Ga-Ga bond length was found to be 2.347(1) A, which is slightly (ca. 0.02 A) longer than that reported for 13. Reaction of Ga[N(Dipp)C(Me)](2)CH, 15 (i.e., GaN(wedge)NDipp(2)), which is sterically related to 1, 4, and 6, with Fe(CO)(5) yielded Dipp(2)N(wedge)NGaFe(CO)(4) (16), whose Ga-Fe bond is slightly longer than that observed in 11. Reaction of the less bulky LiAr"(Ar"= C(6)H(3)-2,6-Mes(2)) with "GaI" afforded the new paramagnetic cluster Ga(11)Ar(4)" (17). The ready dissociation of 1, 4, and 6 in solution, the long Ga-Ga distance in 6, and the chemistry of these compounds showed that the Ga-Ga bonds are significantly weaker than single bonds. The reduction of 1 and 6 with sodium to give 13 and 14 supplies two electrons to the di-gallium unit to generate a single bond (in addition to the weak interaction in the neutral precursor) with retention of the trans-bent geometry. It was concluded that the stability of 13 and 14 depends on the matching size of the sodium ion, and the presence of Na-Ga and Na-Ar interactions that stabilize their Na(2)Ga(2) core structures.

Tissue-specific distribution of the androgen receptor (AR) in the porcine fetus.

PubMed

Burek, Małgorzata; Duda, Małgorzata; Knapczyk, Katarzyna; Koziorowski, Marek; Słomczyńska, Maria

2007-01-01

The aim of this study was to investigate androgen receptor (AR) expression in developing porcine fetuses. The localization of AR was examined on embryos obtained at different days of gestation: days 18, 32, 50, 71, 90 post coitum (p.c.), and in the several tissues collected from the newborn piglets of both sexes. AR expression was first observed on day 32 p.c. in the mesonephron region. RT-PCR did not show AR mRNA on day18 p.c., but the message was present starting from day 32. In the male differentiating gonads and in the male genital ducts AR protein was present at 50, 71 and 90 days of gestation. AR protein was also detected in the cords of stromal cells within the medulla of the ovary and in stromal cells investing the oogonial nests. Pregranulosa cells on day 90 of gestation and on day 1 post partum (p.p.) immunolabelled positively for AR. In the kidney, a number of AR-positive tubules were visible while the mesenchyme in the kidney was AR-negative. Immunoreactive AR was detected predominantly in the nuclei of epithelial cells of the budding component at different stages of gestation of porcine lung. The presence of AR during gestation in non-gonadal tissues suggests a role of androgen in these tissues.

MEIS1 functions as a potential AR negative regulator

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cui, Liang; Department of Urology, Civil Aviation General Hospital/Civil Aviation Medical College of Peking University, Beijing 100123; Li, Mingyang

2014-10-15

The androgen receptor (AR) plays critical roles in human prostate carcinoma progression and transformation. However, the activation of AR is regulated by co-regulators. MEIS1 protein, the homeodomain transcription factor, exhibited a decreased level in poor-prognosis prostate tumors. In this study, we investigated a potential interaction between MEIS1 and AR. We found that overexpression of MEIS1 inhibited the AR transcriptional activity and reduced the expression of AR target gene. A potential protein–protein interaction between AR and MEIS1 was identified by the immunoprecipitation and GST pull-down assays. Furthermore, MEIS1 modulated AR cytoplasm/nucleus translocation and the recruitment to androgen response element in prostatemore » specific antigen (PSA) gene promoter sequences. In addition, MEIS1 promoted the recruitment of NCoR and SMRT in the presence of R1881. Finally, MEIS1 inhibited the proliferation and anchor-independent growth of LNCaP cells. Taken together, our data suggests that MEIS1 functions as a novel AR co-repressor. - Highlights: • A potential interaction was identified between MEIS1 and AR signaling. • Overexpression of MEIS1 reduced the expression of AR target gene. • MEIS1 modulated AR cytoplasm/nucleus translocation. • MEIS1 inhibited the proliferation and anchor-independent growth of LNCaP cells.« less

Endoglucanase and xylanase production by Bacillus sp. AR03 in co-culture.

PubMed

Hero, Johan S; Pisa, José H; Perotti, Nora I; Romero, Cintia M; Martínez, María A

2017-07-03

The behavior of three isolates retrieved from different cellulolytic consortia, Bacillus sp. AR03, Paenibacillus sp. AR247 and Achromobacter sp. AR476-2, were examined individually and as co-cultures in order to evaluate their ability to produce extracellular cellulases and xylanases. Utilizing a peptone-based medium supplemented with carboxymethyl cellulose (CMC), an increase estimation of 1.30 and 1.50 times was obtained by the co-culture containing the strains AR03 and AR247, with respect to enzyme titles registered by their individual cultivation. On the contrary, the extracellular enzymatic production decreased during the co-cultivation of strain AR03 with the non-cellulolytic Achromobacter sp. AR476-2. The synergistic behavior observed through the combined cultivation of the strains AR03 and AR247 might be a consequence of the consumption by Paenibacillus sp. AR247 of the products of the CMC hydrolysis (i.e., cellobiose and/or cello-oligosaccharides), which were mostly generated by the cellulase producer Bacillus sp. AR03. The effect observed could be driven by the requirement to fulfill the nutritional supply from both strains on the substrate evaluated. These results would contribute to a better description of the degradation of the cellulose fraction of the plant cell walls in nature, expected to an efficient utilization of renewable sources.

Selective dry etching of III-V nitrides in Cl{sub 2}/Ar, CH{sub 4}/H{sub 2}/Ar, ICi/Ar, and IBr/Ar

DOE Office of Scientific and Technical Information (OSTI.GOV)

Vartuli, C.B.; Pearton, S.J.; MacKenzie, J.D.

1996-10-01

The selectivity for etching the binary (GaN, AlN, and InN) and ternary nitrides (InGaN and InAlN) relative to each other in Cl{sub 2}/Ar, CH{sub 4}/H{sub 2}/Ar, ICl/Ar, or IBr/Ar electron cyclotron resonance (ECR) plasmas, and Cl{sub 2}/Ar or CH{sub 4}/H{sub 2}/Ar reactive ion (RIE) plasmas was investigated. Cl-based etches appear to be the best choice for maximizing the selectivity of GaN over the other nitrides. GaN/AlN and GaN/InGaN etch rate ratios of {approximately} 10 were achieved at low RF power in Cl{sub 2}/Ar under ECR and RIE conditions, respectively. GaN/InN selectivity of 10 was found in ICl under ECR conditions.more » A relatively high selectivity (> 6) of InN/GaN was achieved in CH{sub 4}/H{sub 2}/Ar under ECR conditions at low RF powers (50 W). Since the high bond strengths of the nitrides require either high ion energies or densities to achieve practical etch rates it is difficult to achieve high selectivities.« less

Ar-40/Ar-39 Studies of Martian Meteorite RBT 04262 and Terrestrial Standards

NASA Technical Reports Server (NTRS)

Park, J.; Herzog, G. F.; Turrin, B.; Lindsay, F. N.; Delaney, J. S.; Swisher, C. C., III; Nagao, K.; Nyquist, L. E.

2014-01-01

Park et al. recently presented an Ar-40/Ar-39 dating study of maskelynite separated from the Martian meteorite RBT 04262. Here we report an additional study of Ar-40/Ar-39 patterns for smaller samples, each consisting of only a few maskelynite grains. Considered as a material for Ar-40/Ar-39 dating, the shock-produced glass maskelynite has both an important strength (relatively high K concentration compared to other mineral phases) and some potentially problematic weaknesses. At Rutgers, we have been analyzing small grains consisting of a single phase to explore local effects that might be averaged and remain hidden in larger samples. Thus, to assess the homogeneity of the RBT maskelynite and for comparison with the results of, we analyzed six approx. 30 microgram samples of the same maskelynite separate they studied. Furthermore, because most Ar-40/Ar-39 are calculated relative to the age of a standard, we present new Ar-40/Ar-39 age data for six standards. Among the most widely used standards are sanidine from Fish Canyon (FCs) and various hornblendes (hb3gr, MMhb-1, NL- 25), which are taken as primary standards because their ages have been determined by independent, direct measurements of K and A-40.

Androgen receptor (AR) pathophysiological roles in androgen-related diseases in skin, bone/muscle, metabolic syndrome and neuron/immune systems: lessons learned from mice lacking AR in specific cells

PubMed Central

Chang, Chawnshang; Yeh, Shuyuan; Lee, Soo Ok; Chang, Ta-min

2013-01-01

The androgen receptor (AR) is expressed ubiquitously and plays a variety of roles in a vast number of physiological and pathophysiological processes. Recent studies of AR knockout (ARKO) mouse models, particularly the cell type- or tissue-specific ARKO models, have uncovered many AR cell type- or tissue-specific pathophysiological roles in mice, which otherwise would not be delineated from conventional castration and androgen insensitivity syndrome studies. Thus, the AR in various specific cell types plays pivotal roles in production and maturation of immune cells, bone mineralization, and muscle growth. In metabolism, the ARs in brain, particularly in the hypothalamus, and the liver appear to participate in regulation of insulin sensitivity and glucose homeostasis. The AR also plays key roles in cutaneous wound healing and cardiovascular diseases, including atherosclerosis and abdominal aortic aneurysm. This article will discuss the results obtained from the total, cell type-, or tissue-specific ARKO models. The understanding of AR cell type- or tissue-specific physiological and pathophysiological roles using these in vivo mouse models will provide useful information in uncovering AR roles in humans and eventually help us to develop better therapies via targeting the AR or its downstream signaling molecules to combat androgen/AR-related diseases. PMID:24653668

Developing a consensus framework and risk profile for agents of opportunity in academic medical centers: implications for public health preparedness.

PubMed

Farmer, Brenna M; Nelson, Lewis S; Graham, Margaret E; Bendzans, Carly; McCrillis, Aileen M; Portelli, Ian; Zhang, Meng; Goldberg, Judith; Rosenberg, Sheldon D; Goldfrank, Lewis R; Tunik, Michael

2010-12-01

Agents of opportunity (AO) in academic medical centers (AMC) are defined as unregulated or lightly regulated substances used for medical research or patient care that can be used as "dual purpose" substances by terrorists to inflict damage upon populations. Most of these agents are used routinely throughout AMC either during research or for general clinical practice. To date, the lack of careful regulations for AOs creates uncertain security conditions and increased malicious potential. Using a consensus-based approach, we collected information and opinions from staff working in an AMC and 4 AMC-affiliated hospitals concerning identification of AO, AO attributes, and AMC risk and preparedness, focusing on AO security and dissemination mechanisms and likely hospital response. The goal was to develop a risk profile and framework for AO in the institution. Agents of opportunity in 4 classes were identified and an AO profile was developed, comprising 16 attributes denoting information critical to preparedness for AO misuse. Agents of opportunity found in AMC present a unique and vital gap in public health preparedness. Findings of this project may provide a foundation for a discussion and consensus efforts to determine a nationally accepted risk profile framework for AO. This foundation may further lead to the implementation of appropriate regulatory policies to improve public health preparedness. Agents of opportunity modeling of dissemination properties should be developed to better predict AO risk.

Argemone oil, an edible oil adulterant, induces systemic immunosuppression in Balb/c mice in an oral 28 days repeated dose toxicity study.

PubMed

Mandal, Payal; Tewari, Prachi; Kumar, Sachin; Yadav, Sarika; Ayanur, Anjaneya; Chaturvedi, Rajnish K; Das, Mukul; Tripathi, Anurag

2018-05-01

Consumption of edible oils contaminated with Argemone oil (AO) leads to a clinical condition called "Epidemic dropsy". Earlier studies have reported that metabolism and oxidative stress primarily contributes to AO toxicity, however, the involvement of immune system has not been assessed so far. Therefore, the present study was undertaken to systematically assess the effect of AO exposure on the function of immune system in Balb/c mice. The repeated exposure of AO for 28 days caused prominent regression of spleen and thymus; severe inflammatory changes in spleen depicted by the loss of distinct follicles, increased megakaryocyte infiltration, and enhanced expression levels of inflammatory markers (iNOS & COX-2). At the functional level, AO exposure significantly abrogated the mixed lymphocyte reaction and mitogen-stimulated lymphoproliferative activity of T and B cells, which is reflective of profound lymphocyte dysfunction upon antigen exposure. In concordance with the loss in functional activity of lymphocytes in AO exposed animals, it was found the AO altered the relative percentage of CD3 + , CD4 + , and CD28  +  T cells. Further, there was a marked decrease in the relative distribution of cells with prominent MHC I and CD1d expression in AO exposed splenocytes. Moreover, reduced levels of immune stimulatory cytokines (TNF-α, IFN-γ, IL-2, IL-4, and IL-6), and increased levels of immunosuppressive cytokine IL-10 were detected in the serum of AO treated mice. Along with T and B cells, AO exposure also affected the phenotype and activation status of macrophages suggesting the inclination towards "alternative activation of macrophages". Altogether, these functional changes in the immune cells are contributing factors in AO induced immunosuppression. Copyright © 2018 Elsevier B.V. All rights reserved.

Association between aortoseptal angle in Golden Retriever puppies and subaortic stenosis in adulthood.

PubMed

Belanger, M C; Côté, E; Beauchamp, G

2014-01-01

Predicting subaortic stenosis (SAS) in adult Golden Retriever dogs (GRs) by evaluating them as puppies is hampered by the progressive expression of the SAS phenotype in youth. In some children who develop SAS as adults, an abnormal aortoseptal angle (AoSA) precedes development of stenosis. To determine the normal AoSA in young adult GRs using echocardiography; to assess the value of AoSA in GR puppies for predicting development of the SAS phenotype. Forty-eight 2- to 6-month-old GR puppies. Prospective study. Puppies were recruited from clients and breeders. Puppies were evaluated with a physical examination and an echocardiogram, and this evaluation was repeated when they were 12-18-month-old adults. Puppies were classified as unaffected (WNL) or affected (SAS) retroactively, based on their results as adults. In WNL young adult GRs, mean ± SD AoSA was 152.3 ± 6.5°. Mean ± SD AoSA in SAS puppies (144.9 ± 8.6°) was significantly different from mean AoSA in WNL puppies (155.7 ± 8.8°, P < .01). No puppy with AoSA >160° had the SAS phenotype as a young adult; 93% (75.7-99.1%) of puppies with AoSA <145° had the SAS phenotype as young adults. Peak LVOT velocity increased significantly between evaluations (P < .0001) whereas AoSA did not (P = .45). A steep AoSA in GR puppies is associated with the SAS phenotype in young adulthood. Some GR puppies have an abnormal AoSA that persists in young adulthood and is detectable before peak LVOT velocity reaches levels consistent with SAS. Copyright © 2014 by the American College of Veterinary Internal Medicine.

Layer-by-layer films and colloidal dispersions of graphene oxide nanosheets for efficient control of the fluorescence and aggregation properties of the cationic dye acridine orange.

PubMed

Hansda, Chaitali; Chakraborty, Utsav; Hussain, Syed Arshad; Bhattacharjee, Debajyoti; Paul, Pabitra Kumar

2016-03-15

Chemically derived graphene oxide (GO) nanosheets have received great deal of interest for technological application such as optoelectronic and biosensors. Aqueous dispersions of GO become an efficient template to induce the association of cationic dye namely Acridine Orange (AO). Interactions of AO with colloidal GO was governed by both electrostatic and π-π stacking cooperative interactions. The type of dye aggregations was found to depend on the concentration of GO in the mixed ensemble. Spectroscopic calculations revealed the formation of both H and J-type dimers, but H-type aggregations were predominant. Preparation of layer-by-layer (LbL) electrostatic self-assembled films of AO and GO onto poly (allylamine hydrochloride) (PAH) coated quartz substrate is also reported in this article. UV-Vis absorption, steady state and time resolve fluorescence and Raman spectroscopic techniques have been employed to explore the detail photophysical properties of pure AO, AO/GO mixed solution and AO/GO LbL films. Scanning electron microscopy was also used for visual evidence of the synthesized nanodimensional GO sheets. The fluorescence quenching of AO in the presence of GO in aqueous solution was due to the interfacial photoinduced electron transfer (PET) from photoexcited AO to GO i.e. GO acts as an efficient quenching agent for the fluorescence emission of AO. The quenching is found to be static in nature. Raman spectroscopic results also confirmed the interaction of AO with GO and the electron transfer. The formation of AO/GO complex via very fast excited state electron transfer mechanism may be proposed as to prepare GO-based fluorescence sensor for biomolecular detection without direct labeling the biomolecules by fluorescent probe. Copyright © 2015 Elsevier B.V. All rights reserved.

Layer-by-layer films and colloidal dispersions of graphene oxide nanosheets for efficient control of the fluorescence and aggregation properties of the cationic dye acridine orange

NASA Astrophysics Data System (ADS)

Hansda, Chaitali; Chakraborty, Utsav; Hussain, Syed Arshad; Bhattacharjee, Debajyoti; Paul, Pabitra Kumar

2016-03-01

Chemically derived graphene oxide (GO) nanosheets have received great deal of interest for technological application such as optoelectronic and biosensors. Aqueous dispersions of GO become an efficient template to induce the association of cationic dye namely Acridine Orange (AO). Interactions of AO with colloidal GO was governed by both electrostatic and π-π stacking cooperative interactions. The type of dye aggregations was found to depend on the concentration of GO in the mixed ensemble. Spectroscopic calculations revealed the formation of both H and J-type dimers, but H-type aggregations were predominant. Preparation of layer-by-layer (LbL) electrostatic self-assembled films of AO and GO onto poly (allylamine hydrochloride) (PAH) coated quartz substrate is also reported in this article. UV-Vis absorption, steady state and time resolve fluorescence and Raman spectroscopic techniques have been employed to explore the detail photophysical properties of pure AO, AO/GO mixed solution and AO/GO LbL films. Scanning electron microscopy was also used for visual evidence of the synthesized nanodimensional GO sheets. The fluorescence quenching of AO in the presence of GO in aqueous solution was due to the interfacial photoinduced electron transfer (PET) from photoexcited AO to GO i.e. GO acts as an efficient quenching agent for the fluorescence emission of AO. The quenching is found to be static in nature. Raman spectroscopic results also confirmed the interaction of AO with GO and the electron transfer. The formation of AO/GO complex via very fast excited state electron transfer mechanism may be proposed as to prepare GO-based fluorescence sensor for biomolecular detection without direct labeling the biomolecules by fluorescent probe.

Importance of Different Grades of Abdominal Obesity on Testosterone Level, Erectile Dysfunction, and Clinical Coincidence.

PubMed

Fillo, Juraj; Levcikova, Michaela; Ondrusova, Martina; Breza, Jan; Labas, Peter

2017-03-01

The aim of the current study was to investigate the influence of different grades of abdominal obesity (AO) on the prevalence of testosterone deficiency syndrome (TDS), erectile dysfunction (ED), and metabolic syndrome (MetS). In a cross-sectional descriptive study, a total of 216 males underwent a complete urological, internal, and hormonal evaluation. Males were divided according to waist circumference into five groups: less than 94 cm (Grade [G] 0), 94 to 101 cm (G1), 102 to 109 cm (G2), 110 to 119 cm (G3), and more than 120 cm (G4). Incidence of ED, TDS, and MetS was compared in these groups and in participants without AO. Some degree of ED was identified in 74.7% of males with AO. In G1, there were 61% of males with ED, in G2 68%, in G3 83%, and in G4 87%. A strong correlation between testosterone (TST) level and AO was identified. Ninety-eight out of 198 (49.5%) males with AO and 1/18 (5.5%) males without AO had TDS. There were significant differences between individual groups. In the group of males with AO G4 (more than 120 cm), 87.1% had TDS. MetS was diagnosed in 105/198 (53.0%) males with AO, but in G4, 83.9% of males with AO had MetS. Males older than 40 years of age with AO have a higher incidence of ED, TDS, and MetS. Dividing males into five groups according to waist circumference seems to be reasonable. With growing AO, there were significantly more males with ED, TDS, and MetS.

Agreement in Cone Density Derived from Gaze-Directed Single Images Versus Wide-Field Montage Using Adaptive Optics Flood Illumination Ophthalmoscopy

PubMed Central

Chew, Avenell L.; Sampson, Danuta M.; Kashani, Irwin; Chen, Fred K.

2017-01-01

Purpose We compared cone density measurements derived from the center of gaze-directed single images with reconstructed wide-field montages using the rtx1 adaptive optics (AO) retinal camera. Methods A total of 29 eyes from 29 healthy subjects were imaged with the rtx1 camera. Of 20 overlapping AO images acquired, 12 (at 3.2°, 5°, and 7°) were used for calculating gaze-directed cone densities. Wide-field AO montages were reconstructed and cone densities were measured at the corresponding 12 loci as determined by field projection relative to the foveal center aligned to the foveal dip on optical coherence tomography. Limits of agreement in cone density measurement between single AO images and wide-field AO montages were calculated. Results Cone density measurements failed in 1 or more gaze directions or retinal loci in up to 58% and 33% of the subjects using single AO images or wide-field AO montage, respectively. Although there were no significant overall differences between cone densities derived from single AO images and wide-field AO montages at any of the 12 gazes and locations (P = 0.01–0.65), the limits of agreement between the two methods ranged from as narrow as −2200 to +2600, to as wide as −4200 to +3800 cones/mm2. Conclusions Cone density measurement using the rtx1 AO camera is feasible using both methods. Local variation in image quality and altered visibility of cones after generating montages may contribute to the discrepancies. Translational Relevance Cone densities from single AO images are not interchangeable with wide-field montage derived–measurements. PMID:29285417

Echocardiographic predictors of survival in dogs with myxomatous mitral valve disease.

PubMed

Sargent, Julia; Muzzi, Ruthnea; Mukherjee, Rajat; Somarathne, Sharlene; Schranz, Katherine; Stephenson, Hannah; Connolly, David; Brodbelt, David; Fuentes, Virginia Luis

2015-03-01

To evaluate vena contracta and other echocardiographic measures of myxomatous mitral valve disease (MMVD) severity in a multivariable analysis of survival in dogs. 70 dogs diagnosed with MMVD from stored echocardiographic images that met study inclusion criteria. Left heart dimensions were measured as well as mitral regurgitant jet area/left atrial area (JAR), early mitral filling velocity (Evel), extent of mitral valve prolapse in right and left views (ProlR, ProlL), Prol indexed to aortic diameter (ProlR:Ao, ProlL:Ao), presence of a flail leaflet (FlailR, FlailL), and mitral regurgitation vena contracta diameter (VCR, VCL) indexed to aortic diameter (VCR:Ao, VCL:Ao). Follow-up from referring veterinarians was obtained by questionnaire or telephone to determine survival times. Inter- and intra-observer agreement was evaluated with Bland-Altman plots and weighted Kappa analysis. Survival was analyzed using Kaplan-Meier curves, logrank tests and Cox's proportional hazards. Logrank analysis showed VCL:Ao, VCR:Ao, FlailL, ProlR:Ao, ProlL:Ao, left ventricular internal dimension in diastole indexed to aortic diameter (LVIDD:Ao) >2.87, left atrium to aorta ratio (LA/Ao) >1.6, and Evel >1.4 m/s were predictors of cardiac mortality. In a multivariable analysis, the independent predictors of cardiac mortality were Evel >1.4 m/s [hazard ratio (HR) 5.0, 95% confidence interval (CI) 2.5-10.3], FlailL (HR 3.1, 95% CI 1.3-7.9), and ProlR:Ao (HR 2.8, 95% CI 1.3-6.3). Echocardiographic measures of mitral regurgitation severity and mitral valve pathology provide valuable prognostic information independent of chamber enlargement in dogs with MMVD. Copyright © 2014 Elsevier B.V. All rights reserved.

Estimation of pulmonary artery pressure in patients with primary pulmonary hypertension by quantitative analysis of magnetic resonance images.

PubMed

Murray, T I; Boxt, L M; Katz, J; Reagan, K; Barst, R J

1994-01-01

The use of magnetic resonance (MR) images for estimating mean pulmonary artery pressure (PAP) was tested by comparing main pulmonary artery (MPA) and middescending thoracic aorta (AO) caliber in 12 patients with primary pulmonary hypertension (PPH) with measurements made in eight other patients who were observed for diseases other than heart disease (controls). The ratio MPA/AO and the ratios of vessel caliber normalized to body surface area (MPAI and AOI, respectively) were computed. The PAP was obtained in all PPH patients and compared with caliber measurements. The PPH MPA (3.6 +/- 0.8 cm) was significantly larger than the control MPA (2.9 +/- 0.3 cm, p = 0.02); the PPH MPAI (2.8 +/- 0.7 cm/M2) was significantly greater than the control MPA (1.7 +/- 0.2 cm/M2, p < 0.0001). Control AO (2.2 +/- 0.3 cm) was significantly greater than PPH AO (1.6 +/- 0.4 cm, p < 0.0001); there was no significant difference between control AOI (1.3 +/- 0.2 cm/M2) and PPH AOI (1.2 +/- 0.2 cm/M2, p = 0.25). The PPH MPA/AO (2.3 +/- 0.6) was significantly greater than the control MPA/AO (1.3 +/- 0.1, p < 0.0001); overlap between MPA in the two groups was eliminated by indexing values to AO caliber (MPA/AO). Among PPH patients there was strong correlation between PAP and MPA/AO (PAP = 24 x MPA/AO + 3.7, r = 0.7, p < 0.01). Increased MPA/AO denotes the presence of pulmonary hypertension and may be used to estimate PAP.

Hypothermia in mouse is caused by adenosine A1 and A3 receptor agonists and AMP via three distinct mechanisms.

PubMed

Carlin, Jesse Lea; Jain, Shalini; Gizewski, Elizabeth; Wan, Tina C; Tosh, Dilip K; Xiao, Cuiying; Auchampach, John A; Jacobson, Kenneth A; Gavrilova, Oksana; Reitman, Marc L

2017-03-01

Small mammals have the ability to enter torpor, a hypothermic, hypometabolic state, allowing impressive energy conservation. Administration of adenosine or adenosine 5'-monophosphate (AMP) can trigger a hypothermic, torpor-like state. We investigated the mechanisms for hypothermia using telemetric monitoring of body temperature in wild type and receptor knock out (Adora1 -/- , Adora3 -/- ) mice. Confirming prior data, stimulation of the A 3 adenosine receptor (AR) induced hypothermia via peripheral mast cell degranulation, histamine release, and activation of central histamine H 1 receptors. In contrast, A 1 AR agonists and AMP both acted centrally to cause hypothermia. Commonly used, selective A 1 AR agonists, including N 6 -cyclopentyladenosine (CPA), N 6 -cyclohexyladenosine (CHA), and MRS5474, caused hypothermia via both A 1 AR and A 3 AR when given intraperitoneally. Intracerebroventricular dosing, low peripheral doses of Cl-ENBA [(±)-5'-chloro-5'-deoxy-N 6 -endo-norbornyladenosine], or using Adora3 -/- mice allowed selective stimulation of A 1 AR. AMP-stimulated hypothermia can occur independently of A 1 AR, A 3 AR, and mast cells. A 1 AR and A 3 AR agonists and AMP cause regulated hypothermia that was characterized by a drop in total energy expenditure, physical inactivity, and preference for cooler environmental temperatures, indicating a reduced body temperature set point. Neither A 1 AR nor A 3 AR was required for fasting-induced torpor. A 1 AR and A 3 AR agonists and AMP trigger regulated hypothermia via three distinct mechanisms. Published by Elsevier Ltd.

Natural variation of potato allene oxide synthase 2 causes differential levels of jasmonates and pathogen resistance in Arabidopsis

PubMed Central

Pajerowska-Mukhtar, Karolina M.; Mukhtar, M. Shahid; Guex, Nicolas; Halim, Vincentius A.; Rosahl, Sabine; Somssich, Imre E.

2008-01-01

Natural variation of plant pathogen resistance is often quantitative. This type of resistance can be genetically dissected in quantitative resistance loci (QRL). To unravel the molecular basis of QRL in potato (Solanum tuberosum), we employed the model plant Arabidopsis thaliana for functional analysis of natural variants of potato allene oxide synthase 2 (StAOS2). StAOS2 is a candidate gene for QRL on potato chromosome XI against the oömycete Phytophthora infestans causing late blight, and the bacterium Erwinia carotovora ssp. atroseptica causing stem black leg and tuber soft rot, both devastating diseases in potato cultivation. StAOS2 encodes a cytochrome P450 enzyme that is essential for biosynthesis of the defense signaling molecule jasmonic acid. Allele non-specific dsRNAi-mediated silencing of StAOS2 in potato drastically reduced jasmonic acid production and compromised quantitative late blight resistance. Five natural StAOS2 alleles were expressed in the null Arabidopsis aos mutant under control of the Arabidopsis AOS promoter and tested for differential complementation phenotypes. The aos mutant phenotypes evaluated were lack of jasmonates, male sterility and susceptibility to Erwinia carotovora ssp. carotovora. StAOS2 alleles that were associated with increased disease resistance in potato complemented all aos mutant phenotypes better than StAOS2 alleles associated with increased susceptibility. First structure models of ‘quantitative resistant’ versus ‘quantitative susceptible’ StAOS2 alleles suggested potential mechanisms for their differential activity. Our results demonstrate how a candidate gene approach in combination with using the homologous Arabidopsis mutant as functional reporter can help to dissect the molecular basis of complex traits in non model crop plants. Electronic supplementary material The online version of this article (doi:10.1007/s00425-008-0737-x) contains supplementary material, which is available to authorized users. PMID:18431595

Expression profiles and functional associations of endogenous androgen receptor and caveolin-1 in prostate cancer cell lines.

PubMed

Bennett, Nigel C; Hooper, John D; Johnson, David W; Gobe, Glenda C

2014-05-01

In prostate cancer (PCa) patients, the protein target for androgen deprivation and blockade therapies is androgen receptor (AR). AR interacts with many proteins that function to either co-activate or co-repress its activity. Caveolin-1 (Cav-1) is not found in normal prostatic epithelium, but is found in PCa, and may be an AR co-regulator protein. We investigated cell line-specific signatures and associations of endogenous AR and Cav-1 in six PCa cell lines of known androgen sensitivity: LNCaP (androgen sensitive); 22Rv1 (androgen responsive); PC3, DU145, and ALVA41 (androgen non-reliant); and RWPE1 (non-malignant). Protein and mRNA expression profiles were compared and electron microscopy used to identify cells with caveolar structures. For cell lines expressing both AR and Cav-1, knockdown techniques using small interfering RNA against AR or Cav-1 were used to test whether diminished expression of one affected the other. Co-sedimentation of AR and Cav-1 was used to test their association. A reporter assay for AR genomic activity was utilized following Cav-1 knockdown. AR-expressing LNCaP and 22Rv1 cells had low endogenous Cav-1 mRNA and protein. Cell lines that expressed little or no AR (DU145, PC3, ALVA41, and RWPE1) expressed high endogenous levels of Cav-1. AR knockdown in LNCaP cells had little effect on Cav-1, but Cav-1 knockdown inhibited AR expression and genomic activity. These data show endogenous AR and Cav-1 mRNA and protein expression is inversely related in PCa cells, with Cav-1 acting on the androgen/AR signaling axis possibly as an AR co-activator, demonstrated by diminished AR genomic activity following Cav-1 knockdown. © 2013 Wiley Periodicals, Inc.

Measuring 36Ar without H35Cl interference

NASA Astrophysics Data System (ADS)

Saxton, John

2015-04-01

Noble gas measurements are usually made in static mode, when the mass spectrometer sensitivity is inversely proportional to volume: this makes the building of very large instruments to obtain high mass resolution impracticable. A particularly challenging interference has hitherto been H35Cl, which differs in mass from 36Ar by 1 part in 3937. We have developed a method which makes improved use of the available MRP to remove interferences, and used it to obtain HCl-free 36Ar measurements on a multicollector instrument with MRP of only ~6000 (MRP= mass resolving power = m/dm 5-95% on side of peak). By arranging that the target mass position on a minor isotope (e.g. 36Ar), from which the interference must be removed, coincides with the ~50% point on the side of a major isotope (e.g. 40Ar), it is possible both to set the mass accurately and to verify the mass position and stability during measurements. The peak top of 40Ar is measured in a separate mass step. Two small corrections are necessary. One compensates for the residual HCl tail at the 36Ar position. The other arises because the peak is not totally flat in the region of interest: 40Ar and 36Ar+HCl are measured on the peak top, whilst 36Ar is measured at the extreme edge, with slightly lower efficiency. The required correction parameters can be obtained from a series of air calibrations with different target/interference ratios. With samples containing 4x10-15to 3x10-14moles of 40Ar, 36Ar/40Ar was measured, without HCl interference, to a 1σ precision of 0.5%, only slightly worse than counting statistics. This is potentially useful for 40Ar/39Ar dating, where 36Ar is used to correct for trapped air, and may be particularly significant for smaller or younger samples.

Interrelation of androgen receptor and miR-30a and miR-30a function in ER-, PR-, AR+ MDA-MB-453 breast cancer cells.

PubMed

Lyu, Shuhua; Liu, Han; Liu, Xia; Liu, Shan; Wang, Yahong; Yu, Qi; Niu, Yun

2017-10-01

The association between androgen-induced androgen receptor (AR) activating signal and microRNA (miR)-30a was investigated, as well as the function of miR-30a in estrogen receptor-negative (ER - ), progesterone receptor-negative (PR - ), and AR-positive (AR + ) MDA-MB-453 breast cancer cells. Androgen-induced AR activating signal upregulated the expression of AR, and downregulated the expression of miR-30a, b and c. Bioinformatics analysis indicated a putative miR-30a, b and c binding site in the 3'-untranslated region of AR mRNA. It was confirmed that the AR gene is a direct target of miR-30a, whereas AR does not target the miR-30a promoter, and AR activating signal may indirectly downregulate miR-30a through other cell signaling pathways. In this positive feedback mechanism AR is then upregulated through miR-30a. Overexpression of miR-30a inhibited cell proliferation, whereas inhibition of miR-30a expression by specific antisense oligonucleotides, increased cell growth. Previously, androgen-induced AR activating signal was demonstrated to inhibit cell proliferation in ER - , PR - and AR + MDA-MB-453 breast cancer cells, but AR activating signal downregulated the expression of miR-30a, relieving the inhibition of MDA-MB-453 cell growth. Therefore, in MDA-MB-453 breast cancer cells, miR-30a has two different functions regarding cell growth: Inhibition of cell proliferation through a positive feedback signaling pathway; and the relative promotion of cell proliferation through downregulation of miR-30a. Thus, the association between AR activating signal and microRNAs is complex, and microRNAs may possess different functions due to different signaling pathways. Although the results of the present study were obtained in one cell line, they contribute to subsequent studies on ER - , PR - and AR + breast cancer.

Impact of ao-dake-humi, Japanese traditional bamboo foot stimulator, on lower urinary tract symptoms, constipation and hypersensitivity to cold: a single-arm prospective pilot study.

PubMed

Minagawa, Tomonori; Saitou, Tetsuichi; Suzuki, Toshiro; Domen, Takahisa; Yokoyama, Hitoshi; Ishikawa, Masakuni; Hirakata, Shiro; Nagai, Takashi; Nakazawa, Masaki; Ogawa, Teruyuki; Ishizuka, Osamu

2016-12-09

Ao-dake-humi is a traditional Japanese bamboo foot stimulator consisting of a half-pipe-shaped step made of bamboo used to stimulate the foot by stepping on it, and is commonly used to promote general health among the elderly in Japan. However, its efficacy has not been reported in the scientific literature. This study was performed to investigate the role of ao-dake-humi focusing on lower urinary tract symptoms (LUTS), constipation, and hypersensitivity to cold (HC). Participants with LUTS, constipation, or HC were enrolled in this study. Ao-dake-humi was used twice a day for 28 days. Before and 28 days after starting ao-dake-humi use, international prostate symptom score (IPSS), quality-of-life (QoL) score, and overactive bladder symptom score (OABSS) were measured to evaluate the efficacy of ao-dake-humi on LUTS. To evaluate the objective efficacy of ao-dake-humi on LUTS, a frequency-volume chart (FVC) was plotted in LUTS patients for 3 days. A visual analogue scale (VAS) was used to evaluate the efficacy of ao-dake-humi on constipation (VAS-constipation) and HC (VAS-HC) in the participants with constipation or HC. A total of 24 participants were enrolled in this study. Twenty-one participants had LUTS, 11 had constipation, and 17 participants had HC. IPSS, especially storage-subscore, QoL score and OABSS, decreased significantly after use of ao-dake-humi. The use of ao-dake-humi increased maximal bladder capacity, resulting in a significant decrease in urinary frequency as determined from the FVC. In accordance with the results of VAS-constipation and VAS-HC, both constipation and HC were significantly relieved after ao-dake-humi use. The results of this prospective pilot study indicated that ao-dake-humi is safe and has therapeutic efficacy in cases of LUTS, constipation and HC. The possibility of using ao-dake-humi as physical neuromodulation therapy was shown in the management of LUTS, constipation and HC. UMIN000019333 (UMIN-CTR, Registered October-15-2015) retrospectively registered.

The Variable Internal Structure of the Mycoplasma penetrans Attachment Organelle Revealed by Biochemical and Microscopic Analyses: Implications for Attachment Organelle Mechanism and Evolution.

PubMed

Distelhorst, Steven L; Jurkovic, Dominika A; Shi, Jian; Jensen, Grant J; Balish, Mitchell F

2017-06-15

Although mycoplasmas have small genomes, many of them, including the HIV-associated opportunist Mycoplasma penetrans , construct a polar attachment organelle (AO) that is used for both adherence to host cells and gliding motility. However, the irregular phylogenetic distribution of similar structures within the mycoplasmas, as well as compositional and ultrastructural differences among these AOs, suggests that AOs have arisen several times through convergent evolution. We investigated the ultrastructure and protein composition of the cytoskeleton-like material of the M. penetrans AO with several forms of microscopy and biochemical analysis, to determine whether the M. penetrans AO was constructed at the molecular level on principles similar to those of other mycoplasmas, such as Mycoplasma pneumoniae and Mycoplasma mobile We found that the M. penetrans AO interior was generally dissimilar from that of other mycoplasmas, in that it exhibited considerable heterogeneity in size and shape, suggesting a gel-like nature. In contrast, several of the 12 potential protein components identified by mass spectrometry of M. penetrans detergent-insoluble proteins shared certain distinctive biochemical characteristics with M. pneumoniae AO proteins, although not with M. mobile proteins. We conclude that convergence between M. penetrans and M. pneumoniae AOs extends to the molecular level, leading to the possibility that the less organized material in both M. pneumoniae and M. penetrans is the substance principally responsible for the organization and function of the AO. IMPORTANCE Mycoplasma penetrans is a bacterium that infects HIV-positive patients and may contribute to the progression of AIDS. It attaches to host cells through a structure called an AO, but it is not clear how it builds this structure. Our research is significant not only because it identifies the novel protein components that make up the material within the AO that give it its structure but also because we find that the M. penetrans AO is organized unlike AOs from other mycoplasmas, suggesting that similar structures have evolved multiple times. From this work, we derive some basic principles by which mycoplasmas, and potentially all organisms, build structures at the subcellular level. Copyright © 2017 American Society for Microbiology.

AO 0235+164 and Surrounding Field: Surprising HST Results

NASA Technical Reports Server (NTRS)

Burbidge, E. M.; Beaver, E. A.; Cohen, Ross D.; Junkkarinen, V. T.; Lyons, R. W.

1996-01-01

Results obtained with the Hubble Space Telescope on the highly variable radio, x-ray, and gamma-ray emitting QSO (or BL Lac object) AO 0235 + 164 are presented and analyzed. WFPC2 images were obtained in 1994 June, when AO 0235 + 164 was bright (m approx. 17), and the results are described in Sec. 3. After subtraction of the PSF of the QSO, hereafter called AO following the nomenclature of Yanny et al. (1989), the companion object named A, 2 sec south of AO, is discovered not to be an elliptical galaxy as hypothesized earlier, but to be an AGN object, with a central UV-bright point-source nucleus and faint surrounding nebulosity extending to AO. The second companion object 1.3 sec east of AO discovered by Yanny et al. (1989) and named object Al, appears more like a normal spiral galaxy. We have measured the positions, luminosities, and colors of some 30 faint objects in the field around AO 0235 + 16; most are extended and may be star-forming galaxies in a loose group or cluster. Our most surprising result of the HST observations comes from FOS spectra obtained in 1995 July, discussed in Sec. 4. Because of a positioning error of the telescope and AO's faintness at that time (m approx. 20), object A was observed instead of the intended target AO. Serendipitously, we discovered A to have broad deep BALQSO-type absorptions of C IV, Si IV, N V shortward of broad emissions. A is thus ejecting high velocity, highly ionized gas into the surrounding IGM. We discuss in Sec. 5 the relationship of the objects in the central 10 sec X 1O sec region around AO, where redshifts z(sub e) = 0.94, z(sub a) = 0.524, 0.851 in AO, (sub e) = 0.524 and Z(sub BAL)=0.511 in A, are found. We hypothesize that some of the 30 faint objects in the 77 sec. x 77 sec. field may be part of a large star-forming region at z approx. 0.5, as suggested for a few objects by Yanny et al. (1989). The proximity of two highly active extragalactic objects, AO 0235+164 and its AGN companion A, is remarkable and one of the authors (EMB) suggests it may require consideration of a non-cosmological component of redshift in AO 0235+164.

The 40Ar/39Ar dating technique applied to planetary sciences

NASA Astrophysics Data System (ADS)

Jourdan, F.

2012-12-01

The 40Ar/39Ar technique is a powerful geochronological method that can help to unravel the evolution of the solar system. The 40Ar/39Ar system can not only record the timing of volcanic and metamorphic processes on asteroids and planets, it finds domain of predilection in dating impact events throughout the solar system. However, the 40Ar/39Ar method is a robust analytical technique if, and only if, the events to be dated are well understood and data are not over interpreted. Yet, too many 'ages' reported in the literature are still based on over-interpretation of perturbed age spectra which tends to blur the big picture. This presentation is centred on the most recent applications of the 40Ar/39Ar technique applied to planetary material and through several examples, will attempt to demonstrate the benefit of focusing on statistically robust data. For example, 40Ar/39Ar dating of volcanic events on the Moon suggests that volcanism was mostly concentrated between ca. 3.8 and 3.1 Ga but statistical filtering of the data allow identifying a few well-defined eruptive events. The study of lunar volcanism would also benefit from dating of volcanic spherules. Rigorous filtering of the 40Ar/39Ar age database of lunar melt breccias yielded concordant and ages with high precision for two major basins (i.e. Imbrium & Serenitatis) of the Moon. 40Ar/39Ar dating of lunar impact spherules recovered from four different sites and with high- and low-K compositions shows an increase of ages younger than 400 Ma suggesting a recent increase in the impact flux. The impact history of the LL parent body (bodies?) has yet to be well constrained but may mimic the LHB observed on the Moon, which would indicate that the LL parent body was quite large. 40Ar/39Ar dating (in progress) of grains from the asteroid Itokawa recovered by the japanese Hayabusa mission have the potential to constrain the formation history and exposure age of Itokawa and will allow us to compare the results with the impact history recorded by LL chondrites. Basaltic meteorites (HEDs) show a 40Ar/39Ar age range between 4.1 and 3.4 Ga, suggesting a diffuse LHB event; however, the spread of apparent ages may be a data interpretation artefact, as new solid plateau age data suggest that the bombardment by large asteroids might have occurred over a briefer period between 3.5 and 3.8 Ga.

Activation of p300 histone acetyltransferase activity and acetylation of the androgen receptor by bombesin in prostate cancer cells.

PubMed

Gong, J; Zhu, J; Goodman, O B; Pestell, R G; Schlegel, P N; Nanus, D M; Shen, R

2006-03-30

Androgen receptor signaling in prostate cancer cells is augmented by the androgen receptor (AR) coactivator p300, which transactivates and acetylates the AR in the presence of dihydrotestosterone (DHT). As prostate cancer (PC) cells progress to androgen independence, AR signaling remains intact, indicating that other factors stimulate AR activities in the absence of androgen. We previously reported that neuropeptide growth factors could transactivate the AR in the presence of very low concentrations of DHT. Here, we examine the involvement of p300 in neuropeptide activation of AR signaling. Transfection of increasing concentrations of p300 in the presence of bombesin into PC-3 cells resulted in a linear increase in AR transactivation, suggesting that p300 acts as a coactivator in neuropeptide-mediated AR transactivation. P300 is endowed with histone acetyltransferase (HAT) activity. Therefore, we examine the effect of bombesin on p300 HAT activity. At 4 h after the addition of bombesin, p300 HAT activity increased 2.0-fold (P<0.01). Incubation with neutral endopeptidase, which degrades bombesin, or bombesin receptor antagonists blocked bombesin-induced p300 HAT activity. To explore the potential signaling pathways involved in bombesin-induced p300 HAT activity, we examined Src and PKCdelta pathways that mediate bombesin signaling. Inhibitors of Src kinase activity or Src kinase siRNA blocked bombesin-induced p300 HAT activity, whereas PKCdelta inhibitors or PKCdelta siRNA significantly increased bombesin-induced p300 HAT activity suggesting that Src kinase and PKCdelta kinase are involved in the regulation of p300 HAT activity. As AR is acetylated in the presence of 100 nM DHT, we next examined whether bombesin-induced p300 HAT activity would result in enhanced AR acetylation. Bombesin-induced AR acetylation at the same motif KLKK observed in DHT-induced acetylation. Elimination of p300 using p300 siRNA reduced AR acetylation, demonstrating that AR acetylation was mediated by p300. AR acetylation results in AR transactivation and the expression of the AR-regulated gene prostate-specific antigen (PSA). Therefore, we examined bombesin-induced AR transactivation and PSA expression in the presence and absence of p300 siRNA and found inhibition of p300 expression reduced bombesin-induced AR transactivation and PSA expression. Together these results demonstrate that bombesin, via Src and PKCdelta signaling pathways, activates p300 HAT activity which leads to enhanced acetylation of AR resulting in increased expression of AR-regulated genes.

Legacy K/Ar and 40Ar/39Ar geochronologic data from the Alaska-Aleutian Range batholith of south-central Alaska

USGS Publications Warehouse

Koeneman, Lisa L.; Wilson, Frederic H.

2018-04-06

Sample descriptions and analytical data for more than 200 K/Ar and 40Ar/39Ar analyses from rocks of the Alaska-Aleutian Range batholith of south-central Alaska are reported here. Samples were collected over a period of 20 years by Bruce R. Reed and Marvin A. Lanphere (both U.S. Geological Survey) as part of their studies of the batholith.

Cross sections of the 36Ar(d,α)34mCl, 40Ar(d,α)38Cl, and 40Ar(d,p)41Ar nuclear reactions below 8.4 MeV.

PubMed

Engle, J W; Severin, G W; Barnhart, T E; Knutson, L D; Nickles, R J

2012-02-01

We have measured the cross section for production of the medically interesting isotope (34m)Cl, along with (38)Cl and (41)Ar, using deuteron bombardments of (36)Ar and (40)Ar below 8.4 MeV. ALICE/ASH analytical codes were employed to determine the shape of nuclear excitation functions, and experiments were performed using the University of Wisconsin tandem electrostatic accelerator to irradiate thin targets of argon gas. Copyright © 2011 Elsevier Ltd. All rights reserved.

Armenian Astronomical Society Annual Activities in 2014

NASA Astrophysics Data System (ADS)

Mickaelian, A. M.

2015-07-01

A report is given on the achievements of the Armenian astronomy during the last year and on the present activities of the Armenian Astronomical Society (ArAS). ArAS membership, ArAS electronic newsletters (ArASNews), ArAS webpage, annual meetings, Annual Prize for Young Astronomers (Yervant Terzian Prize) and other awards, international relations, presence in international organizations, summer schools, astronomical Olympiads and other events, matters related to astronomical education, astronomical heritage, astronomy outreach and ArAS further projects are discussed. The present meeting, BAO Science Camp, ArAS School lectures are among 2014 events as well.

AR4VI: AR as an Accessibility Tool for People with Visual Impairments

PubMed Central

Coughlan, James M.; Miele, Joshua

2017-01-01

Although AR technology has been largely dominated by visual media, a number of AR tools using both visual and auditory feedback have been developed specifically to assist people with low vision or blindness – an application domain that we term Augmented Reality for Visual Impairment (AR4VI). We describe two AR4VI tools developed at Smith-Kettlewell, as well as a number of pre-existing examples. We emphasize that AR4VI is a powerful tool with the potential to remove or significantly reduce a range of accessibility barriers. Rather than being restricted to use by people with visual impairments, AR4VI is a compelling universal design approach offering benefits for mainstream applications as well. PMID:29303163

AR4VI: AR as an Accessibility Tool for People with Visual Impairments.

PubMed

Coughlan, James M; Miele, Joshua

2017-10-01

Although AR technology has been largely dominated by visual media, a number of AR tools using both visual and auditory feedback have been developed specifically to assist people with low vision or blindness - an application domain that we term Augmented Reality for Visual Impairment (AR4VI). We describe two AR4VI tools developed at Smith-Kettlewell, as well as a number of pre-existing examples. We emphasize that AR4VI is a powerful tool with the potential to remove or significantly reduce a range of accessibility barriers. Rather than being restricted to use by people with visual impairments, AR4VI is a compelling universal design approach offering benefits for mainstream applications as well.

A pulsed plasma jet with the various Ar/N2 mixtures

NASA Astrophysics Data System (ADS)

Barkhordari, A.; Ganjovi, A.; Mirzaei, I.; Falahat, A.; Rostami Ravari, M. N.

2017-12-01

In this paper, using the Optical Emission Spectroscopy technique, the physical properties of a fabricated pulsed DBD plasma jet are studied. Ar/N2 gaseous mixture is taken as operational gas, and Ar contribution in Ar/N2 mixture is varied from 75 to 95%. Through the optical emission spectra analysis of the pulsed DBD plasma jet, the rotational, vibrational and excitation temperatures and density of electrons in plasma medium of the pulsed plasma jet are obtained. It is seen that, at the wavelength of 750.38 nm, the radiation intensity from the Ar 4p → 4 s transition increases at the higher Ar contributions in Ar/N2 mixture. It is found that, for 95% of Ar presence in the mixture, the emission intensities from argon and molecular nitrogen are higher, and the emission line intensities will increase nonlinearly. In addition, it is observed that the quenching of Ar* by N2 results in the higher intensities of N2 excited molecules. Moreover, at the higher percentages of Ar in Ar/N2 mixture, while all the plasma temperatures are increased, the plasma electron density is reduced.

Optical characteristics of a RF DBD plasma jet in various {Ar}/ {O}_{2}Ar/O2 mixtures

NASA Astrophysics Data System (ADS)

Falahat, A.; Ganjovi, A.; Taraz, M.; Ravari, M. N. Rostami; Shahedi, A.

2018-02-01

In this paper, using the optical emission spectroscopy (OES) technique, the optical characteristics of a radiofrequency (RF) plasma jet are examined. The Ar/O2 mixture is taken as the operational gas and, the Ar percentage in the Ar/O2 mixture is varied from 70% to 95%. Using the optical emission spectrum analysis of the RF plasma jet, the excitation temperature is determined based on the Boltzmann plot method. The electron density in the plasma medium of the RF plasma jet is obtained by the Stark broadening of the hydrogen Balmer H_{β }. It is mostly seen that, the radiation intensity of Ar 4p→ 4s transitions at higher argon contributions in Ar/O2 mixture is higher. It is found that, at higher Ar percentages, the emission intensities from atomic oxygen (O) are higher and, the line intensities from the argon atoms and ions including O atoms linearly increase. It is observed that the quenching of Ar^{*} with O2 results in higher O species with respect to O2 molecules. In addition, at higher percentages of Ar in the Ar/O2 mixture, while the excitation temperature is decreased, the electron density is increased.

40Ar/39Ar technique of KAr dating: a comparison with the conventional technique

USGS Publications Warehouse

Brent, Dalrymple G.; Lanphere, M.A.

1971-01-01

K-Ar ages have been determined by the 40Ar/39Ar total fusion technique on 19 terrestrial samples whose conventional K-Ar ages range from 3.4 my to nearly 1700 my. Sample materials included biotite, muscovite, sanidine, adularia, plagioclase, hornblende, actinolite, alunite, dacite, and basalt. For 18 samples there are no significant differences at the 95% confidence level between the KAr ages obtained by these two techniques; for one sample the difference is 4.3% and is statistically significant. For the neutron doses used in these experiments (???4 ?? 1018 nvt) it appears that corrections for interfering Ca- and K-derived Ar isotopes can be made without significant loss of precision for samples with K/Ca > 1 as young as about 5 ?? 105 yr, and for samples with K/Ca < 1 as young as about 107 yr. For younger samples the combination of large atmospheric Ar corrections and large corrections for Ca- and K-derived Ar may make the precision of the 40Ar/39Ar technique less than that of the conventional technique unless the irradiation parameters are adjusted to minimize these corrections. ?? 1971.

KDM4B and KDM4A promote endometrial cancer progression by regulating androgen receptor, c-myc, and p27kip1

PubMed Central

Kwan, Suet-Ying; Chen, Limo; Chen, Jin-Hong; Ying, Zuo-Lin; Zhou, Ye; Gu, Wei; Wang, Li-Hua; Cheng, Wei-Wei; Zeng, Jianfang; Wan, Xiao-Ping; Mok, Samuel C.; Wong, Kwong-Kwok; Bao, Wei

2015-01-01

Epidemiological evidence suggests that elevated androgen levels and genetic variation related to the androgen receptor (AR) increase the risk of endometrial cancer (EC). However, the role of AR in EC is poorly understood. We report that two members of the histone demethylase KDM4 family act as major regulators of AR transcriptional activityin EC. In the MFE-296 cell line, KDM4B and AR upregulate c-myc expression, while in AN3CA cells KDM4A and AR downregulate p27kip1. Additionally, KDM4B expression is positively correlated with AR expression in EC cell lines with high baseline AR expression, while KDM4A and AR expression are positively correlated in low-AR cell lines. In clinical specimens, both KDM4B and KDM4A expression are significantly higher in EC tissues than that in normal endometrium. Finally, patients with alterations in AR, KDM4B, KDM4A, and c-myc have poor overall and disease-free survival rates. Together, these findings demonstrate that KDM4B and KDM4A promote EC progression by regulating AR activity. PMID:26397136

A novel prostate cancer therapeutic strategy using icaritin-activated arylhydrocarbon-receptor to co-target androgen receptor and its splice variants

PubMed Central

Sun, Feng; Indran, Inthrani R.; Zhang, Zhi Wei; Tan, M.H.Eileen; Li, Yu; Lim, Z.L.Ryan; Hua, Rui; Yang, Chong; Soon, Fen-Fen; Li, Jun; Xu, H.Eric; Cheung, Edwin; Yong, Eu-Leong

2015-01-01

Persistent androgen receptor (AR) signaling is the key driving force behind progression and development of castration-resistant prostate cancer (CRPC). In many patients, AR COOH-terminal truncated splice variants (ARvs) play a critical role in contributing to the resistance against androgen depletion therapy. Unfortunately, clinically used antiandrogens like bicalutamide (BIC) and enzalutamide (MDV), which target the ligand binding domain, have failed to suppress these AR variants. Here, we report for the first time that a natural prenylflavonoid, icaritin (ICT), can co-target both persistent AR and ARvs. ICT was found to inhibit transcription of key AR-regulated genes, such as KLK3 [prostate-specific antigen (PSA)] and ARvs-regulated genes, such as UBE2C and induce apoptosis in AR-positive prostate cancer (PC) cells. Mechanistically, ICT promoted the degradation of both AR and ARvs by binding to arylhydrocarbon-receptor (AhR) to mediate ubiquitin-proteasomal degradation. Therefore, ICT impaired AR transactivation in PC cells. Knockdown of AhR gene restored AR stability and partially prevented ICT-induced growth suppression. In clinically relevant murine models orthotopically implanted with androgen-sensitive and CRPC cells, ICT was able to target AR and ARvs, to inhibit AR signaling and tumor growth with no apparent toxicity. Our results provide a mechanistic framework for the development of ICT, as a novel lead compound for AR-positive PC therapeutics, especially for those bearing AR splice variants. PMID:25908644

Characteristics of southern California atmospheric rivers

NASA Astrophysics Data System (ADS)

Harris, Sarah M.; Carvalho, Leila M. V.

2018-05-01

Atmospheric rivers (ARs) are channels of high water vapor flux that transport moisture from low to higher latitudes on synoptic timescales. In areas of topographical variability, ARs may lead to high-intensity precipitation due to orographic forcing. ARs landfalling along North America's west coast are linked to extreme events including those leading to flooding and landslides. In southern California (SCA), proper AR forecasting is important for regional water resources as well as hazard mitigation and as the area's annual precipitation totals occur from relatively few storms per season, any changes to storm frequency and/or intensity may have dramatic consequences. Yet, as most regional AR studies focus on the Pacific Northwest, there is little information about SCA ARs. We develop an algorithm to identify ARs landfalling on North America's west coast between 1979 and 2013 within total precipitable water reanalysis fields. ARs are then categorized according to landfall region. To determine and differentiate the characteristics and spatial distributions of ARs affecting these areas, we examine lag composites of various atmospheric variables for each landfall region. SCA ARs differ from ARs landfalling farther north in the days prior to landfall with the position and amplitude of a trough offshore from the Asian continent and ridge over Alaska, as well as the displacement and eastward extension of the jet core that potentially guides AR moisture southwards. The relationships between AR landfalls and the El Niño/Southern Oscillation (ENSO), the Madden-Julian Oscillation (MJO), and the Pacific/North American Teleconnection Pattern (PNA) are also investigated.

Artesunate-modified nano-graphene oxide for chemo-photothermal cancer therapy

PubMed Central

Pang, Yilin; Mai, Zihao; Wang, Bin; Wang, Lu; Wu, Liping; Wang, Xiaoping; Chen, Tongsheng

2017-01-01

Poor water-solubility of artesunate (ARS) hampers its clinical application. We here covalently linked ARS to PEGylated nanographene oxide (nGO-PEG) to obtain ARS-modified nGO-PEG (nGO-PEG-ARS) with excellent photothermal effect and dispersibility in physiological environment. nGO-PEG-ARS induced reactive oxygen species (ROS) and peroxynitrite (ONOO─) generations. Although nGO-PEG with near-infrared (NIR) irradiation did not induce cytotoxicity, the photothermal effect of nGO-PEG under NIR irradiation enhanced not only cell uptake but also ONOO─ generation of nGO-PEG-ARS, resulting in the synergistic chemo-photothermal effect of nGO-PEG-ARS in killing HepG2 cells. Pretreatment with Fe(III) 5,10,15,20-tetrakis (4-sulfonatophenyl) porphyrinato chloride (FeTTPS, a ONOO─ scavenger) instead of antioxidant N-Acetyle-Cysteine (NAC, an ROS scavenger) significantly blocked the cytotoxicity of nGO-PEG-ARS with or without NIR irradiation, demonstrating that ONOO─ instead of ROS dominated the synergistic chemo-photothermal anti-cancer action of nGO-PEG-ARS. nGO-PEG-ARS with NIR irradiation resulted in a complete tumor cure within 15 days earlier than other treatment groups, and did not induce apparent histological lesion for the mice treated with nGO-PEG-ARS with or without NIR irradiation for 30 days, further proving the synergistic chemo-photothermal anti-cancer effect of nGO-PEG-ARS. Collectively, nGO-PEG-ARS is a versatile nano-platform for multi-modal synergistic cancer therapy. PMID:29212190

Prostate Cancer Cells Express More Androgen Receptor (AR) Following Androgen Deprivation, Improving Recognition by AR-Specific T Cells.

PubMed

Olson, Brian M; Gamat, Melissa; Seliski, Joseph; Sawicki, Thomas; Jeffery, Justin; Ellis, Leigh; Drake, Charles G; Weichert, Jamey; McNeel, Douglas G

2017-12-01

Androgen deprivation is the primary therapy for recurrent prostate cancer, and agents targeting the androgen receptor (AR) pathway continue to be developed. Because androgen-deprivation therapy (ADT) has immmunostimulatory effects as well as direct antitumor effects, AR-targeted therapies have been combined with other anticancer therapies, including immunotherapies. Here, we sought to study whether an antigen-specific mechanism of resistance to ADT (overexpression of the AR) may result in enhanced AR-specific T-cell immune recognition, and whether this might be strategically combined with an antitumor vaccine targeting the AR. Androgen deprivation increased AR expression in human and murine prostate tumor cells in vitro and in vivo The increased expression persisted over time. Increased AR expression was associated with recognition and cytolytic activity by AR-specific T cells. Furthermore, ADT combined with vaccination, specifically a DNA vaccine encoding the ligand-binding domain of the AR, led to improved antitumor responses as measured by tumor volumes and delays in the emergence of castrate-resistant prostate tumors in two murine prostate cancer models (Myc-CaP and prostate-specific PTEN-deficient mice). Together, these data suggest that ADT combined with AR-directed immunotherapy targets a major mechanism of resistance, overexpression of the AR. This combination may be more effective than ADT combined with other immunotherapeutic approaches. Cancer Immunol Res; 5(12); 1074-85. ©2017 AACR . ©2017 American Association for Cancer Research.

Binding of bisphenol A, bisphenol AF, and bisphenol S on the androgen receptor: Coregulator recruitment and stimulation of potential interaction sites.

PubMed

Perera, Lalith; Li, Yin; Coons, Laurel A; Houtman, Rene; van Beuningen, Rinie; Goodwin, Bonnie; Auerbach, Scott S; Teng, Christina T

2017-10-01

Bisphenol A (BPA), bisphenol AF (BPAF), and bisphenol S (BPS) are well known endocrine disruptors. Previous in vitro studies showed that these compounds antagonize androgen receptor (AR) transcriptional activity; however, the mechanisms of action are unclear. In the present study, we investigated interactions of coregulator peptides with BPA, BPAF, or BPS at the AR complexes using Micro Array for Real-time Coregulator Nuclear Receptor Interaction (MARCoNI) assays and assessed the binding of these compounds on AR by molecular dynamics (MD) simulations. The set of coregulator peptides that are recruited by BPA-bound AR, either positively/or negatively, are different from those recruited by the agonist R1881-bound AR. Therefore, the data indicates that BPA shows no similarities to R1881 and suggests that it may recruit other coregulators to the AR complex. BPAF-bound AR recruits about 70-80% of the same coregulator peptides as BPA-bound AR. Meanwhile, BPS-bound AR interacts with only few peptides compared to BPA or BPAF-bound AR. MD results show that multiple binding sites with varying binding affinities are available on AR for BPA, BPAF, and BPS, indicating the availability of modified binding surfaces on AR for coregulator interactions. These findings help explain some of the distinct AR-related toxicities observed with bisphenol chemicals and raise concern for the use of substitutes for BPA in commercial products. Published by Elsevier Ltd.

The 40Ar/39Ar and K/Ar dating of lavas from the Hilo 1-km core hole, Hawaii Scientific Drilling Project

USGS Publications Warehouse

Sharp, W.D.; Turrin, B.D.; Renne, P.R.; Lanphere, M.A.

1996-01-01

Mauna Kea lava flows cored in the HilIo hole range in age from <200 ka to about 400 ka based on 40Ar/39Ar incremental heating and K-Ar analyses of 16 groundmass samples and one coexisting plagioclase. The lavas, all subaerially deposited, include a lower section consisting only of tholeiitic basalts and an upper section of interbedded alkalic, transitional tholeiitic, and tholeiitic basalts. The lower section has yielded predominantly complex, discordant 40Ar/39Ar age spectra that result from mobility of 40Ar and perhaps K, the presence of excess 40Ar, and redistribution of 39Ar by recoil. Comparison of K-Ar ages with 40Ar/39Ar integrated ages indicates that some of these samples have also lost 39Ar. Nevertheless, two plateau ages of 391 ?? 40 and 400 ?? 26 ka from deep in the hole, combined with data from the upper section, show that the tholeiitic section accumulated at an average rate of about 7 to 8 m/kyr and has an mean recurrence interval of 0.5 kyr/flow unit. Samples from the upper section yield relatively precise 40Ar/39Ar plateau and isotope correlation ages of 326 ?? 23, 241 ?? 5, 232 ?? 4, and 199 ?? 9 ka for depths of -415.7 m to -299.2 m. Within their uncertainty, these ages define a linear relationship with depth, with an average accumulation rate of 0.9 m/kyr and an average recurrence interval of 4.8 kyr/flow unit. The top of the Mauna Kea sequence at -280 m must be older than the plateau age of 132 ?? 32 ka, obtained for the basal Mauna Loa flow in the corehole. The upward decrease in lava accumulation rate is a consequence of the decreasing magma supply available to Mauna Kea as it rode the Pacific plate away from its magma source, the Hawaiian mantle plume. The age-depth relation in the core hole may be used to test and refine models that relate the growth of Mauna Kea to the thermal and compositional structure of the mantle plume.

Adult body size and physical activity in relation to risk of breast cancer according to tumor androgen receptor status.

PubMed

Zhang, Xuehong; Eliassen, A Heather; Tamimi, Rulla M; Hazra, Aditi; Beck, Andrew H; Brown, Myles; Collins, Laura C; Rosner, Bernard; Hankinson, Susan E

2015-06-01

Obesity and physical activity have been hypothesized to affect breast cancer risk partly via the androgen signaling pathway. We conducted the first study to evaluate these associations by tumor androgen receptor (AR) status. Height, weight, and physical activity were assessed using questionnaires in the Nurses' Health Study. AR, estrogen receptor (ER), and progesterone receptor (PR) status were determined using immunohistochemistry on tumor tissue and medical/pathology reports. A total of 1,701 AR(+) and 497 AR(-) cases were documented during 26 years of follow-up of 103,577 women. After adjusting for ER/PR status and other risk factors, the relative risks (RR) and 95% confidence intervals (95% CI) for every 5 kg/m(2) increase in body mass index (BMI) were 1.07 (1.01-1.13) for AR(+) and 1.16 (1.05-1.29) for AR(-) tumors (P-heterogeneity = 0.17). The RRs (95% CIs) per 5 hours of brisk walking/week were 0.87 (0.73-1.04) for AR(+) and 0.67 (0.45-0.99) for AR(-) tumors (P-heterogeneity = 0.22). Further, BMI, but not physical activity, associations differed significantly across ER/PR/AR subtypes (P-heterogeneity = 0.04 and 0.63, respectively). The RRs (95% CIs) for 5 kg/m(2) increase in BMI were 1.23 (1.04-1.45) for ER(+)PR(+)AR(-), 1.19 (1.01-1.39) for ER(-)PR(-)AR(-), 1.15 (1.08-1.23) for ER(+)PR(+)AR(+), and 0.88 (0.75-1.03) for ER(+)PR(-)AR(+) tumors. Higher BMI was associated with an increased risk of both AR(+) and AR(-) breast tumors in postmenopausal women, whereas physical activity, including brisk walking, was associated with a reduced risk of both subtypes. In addition, a significant positive association was observed between higher BMI and ER(-)PR(-)AR(-) tumors. The similar associations observed by AR status suggest that mechanisms other than androgen signaling underlie these two breast cancer risk factors. ©2015 American Association for Cancer Research.

Ar-Ar and I-Xe Ages and the Thermal History of IAB Meteorites

NASA Technical Reports Server (NTRS)

Bogard, Donald D.; Garrison, Daniel H.; Takeda, Hiroshi

2005-01-01

Studies of several samples of the large Caddo County IAB iron meteorite reveal andesitic material, enriched in Si, Na, Al and Ca, which is essentially unique among meteorites. This material is believed to have formed from a chondritic source by partial melting and to have further segregated by grain coarsening. Such an origin implies extended metamorphism of the IAB parent body. New Ar-39- Ar-40 ages for silicate from three different Caddo samples are consistent with a common age of 4.50-4.51 Gyr ago. Less well defined Ar-Ar degassing ages for inclusions from two other IABs, EET8333 and Udei Station, are approx.4.32 Gyr, whereas the age for Campo del Cielo varies considerably over approx.3.23-4.56 Gyr. New I-129-Xe-129 ages for Caddo County and EET8333 are 4557.9+/-0.1 Myr and 4557-4560 Myr, respectively, relative to an age of 4562.3 Myr for Shallowater. Considering all reported Ar-Ar degassing ages for IABs and related winonaites, the range is approx.4.32-4.53 Gyr, but several IABs give similar Ar ages of 4.50-4.52 Gyr. We interpret these older Ar ages to represent cooling after the time of last significant metamorphism on the parent body, and the younger ages to represent later 40Ar diffusion loss. The older Ar-Ar ages for IABs are similar to Sm-Nd and Rb-Sr isochron ages reported in the literature for Caddo County. Considering the possibility that IAB parent body formation was followed by impact disruption, reassembly, and metamorphism (e.g., Benedix et al. 2000), the Ar-Ar ages and IAB cooling rates deduced from Ni concentration profiles in IAB metal (Herpfer et al., 1994) are consistent if the time of the post-assembly metamorphism was as late as approx.4.53 Gyr ago. However, I-Xe ages reported for some IABs define much older ages of approx.4558-4566 Myr, which cannot easily be reconciled with the much younger Ar-Ar and Sm-Nd ages. An explanation for the difference in radiometric ages of IABs may reside in combinations of the following: a) I-Xe ages have very high closure temperatures and were not reset during metamorphism approx.4.53 Gyr ago; b) a bias exists in the 40K decay constants which makes these Ar-Ar ages approx.30 Myr too young; c) the reported Sm-Nd and Rb-Sr ages for Caddo are in error by amounts equal to or exceeding their reported 2-sigma uncertainties; and d) about 30 Myr after the initial heating that produced differentiation of Caddo silicate and mixing of silicate and metal, a mild metamorphism of the IAB parent body reset the Ar-Ar ages.

High resolution observations using adaptive optics: Achievements and future needs

NASA Astrophysics Data System (ADS)

Sankarasubramanian, K.; Rimmele, T.

2008-06-01

Over the last few years, several interesting observations were obtained with the help of solar Adaptive Optics (AO). In this paper, few observations made using the solar AO are enlightened and briefly discussed. A list of disadvantages with the current AO system are presented. With telescopes larger than 1.5 m expected during the next decade, there is a need to develop the existing AO technologies for large aperture telescopes. Some aspects of this development are highlighted. Finally, the recent AO developments in India are also presented.

Apraxia of speech: an overview.

PubMed

Ogar, Jennifer; Slama, Hilary; Dronkers, Nina; Amici, Serena; Gorno-Tempini, Maria Luisa

2005-12-01

Apraxia of speech (AOS) is a motor speech disorder that can occur in the absence of aphasia or dysarthria. AOS has been the subject of some controversy since the disorder was first named and described by Darley and his Mayo Clinic colleagues in the 1960s. A recent revival of interest in AOS is due in part to the fact that it is often the first symptom of neurodegenerative diseases, such as primary progressive aphasia and corticobasal degeneration. This article will provide a brief review of terminology associated with AOS, its clinical hallmarks and neuroanatomical correlates. Current models of motor programming will also be addressed as they relate to AOS and finally, typical treatment strategies used in rehabilitating the articulation and prosody deficits associated with AOS will be summarized.

Design of active orthoses for a robotic gait rehabilitation system

NASA Astrophysics Data System (ADS)

Villa-Parra, A. C.; Broche, L.; Delisle-Rodríguez, D.; Sagaró, R.; Bastos, T.; Frizera-Neto, A.

2015-09-01

An active orthosis (AO) is a robotic device that assists both human gait and rehabilitation therapy. This work proposes portable AOs, one for the knee joint and another for the ankle joint. Both AOs will be used to complete a robotic system that improves gait rehabilitation. The requirements for actuator selection, the biomechanical considerations during the AO design, the finite element method, and a control approach based on electroencephalographic and surface electromyographic signals are reviewed. This work contributes to the design of AOs for users with foot drop and knee flexion impairment. However, the potential of the proposed AOs to be part of a robotic gait rehabilitation system that improves the quality of life of stroke survivors requires further investigation.

High Spatial Resolution 40Ar/39Ar Geochronology of Lunar Impact Melt Rocks

NASA Astrophysics Data System (ADS)

Mercer, Cameron Mark

Impact cratering has played a key role in the evolution of the solid surfaces of Solar System bodies. While much of Earth’s impact record has been erased, its Moon preserves an extensive history of bombardment. Quantifying the timing of lunar impact events is crucial to understanding how impacts have shaped the evolution of early Earth, and provides the basis for estimating the ages of other cratered surfaces in the Solar System. Many lunar impact melt rocks are complex mixtures of glassy and crystalline “melt” materials and inherited clasts of pre-impact minerals and rocks. If analyzed in bulk, these samples can yield complicated incremental release 40Ar/39Ar spectra, making it challenging to uniquely interpret impact ages. Here, I have used a combination of high-spatial resolution 40Ar/39Ar geochronology and thermal-kinetic modeling to gain new insights into the impact histories recorded by such lunar samples. To compare my data to those of previous studies, I developed a software tool to account for differences in the decay, isotopic, and monitor age parameters used for different published 40Ar/39Ar datasets. Using an ultraviolet laser ablation microprobe (UVLAMP) system I selectively dated melt and clast components of impact melt rocks collected during the Apollo 16 and 17 missions. UVLAMP 40Ar/39Ar data for samples 77135, 60315, 61015, and 63355 show evidence of open-system behavior, and provide new insights into how to interpret some complexities of published incremental heating 40Ar/39Ar spectra. Samples 77115, 63525, 63549, and 65015 have relatively simple thermal histories, and UVLAMP 40Ar/39Ar data for the melt components of these rocks indicate the timing of impact events—spanning hundreds of millions of years—that influenced the Apollo 16 and 17 sites. My modeling and UVLAMP 40Ar/39Ar data for sample 73217 indicate that some impact melt rocks can quantitatively retain evidence for multiple melt-producing impact events, and imply that such polygenetic rocks should be regarded as high-value sampling opportunities during future exploration missions to cratered planetary surfaces. Collectively, my results complement previous incremental heating 40Ar/39Ar studies, and support interpretations that the Moon experienced a prolonged period of heavy bombardment early in its history.

Ar-39-Ar-40 Evidence for Early Impact Events on the LL Parent Body

NASA Technical Reports Server (NTRS)

Dixon, E. T.; Bogard, D. D.; Garrison, D. H.; Rubin, A. E.

2006-01-01

We determined Ar-39-Ar-40 ages of eight LL chondrites, and one igneous inclusion from an LL chondrite, with the object of understanding the thermal history of the LL-chondrite parent body. The meteorites in this study have a range of petrographic types from LL3.3 to LL6, and shock stages from S1 to S4. These meteorites reveal a range of K-Ar ages from 23.66 to 24.50 Ga, and peak ages from 23.74 to 24.55 Ga. Significantly, three of the eight chondrites (LL4, 5, 6) have K-Ar ages of -4.27 Ga. One of these (MIL99301) preserves an Ar-39-Ar-40 age of 4.23 +/- 0.03 Ga from low-temperature extractions, and an older age of 4.52 +/- 0.08 Ga from the highest temperature extractions. In addition, an igneous-textured impact melt DOM85505,22 has a peak Ar-39-Ar-40 age of >= 4.27 Ga. We interpret these results as evidence for impact events that occurred at about 4.27 Ga on the LL parent body that produced local impact melts, reset the Ar-39-Ar-40 ages of some meteorites, and exhumed (or interred) others, resulting in a range of cooling ages. The somewhat younger peak age of 3.74 Ga from GR095658 (LL3.3) suggests an additional impact event close to timing of impact-reset ages of some other ordinary chondrites between 3.6-3.8 Ga. The results from MIL99301 suggest that some apparently unshocked (Sl) chondrites may have substantially reset Ar-39-Ar-40 ages. A previous petrographic investigation of MIL99301 suggested that reheating to temperatures less than or equal to type 4 petrographic conditions (600C) caused fractures in olivine to anneal, resulting in a low apparent shock stage of S1 (unshocked). The Ar-39-Ar-40 age spectrum of MIL99301 is consistent with this interpretation. Older ages from high-T extractions may date an earlier impact event at 4.52 +/- 0.08 Ga, whereas younger ages from lower-T extractions date a later impact event at 4.23 Ar-39-Ar-40 0.03 Ga that may have caused annealing of feldspar and olivine

Landfalling Atmospheric Rivers in California—Historical and Future Impacts

NASA Astrophysics Data System (ADS)

Dettinger, M. D.; Ralph, F. M.

2014-12-01

During the past decade, a wide range of insights about the character and causes of extreme orographic precipitation in California has emerged, based on our growing understanding of the presence, mechanisms and impacts of "atmospheric rivers" (ARs) in the extratropical atmosphere. When an AR reaches and encounters the Coastal Ranges and Sierra Nevada of California, the resulting orographically driven storms are key players in many important weather, hydrologic and ecological processes in the State, including floods and floodplain inundations, droughts, groundwater recharge, and surface-water resources (see table). The intensities, storm totals, geographical distributions and impacts of AR storms in California are determined by many factors, including among the most straightforward: The numbers of ARs making landfall each year The amounts of vapor being transported by the ARs The direction of vapor transport by the AR relative to perpendiculars to the mountain ranges (for maximum uplift) The duration of AR passage overhead of a given location The temperature of an AR as a determinant of snowline altitudes The stability of the atmosphere within which the AR is embedded The closeness of the air in the AR to saturation (how much uplift is needed to drive intense precipitation) ARs are present in weather forecast models as well as in the long-range climate models used to project future climate changes in response to increasing greenhouse-gas concentrations in the atmosphere. Research into the future of ARs over California was first reported in the literature in 2011 (based on IPCC AR4 climate models) and is being extended now (to IPCC AR5 models) to assess projected changes in the full range of factors listed above with the aim of predicting how climate change will affect these important storms and their impacts in coming decades.

Galbanic acid decreases androgen receptor abundance and signaling and induces G1 arrest in prostate cancer cells

PubMed Central

Zhang, Yong; Kim, Kwan-Hyun; Zhang, Wei; Guo, Yinglu; Kim, Sung-Hoon; Lü, Junxuan

2011-01-01

Androgen receptor (AR) signaling is crucial for the genesis and progression of prostate cancer (PCa). We compared the growth responses of AR(+) LNCaP and LNCaP C4-2 vs. AR(−) DU145 and PC-3 PCa cell lines to galbanic acid (GBA) isolated from the resin of medicinal herb Ferula assafoetida and assessed their connection to AR signaling and cell cycle regulatory pathways. Our results showed that GBA preferentially suppressed AR(+) PCa cell growth than AR(−) PCa cells. GBA induced a caspase-mediated apoptosis that was attenuated by a general caspase inhibitor. Subapoptotic GBA down-regulated AR protein in LNCaP cells primarily through promoting its proteasomal degradation, and inhibited AR-dependent transcription without affecting AR nuclear translocation. Whereas docking simulations predicted binding of GBA to the AR ligand binding domain with similarities and differences with the AR antagonist drug bicalutamide, LNCaP cell culture assays did not detect agonist activity of GBA. GBA and bicalutamide exerted greater than additive inhibitory effect on cell growth when used together. Subapoptotic GBA induced G1 arrest associated with an inhibition of cyclin/CDK4/6 pathway, especially cyclin D1 without the causal involvement of CDK inhibitory proteins P21Cip1 and P27Kip1. In summary, the novelty of GBA as an anti-AR compound resides in the distinction between GBA and bicalutamide with respect to AR protein turnover and a lack of agonist effect. Our observations of anti-AR and cell cycle arrest actions plus the anti-angiogenesis effect reported elsewhere suggest GBA as a multi-targeting drug candidate for the prevention and therapy of PCa. PMID:21328348

Androgen receptor-dependent and -independent mechanisms driving prostate cancer progression: Opportunities for therapeutic targeting from multiple angles

PubMed Central

Hoang, David T; Iczkowski, Kenneth A; Kilari, Deepak; See, William; Nevalainen, Marja T

2017-01-01

Despite aggressive treatment for localized cancer, prostate cancer (PC) remains a leading cause of cancer-related death for American men due to a subset of patients progressing to lethal and incurable metastatic castrate-resistant prostate cancer (CRPC). Organ-confined PC is treated by surgery or radiation with or without androgen deprivation therapy (ADT), while options for locally advanced and disseminated PC include radiation combined with ADT, or systemic treatments including chemotherapy. Progression to CRPC results from failure of ADT, which targets the androgen receptor (AR) signaling axis and inhibits AR-driven proliferation and survival pathways. The exact mechanisms underlying the transition from androgen-dependent PC to CRPC remain incompletely understood. Reactivation of AR has been shown to occur in CRPC despite depletion of circulating androgens by ADT. At the same time, the presence of AR-negative cell populations in CRPC has also been identified. While AR signaling has been proposed as the primary driver of CRPC, AR-independent signaling pathways may represent additional mechanisms underlying CRPC progression. Identification of new therapeutic strategies to target both AR-positive and AR-negative PC cell populations and, thereby, AR-driven as well as non-AR-driven PC cell growth and survival mechanisms would provide a two-pronged approach to eliminate CRPC cells with potential for synthetic lethality. In this review, we provide an overview of AR-dependent and AR-independent molecular mechanisms which drive CRPC, with special emphasis on the role of the Jak2-Stat5a/b signaling pathway in promoting castrate-resistant growth of PC through both AR-dependent and AR-independent mechanisms. PMID:27741508

Cellular androgen content influences enzalutamide agonism of F877L mutant androgen receptor

PubMed Central

Coleman, Daniel J.; Van Hook, Kathryn; King, Carly J.; Schwartzman, Jacob; Lisac, Robert; Urrutia, Joshua; Sehrawat, Archana; Woodward, Josha; Wang, Nicholas J.; Gulati, Roman; Thomas, George V.; Beer, Tomasz M.; Gleave, Martin; Korkola, James E.; Gao, Lina; Heiser, Laura M.; Alumkal, Joshi J.

2016-01-01

Prostate cancer is the most commonly diagnosed and second-most lethal cancer among men in the United States. The vast majority of prostate cancer deaths are due to castration-resistant prostate cancer (CRPC) – the lethal form of the disease that has progressed despite therapies that interfere with activation of androgen receptor (AR) signaling. One emergent resistance mechanism to medical castration is synthesis of intratumoral androgens that activate the AR. This insight led to the development of the AR antagonist enzalutamide. However, resistance to enzalutamide invariably develops, and disease progression is nearly universal. One mechanism of resistance to enzalutamide is an F877L mutation in the AR ligand-binding domain that can convert enzalutamide to an agonist of AR activity. However, mechanisms that contribute to the agonist switch had not been fully clarified, and there were no therapies to block AR F877L. Using cell line models of castration-resistant prostate cancer (CRPC), we determined that cellular androgen content influences enzalutamide agonism of mutant F877L AR. Further, enzalutamide treatment of AR F877L-expressing cell lines recapitulated the effects of androgen activation of F877L AR or wild-type AR. Because the BET bromodomain inhibitor JQ-1 was previously shown to block androgen activation of wild-type AR, we tested JQ-1 in AR F877L-expressing CRPC models. We determined that JQ-1 suppressed androgen or enzalutamide activation of mutant F877L AR and suppressed growth of mutant F877L AR CRPC tumors in vivo, demonstrating a new strategy to treat tumors harboring this mutation. PMID:27276681

Androgen receptor activity modulates responses to cisplatin treatment in bladder cancer.

PubMed

Kashiwagi, Eiji; Ide, Hiroki; Inoue, Satoshi; Kawahara, Takashi; Zheng, Yichun; Reis, Leonardo O; Baras, Alexander S; Miyamoto, Hiroshi

2016-08-02

Cisplatin (CDDP)-based combination chemotherapy remains the mainstream treatment for advanced bladder cancer. However, its efficacy is often limited due to the development of resistance for which underlying mechanisms are poorly understood. Meanwhile, emerging evidence has indicated the involvement of androgen-mediated androgen receptor (AR) signals in bladder cancer progression. In this study, we aimed to investigate whether AR signals have an impact on sensitivity to CDDP in bladder cancer cells. UMUC3-control-short hairpin RNA (shRNA) cells with endogenous AR and AR-negative 647V/5637 cells stably expressing AR were significantly more resistant to CDDP treatment at its pharmacological concentrations, compared with UMUC3-AR-shRNA and 647V-vector/5637-vector control cells, respectively. A synthetic androgen R1881 significantly reduced CDDP sensitivity in UMUC3, 647V-AR, or 5637-AR cells, and the addition of an anti-androgen hydroxyflutamide inhibited the effect of R1881. In these AR-positive cells, R1881 treatment also induced the expression levels of NF-κB, which is known to involve CDDP resistance, and its phosphorylated form, as well as nuclear translocation of NF-κB. In CDDP-resistant bladder cancer sublines established following long-term culture with CDDP, the expression levels of AR as well as NF-κB and phospho-NF-κB were considerably elevated, compared with respective control sublines. In bladder cancer specimens, there was a strong trend to correlate between AR positivity and chemoresistance. These results suggest that AR activation correlates with CDDP resistance presumably via modulating NF-κB activity in bladder cancer cells. Targeting AR during chemotherapy may thus be a useful strategy to overcome CDDP resistance in patients with AR-positive bladder cancer.

ID4 promotes AR expression and blocks tumorigenicity of PC3 prostate cancer cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Komaragiri, Shravan Kumar; Bostanthirige, Dhanushka H.; Morton, Derrick J.

Deregulation of tumor suppressor genes is associated with tumorigenesis and the development of cancer. In prostate cancer, ID4 is epigenetically silenced and acts as a tumor suppressor. In normal prostate epithelial cells, ID4 collaborates with androgen receptor (AR) and p53 to exert its tumor suppressor activity. Previous studies have shown that ID4 promotes tumor suppressive function of AR whereas loss of ID4 results in tumor promoter activity of AR. Previous study from our lab showed that ectopic ID4 expression in DU145 attenuates proliferation and promotes AR expression suggesting that ID4 dependent AR activity is tumor suppressive. In this study, wemore » examined the effect of ectopic expression of ID4 on highly malignant prostate cancer cell, PC3. Here we show that stable overexpression of ID4 in PC3 cells leads to increased apoptosis and decreased cell proliferation and migration. In addition, in vivo studies showed a decrease in tumor size and volume of ID4 overexpressing PC3 cells, in nude mice. At the molecular level, these changes were associated with increased androgen receptor (AR), p21, and AR dependent FKBP51 expression. At the mechanistic level, ID4 may regulate the expression or function of AR through specific but yet unknown AR co-regulators that may determine the final outcome of AR function. - Highlights: • ID4 expression induces AR expression in PC3 cells, which generally lack AR. • ID4 expression increased apoptosis and decreased cell proliferation and invasion. • Overexpression of ID4 reduces tumor growth of subcutaneous xenografts in vivo. • ID4 induces p21 and FKBP51 expression- co-factors of AR tumor suppressor activity.« less

Effects of a preemptive alveolar recruitment strategy on arterial oxygenation during one-lung ventilation with different tidal volumes in patients with normal pulmonary function test.

PubMed

Jung, Jong Dal; Kim, Sang Hun; Yu, Byung Sik; Kim, Hye Ji

2014-08-01

Hypoxemia during one-lung ventilation (OLV) remains a major concern. The present study compared the effect of alveolar recruitment strategy (ARS) on arterial oxygenation during OLV at varying tidal volumes (Vt) with or without positive end-expiratory pressure (PEEP). In total, 120 patients undergoing wedge resection by video assisted thoracostomy were randomized into four groups comprising 30 patients each: those administered a 10 ml/kg tidal volume with or without preemptive ARS (Group H and Group H-ARS, respectively) and those administered a 6 ml/kg tidal volume and a 8 cmH2O PEEP with or without preemptive ARS (Group L and Group L-ARS, respectively). ARS was performed using pressure-controlled ventilation with a 40 cmH2O plateau airway pressure and a 15 cmH2O PEEP for at least 10 breaths until OLV began. Preemptive ARS significantly improved the PaO2/FiO2 ratio compared to the groups that did not receive ARS (P < 0.05). The H-ARS group showed a highest PaO2/FiO2 ratio during OLV, the L-ARS and H groups showed similarly improved arterial oxygenation, which was significantly higher than in group L (P < 0.05). The plateau airway pressure in group H-ARS was significantly higher than in group L-ARS (P < 0.05). Preemptive ARS can improve arterial oxygenation during OLV. Furthermore, a 6 ml/kg tidal volume combined with 8 cmH2O PEEP after preemptive ARS may reduce the risk of pulmonary injury caused by high tidal volume during one-lung ventilation in patients with normal pulmonary function.

Functional potentiation of leptin-signal transducer and activator of transcription 3 signaling by the androgen receptor.

PubMed

Fan, WuQiang; Yanase, Toshihiko; Nishi, Yoshihiro; Chiba, Seiichi; Okabe, Taijiro; Nomura, Masatoshi; Yoshimatsu, Hironobu; Kato, Shigeaki; Takayanagi, Ryoichi; Nawata, Hajime

2008-12-01

Hypogonadism is associated with increased fat mass and dysregulation of metabolic homeostasis in men. Our previous study revealed that androgen receptor (AR)-null male mice (ARL-/Y) develop late-onset obesity and are leptin-resistant. The present study evaluated how hypothalamic AR contributes to central leptin-signal transducer and activator of transcription 3 (STAT3) signaling. We evaluated leptin action in wild-type and ARL-/Y mice, the anatomic co-relationship between AR and leptin signaling in the hypothalamus, and the effects of AR on leptin-mediated STAT3 transactivation and nuclear translocation. AR deletion in male mice results in a weaker leptin-induced suppression of food intake and body weight drop even before the onset of overt obesity. In wild-type male but not female mice, AR was highly expressed in various hypothalamic nuclei that also expressed the long-form leptin receptor (OBRB) and co-resided with OBRB directly in the arcuate neurons. In vitro, AR significantly enhanced STAT3-mediated transcription of leptin target genes including POMC and SOCS3. This effect relied on the AR N-terminal activation function-1 (AF-1) domain and was specific to AR in that none of the other sex steroid hormone receptors tested showed similar effects. AR enhanced the low concentrations of leptin-induced STAT3 nuclear translocation in vitro, and ARL-/Y mice receiving leptin had impaired STAT3 nuclear localization in the arcuate neurons. These findings indicate that AR in the hypothalamus functions as a regulator of central leptin-OBRB-STAT3 signaling and has a physiological role in energy homeostasis and metabolic regulation in male mice.

Army Family Policies and Practices: A Summary of Regulations, Letters, Pamphlets, and Circulars That Impact on Army Families

DTIC Science & Technology

1990-05-01

AR 60-10 Army and Air Force Exchange Service (AAFES) General Policies.. ................. . . . 12 AR 60-2 0 Army and Air Force Exchange Service (AAFES...Initial Active Duty, Initial Active Duty for Training, and Reserve Forces Duty . . . . . . ........... 29 AR 601-27 Military Entrance Processing...AR 608-20 Voting by Personnel of the Armed Forces . . . . .... 35 AR 608-25 Retirement Services Program . ...... 36 AR 608-61 Application for

Prostaglandins, steroids and reception (an attempt to model the structure of the active centers of adrenoreception).

PubMed

Podymov, V K; Piruzyan, L A; Gladkikh, S P; Kats, M M; Nizhnii, S V

1980-01-01

On the basis of numerous results of investigations on adrenergic systems, an orientational model of the adrenoreceptor (AR) is postulated. Its active center includes low-molecular-weight components--prostaglandins (PGE, PGF), steroids (cortisone, hydrocortisone), S+-adenosylmethionine, Ca, Mg, and Mn ions. Appraisal of the stereospecific characteristics of such a functional unit of AR explains the difference in the nature and magnitude of the effects of interaction of the catecholamines, their agonists and antagonists will the so-called alpha- and beta-AR. Depending on the organ or tissue in which the AR is located, its protein subunits comprise adenylcyclase (beta-AR) or Na,K-ATPase (alpha-AR). An obligatory component of the AR is catechol-O-methyltransferase. The model elaborated describes satisfactorily the molecular mechanisms of action of many pharmacological agents, explains why attempts to isolate and reconstruct the AR have proved fruitless, and gives grounds for rejecting the hypothesis that there exist steroid, prostaglandin, and purinergic receptors, linking the exceptionally high and diverse activity of these biologically active substances with their participation in adrenoreception among other reasons. A conception of the active centers of the AR as low-molecular-weight entities permits the explanation of such phenomena as the desensitization of the AR, the "interconversion" of beta-AR into alpha-AR with a change in the parameters of the medium, and certain components of the pathogenesis of bronchial asthma, etc.

Differences in the cancer burden among foreign-born and US-born Arab Americans living in metropolitan Detroit.

PubMed

Khan, Fatima; Ruterbusch, Julie J; Gomez, Scarlett L; Schwartz, Kendra

2013-11-01

Migrant studies often provide clues for cancer etiology. We estimated the cancer burden among Arab Americans (ArA) by immigrant status in the metropolitan Detroit area, home to one of the highest concentrations of ArA in USA. A validated name algorithm was used to identify ArA cancer cases diagnosed 1990-2009 in the Detroit SEER database. Recorded birthplace was supplemented with imputation of nativity using birthdate and social security number. Age-adjusted, gender-specific proportional incidence ratios and 95 % confidence intervals were calculated comparing all ArA, foreign-born ArA, and US-born ArA, to non-Hispanic Whites (NHW). Foreign-born ArA males had higher proportions of multiple myeloma, leukemia, kidney, liver, stomach, and bladder cancer than NHW, while bladder cancer and leukemia were higher among US-born ArA males. For ArA women, gall bladder and thyroid cancers were proportionally higher among both foreign- and US-born compared with NHW. Stomach cancer was proportionally higher only among foreign-born women. Cancer proportional incidence patterns among ArA show some similarity to other migrant groups, with higher proportional incidences of stomach and liver cancers among foreign-born than US-born. Other patterns, such as tobacco-related cancers among ArA men and gall bladder and thyroid cancers among ArA women, will require more investigation of genetic, epigenetic, and environmental factors.

Affordances of Augmented Reality in Science Learning: Suggestions for Future Research

NASA Astrophysics Data System (ADS)

Cheng, Kun-Hung; Tsai, Chin-Chung

2013-08-01

Augmented reality (AR) is currently considered as having potential for pedagogical applications. However, in science education, research regarding AR-aided learning is in its infancy. To understand how AR could help science learning, this review paper firstly has identified two major approaches of utilizing AR technology in science education, which are named as image- based AR and location- based AR. These approaches may result in different affordances for science learning. It is then found that students' spatial ability, practical skills, and conceptual understanding are often afforded by image-based AR and location-based AR usually supports inquiry-based scientific activities. After examining what has been done in science learning with AR supports, several suggestions for future research are proposed. For example, more research is required to explore learning experience (e.g., motivation or cognitive load) and learner characteristics (e.g., spatial ability or perceived presence) involved in AR. Mixed methods of investigating learning process (e.g., a content analysis and a sequential analysis) and in-depth examination of user experience beyond usability (e.g., affective variables of esthetic pleasure or emotional fulfillment) should be considered. Combining image-based and location-based AR technology may bring new possibility for supporting science learning. Theories including mental models, spatial cognition, situated cognition, and social constructivist learning are suggested for the profitable uses of future AR research in science education.

Nitrate affects sensu-stricto germination of after-ripened Sisymbrium officinale seeds by modifying expression of SoNCED5, SoCYP707A2 and SoGA3ox2 genes.

PubMed

Carrillo-Barral, Néstor; Matilla, Angel J; Rodríguez-Gacio, María del Carmen; Iglesias-Fernández, Raquel

2014-03-01

The influence of nitrate upon the germination of Sisymbrium officinale seeds is not entirely controlled by after-ripening (AR), a process clearly influenced by nitrate. Recently, we have reported that nitrate affects sensu-stricto germination of non-AR (AR0) seeds by modifying the expression of crucial genes involved in the metabolism of GA and ABA. In this study, we demonstrate that nitrate affects also the germination of AR seeds because: (i) the AR negatively alters the ABA sensitivity being the seed more ABA-sensible as the AR is farthest from optimal (AR0 and AR20 versus AR7); in the presence of diniconazole (DZ), a competitive inhibitor of ABA 8'-hydroxylase, testa rupture is affected while the endosperm rupture is not. (ii) AR7 seed-coat rupture is not inhibited by paclobutrazol (PBZ) suggesting that nitrate can act by a mechanism GA-independent. (iii) The germination process is accelerated by nitrate, most probably by the increase in the expression of SoNCED5, SoCYP707A2 and SoGA3ox2 genes. Taken together, these and previous results demonstrate that nitrate promotes germination of AR and non-AR seeds through transcriptional changes of different genes involved in ABA and GA metabolism. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Leveraging Multimodal Redundancy for Dynamic Learning, with SHACER - a Speech and HAndwriting reCognizER

DTIC Science & Technology

2007-04-01

EG’,’Visor’,’i-g’,tg,’Tier’,’i-or’,’Ii-or’,’Ti-or’,’ii-or’]) ’Arrive’,[’ARNE’,arrive,’ARNIE’,’ARCANE’,’AR Rue’,’AR Rive’,’AR RWE’,’AR RUNE ’,’AR

CNPY2 inhibits MYLIP-mediated AR protein degradation in prostate cancer cells.

PubMed

Ito, Saya; Ueno, Akihisa; Ueda, Takashi; Nakagawa, Hideo; Taniguchi, Hidefumi; Kayukawa, Naruhiro; Fujihara-Iwata, Atsuko; Hongo, Fumiya; Okihara, Koji; Ukimura, Osamu

2018-04-03

The androgen receptor (AR) is a ligand-dependent transcription factor that promotes prostate cancer (PC) cell growth through control of target gene expression. This report suggests that Canopy FGF signaling regulator 2 (CNPY2) controls AR protein levels in PC cells. We found that AR was ubiquitinated by an E3 ubiquitin ligase, myosin regulatory light chain interacting protein (MYLIP) and then degraded through the ubiquitin-proteasome pathway. CNPY2 decreased the ubiquitination activity of MYLIP by inhibition of interaction between MYLIP and UBE2D1, an E2 ubiquitin ligase. CNPY2 up-regulated gene expression of AR target genes such as KLK3 gene which encodes the prostate specific antigen (PSA) and promoted cell growth of PC cells. The cell growth inhibition by CNPY2 knockdown was rescued by AR overexpression. Furthermore, positive correlation of expression levels between CNPY2 and AR/AR target genes was observed in tissue samples from human prostate cancer patients. Together, these results suggested that CNPY2 promoted cell growth of PC cells by inhibition of AR protein degradation through MYLIP-mediated AR ubiquitination.

Functional analysis of ars gene cluster of Pannonibacter indicus strain HT23(T) (DSM 23407(T)) and identification of a proline residue essential for arsenate reductase activity.

PubMed

Bandyopadhyay, Saumya; Das, Subrata K

2016-04-01

Arsenic is a naturally occurring ubiquitous highly toxic metalloid. In this study, we have identified ars gene cluster in Pannonibacter indicus strain HT23(T) (DSM 23407(T)), responsible for reduction of toxic pentavalent arsenate. The ars gene cluster is comprised of four non-overlapping open reading frames (ORFs) encoding a transcriptional regulator (ArsR), a low molecular weight protein tyrosine phosphatases (LMW-PTPase) with hypothetical function, an arsenite efflux pump (Acr3), and an arsenate reductase (ArsC). Heterologous expression of arsenic inducible ars gene cluster conferred arsenic resistance to Escherichia coli ∆ars mutant strain AW3110. The recombinant ArsC was purified and assayed. Site-directed mutagenesis was employed to ascertain the role of specific amino acids in ArsC catalysis. Pro94X (X = Ala, Arg, Cys, and His) amino acid substitutions led to enzyme inactivation. Circular dichroism spectra analysis suggested Pro94 as an essential amino acid for enzyme catalytic activity as it is indispensable for optimum protein folding in P. indicus Grx-coupled ArsC.

The role of DAB2IP in androgen receptor activation during prostate cancer progression.

PubMed

Wu, K; Liu, J; Tseng, S-F; Gore, C; Ning, Z; Sharifi, N; Fazli, L; Gleave, M; Kapur, P; Xiao, G; Sun, X; Oz, O K; Min, W; Alexandrakis, G; Yang, C-R; Hsieh, C-L; Wu, H-C; He, D; Xie, D; Hsieh, J-T

2014-04-10

Altered androgen-receptor (AR) expression and/or constitutively active AR are commonly associated with prostate cancer (PCa) progression. Targeting AR remains a focal point for designing new strategy of PCa therapy. Here, we have shown that DAB2IP, a novel tumor suppressor in PCa, can inhibit AR-mediated cell growth and gene activation in PCa cells via distinct mechanisms. DAB2IP inhibits the genomic pathway by preventing AR nuclear translocation or phosphorylation and suppresses the non-genomic pathway via its unique functional domain to inactivate c-Src. Also, DAB2IP is capable of suppressing AR activation in an androgen-independent manner. In addition, DAB2IP can inhibit several AR splice variants showing constitutive activity in PCa cells. In DAB2IP(-/-) mice, the prostate gland exhibits hyperplastic epithelia, in which AR becomes more active. Consistently, DAB2IP expression inversely correlates with AR activation status particularly in recurrent or metastatic PCa patients. Taken together, DAB2IP is a unique intrinsic AR modulator in normal cells, and likely can be further developed into a therapeutic agent for PCa.

CNPY2 inhibits MYLIP-mediated AR protein degradation in prostate cancer cells

PubMed Central

Ito, Saya; Ueno, Akihisa; Ueda, Takashi; Nakagawa, Hideo; Taniguchi, Hidefumi; Kayukawa, Naruhiro; Fujihara-Iwata, Atsuko; Hongo, Fumiya; Okihara, Koji; Ukimura, Osamu

2018-01-01

The androgen receptor (AR) is a ligand-dependent transcription factor that promotes prostate cancer (PC) cell growth through control of target gene expression. This report suggests that Canopy FGF signaling regulator 2 (CNPY2) controls AR protein levels in PC cells. We found that AR was ubiquitinated by an E3 ubiquitin ligase, myosin regulatory light chain interacting protein (MYLIP) and then degraded through the ubiquitin-proteasome pathway. CNPY2 decreased the ubiquitination activity of MYLIP by inhibition of interaction between MYLIP and UBE2D1, an E2 ubiquitin ligase. CNPY2 up-regulated gene expression of AR target genes such as KLK3 gene which encodes the prostate specific antigen (PSA) and promoted cell growth of PC cells. The cell growth inhibition by CNPY2 knockdown was rescued by AR overexpression. Furthermore, positive correlation of expression levels between CNPY2 and AR/AR target genes was observed in tissue samples from human prostate cancer patients. Together, these results suggested that CNPY2 promoted cell growth of PC cells by inhibition of AR protein degradation through MYLIP-mediated AR ubiquitination. PMID:29707137

ACK1/TNK2 Regulates Histone H4 Tyr88-phosphorylation and AR Gene Expression in Castration-Resistant Prostate Cancer.

PubMed

Mahajan, Kiran; Malla, Pavani; Lawrence, Harshani R; Chen, Zhihua; Kumar-Sinha, Chandan; Malik, Rohit; Shukla, Sudhanshu; Kim, Jongphil; Coppola, Domenico; Lawrence, Nicholas J; Mahajan, Nupam P

2017-06-12

The androgen receptor (AR) is critical for the progression of prostate cancer to a castration-resistant (CRPC) state. AR antagonists are ineffective due to their inability to repress the expression of AR or its splice variant, AR-V7. Here, we report that the tyrosine kinase ACK1 (TNK2) phosphorylates histone H4 at tyrosine 88 upstream of the AR transcription start site. The WDR5/MLL2 complex reads the H4-Y88-phosphorylation marks and deposits the transcriptionally activating H3K4-trimethyl marks promoting AR transcription. Reversal of the pY88-H4 epigenetic marks by the ACK1 inhibitor (R)-9bMS-sensitized naive and enzalutamide-resistant prostate cancer cells and reduced AR and AR-V7 levels to mitigate CRPC tumor growth. Thus, a feedforward ACK1/pY88-H4/WDR5/MLL2/AR epigenetic circuit drives CRPC and is necessary for maintenance of the malignant state. Copyright © 2017 Elsevier Inc. All rights reserved.

AR copy number and AR signaling-directed therapies in castration-resistant prostate cancer.

PubMed

Salvi, Samanta; Conteduca, Vincenza; Lolli, Cristian; Testoni, Sara; Casadio, Valentina; Zaccheroni, Andrea; Rossi, Lorena; Burgio, Salvatore Luca; Menna, Cecilia; Schepisi, Giuseppe; De Giorgi, Ugo

2017-11-22

Adaptive upregulation of androgen receptor (AR) is the most common event involved in the progression from hormone sensitive to castration-resistant prostate cancer (CRPC). AR signaling remains the main target of new AR signalling-directed therapies such as abiraterone and enzalutamide in CRPC patients. In this review, we discuss general mechanisms of resistance to AR-targeted therapies, with a focus on the role of AR copy number (CN). We reported methods and clinical applications of AR CN evaluation in tissue and liquid biopsy, thus to have a complete information regarding its role as predictive and prognostic biomarker. Outcomes of CRPC patients are reported to be highly variable as consequence of tumor heterogeneity. AR CN could contribute to patient selection and tumor monitoring in CRPC treated with new anti-cancer treatment as abiraterone and enzalutamide. Further studies to investigate AR CN effect to these agents and its potential combination with other prognostic or predictive clinical factors are necessary in the context of harmonized clinical trial design. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

A comprehensive analysis of coregulator recruitment, androgen receptor function and gene expression in prostate cancer

PubMed Central

Hu, Qiang; Senapati, Dhirodatta; Venkadakrishnan, Varadha Balaji; Wang, Dan; DePriest, Adam D; Schlanger, Simon E; Ben-Salem, Salma; Valenzuela, Malyn May; Willard, Belinda; Mudambi, Shaila; Swetzig, Wendy M; Das, Gokul M; Shourideh, Mojgan; Koochekpour, Shahriah; Falzarano, Sara Moscovita; Magi-Galluzzi, Cristina; Yadav, Neelu; Chen, Xiwei; Lao, Changshi; Wang, Jianmin; Billaud, Jean-Noel

2017-01-01

Standard treatment for metastatic prostate cancer (CaP) prevents ligand-activation of androgen receptor (AR). Despite initial remission, CaP progresses while relying on AR. AR transcriptional output controls CaP behavior and is an alternative therapeutic target, but its molecular regulation is poorly understood. Here, we show that action of activated AR partitions into fractions that are controlled preferentially by different coregulators. In a 452-AR-target gene panel, each of 18 clinically relevant coregulators mediates androgen-responsiveness of 0–57% genes and acts as a coactivator or corepressor in a gene-specific manner. Selectivity in coregulator-dependent AR action is reflected in differential AR binding site composition and involvement with CaP biology and progression. Isolation of a novel transcriptional mechanism in which WDR77 unites the actions of AR and p53, the major genomic drivers of lethal CaP, to control cell cycle progression provides proof-of-principle for treatment via selective interference with AR action by exploiting AR dependence on coregulators. PMID:28826481

Agent Orange exposure and risk of death in Korean Vietnam veterans: Korean Veterans Health Study.

PubMed

Yi, Sang-Wook; Ryu, So-Yeon; Ohrr, Heechoul; Hong, Jae-Seok

2014-12-01

Agent Orange (AO) was a mixture of phenoxy herbicides, containing several dioxin impurities including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Various military herbicides, including AO, were sprayed by the US military and allied forces for military purposes during the Vietnam War. This study was performed to identify the associations between the AO exposure and mortality in Korean Vietnam veterans. From 1 January 1992 to 31 December 2005, 180 639 Korean Vietnam veterans were followed up for vital status and cause of death. The AO exposure index was based on the proximity of the veteran's unit to AO-sprayed areas, using a geographical information system-based model. The adjusted hazard ratios and 95% confidence intervals were calculated by Cox's proportional hazard model. The mortality from all causes of death was elevated with AO exposure. The deaths due to all sites of cancers combined and some specific cancers, including cancers of the stomach, small intestine, liver, larynx, lung, bladder and thyroid gland, as well as chronic myeloid leukaemia, were positively associated with AO exposure. The deaths from angina pectoris, chronic obstructive pulmonary disease and liver disease including liver cirrhosis were also increased with an increasing AO exposure. Overall, this study suggests that AO/TCDD exposure may account for mortality from various diseases even several decades after exposure. Further research is needed to better understand the long-term effects of AO/TCDD exposure on human health. © The Author 2014; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.

Dermal carotenoid level and kinetics after topical and systemic administration of antioxidants: enrichment strategies in a controlled in vivo study.

PubMed

Darvin, Maxim E; Fluhr, Joachim W; Schanzer, Sabine; Richter, Heike; Patzelt, Alexa; Meinke, Martina C; Zastrow, Leonhard; Golz, Karin; Doucet, Olivier; Sterry, Wolfram; Lademann, Juergen

2011-10-01

High doses of sun-emitted UV-radiation induce reactive oxygen species (ROS) as major pro-oxidants thus inducing premature skin aging. The best prevention of the destructive action of free radicals in human skin is textile coverings, topical sunscreens and the development of a high antioxidative protective network. The effects of topical, systemic and combined application of antioxidants (AO) were investigated on human skin in vivo. Topical application of creams and systemic incorporation of tablets both containing AO was investigated in vivo by resonance Raman spectroscopy. Topical, systemic and combined AO-treatments induced a statistically significant increase of AO levels in human skin while placebo did not show any changes. The highest accumulation was induced by the combination of topical and systemic AO. Carotenoid-tablets combined with placebo-cream induced less carotenoid accumulation than carotenoid-tablets alone. Carotenoid levelling after the end of treatment lasted for around 2 weeks following the topical application of AOs, and up to 5 weeks after systemic administration, depending on the BMI of volunteers. Topically applied AO are stored in the SC for a short time only due to the rapid AO-depletion by desquamation, textile contact, washing and environmental stress. In contrast to topical application, the systemically applied carotenoids are stored in the body fat tissue and slowly released onto the skin surface with sweat and sebum. The combined topical and systemic application of AO represents an optimal form of protection of the AO-network. Copyright © 2011 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.

Preparation and characterization of highly water-soluble magnetic Fe3O4 nanoparticles via surface double-layered self-assembly method of sodium alpha-olefin sulfonate

NASA Astrophysics Data System (ADS)

Li, Honghong; Qin, Li; Feng, Ying; Hu, Lihua; Zhou, Chunhua

2015-06-01

A kind of double-layered self-assembly sodium alpha-olefin sulfonate (AOS) capped Fe3O4 magnetic nanoparticles (Fe3O4-AOS-MN) with highly water-solubility was prepared by a wet co-precipitation method with a pH of 4.8. The resulting Fe3O4-AOS-MN could be dispersed into water to form stable magnetic fluid without other treatments. The result of X-ray diffraction (XRD) indicated that the Fe3O4-AOS-MN maintained original crystalline structure and exhibited a diameter of about 7.5 nm. The iron oxide phase of nanoparticles determined by Raman spectroscopy is Fe3O4. Transmission electron microscopy (TEM) analysis confirmed that the Fe3O4-AOS-MN with spherical morphology were uniformly dispersed in water. FT-IR spectroscopy (FT-IR) and thermo-gravimetric analysis (TGA) verified the successful preparation of Fe3O4-AOS-MN capped with double-layered self-assembled AOS. The corresponding capacities of monolayer chemical absorption and the second-layer self-assembly absorption were respectively 4.07 and 14.71 wt% of Fe3O4-MN, which were much lower than those of other surfactants. Vibrating sample magnetometer (VSM) test result showed Fe3O4-AOS-MN possessed superparamagnetic behavior with the saturation magnetization value of about 44.45 emu/g. The blocking temperature TB of Fe3O4-AOS-MN capped with double-layered AOS is 170 K.

Adaptive optics program update at TMT

NASA Astrophysics Data System (ADS)

Boyer, C.; Ellerbroek, B.

2016-07-01

The TMT first light AO facility consists of the Narrow Field Infra-Red AO System (NFIRAOS), the associated Laser Guide Star Facility (LGSF) and the AO Executive Software (AOESW). Design, fabrication and prototyping activities of the TMT first light AO systems and their components have significantly ramped up in Canada, China, France, and in the US. NFIRAOS is an order 60 x 60 laser guide star (LGS) multi-conjugate AO (MCAO) system, which provides uniform, diffraction-limited performance in the J, H, and K bands over 34 x 34 arc sec fields with 50 per cent sky coverage at the galactic pole, as required to support the TMT science cases. NFIRAOS includes two deformable mirrors, six laser guide star wavefront sensors, one high order Pyramid WFS for natural guide star AO, and up to three low-order, IR, natural guide star on-instrument wavefront sensors (OIWFS) and four on-detector guide windows (ODGW) within each client instrument. The first light LGSF system includes six sodium lasers to generate the NFIRAOS laser guide stars. In this paper, we will provide an update on the progress in designing, prototyping, fabricating and modeling the TMT first light AO systems and their AO components over the last two years. TMT is continuing with detailed AO modeling to support the design and development of the first light AO systems and components. Major modeling topics studied during the last two years include further studies in the area of pyramid wavefront sensing, high precision astrometry, PSF reconstruction for LGS MCAO, LGSF wavefront error budget and sophisticated low order mode temporal filtering.

The Influence of Abdominal and Ectopic Fat Accumulation on Carotid Intima-Media Thickness: A Chongqing Study.

PubMed

Yi, Xu; Liu, Yu-Hui; Zhou, Xin-Fu; Wang, Yan-Jiang; Deng, Juan; Liu, Juan; He, Hong-Bo; Xu, Zhi-Qiang

2018-04-16

To investigate the effects of abdominal obesity (AO) and nonalcoholic fatty liver disease (NAFLD) with or without AO on carotid arteries by determining carotid intima-media thickness (CIMT). A total of 2745 Chinese Han adults (aged between 40 and 50 years old) were recruited and divided into 4 groups: (1) NW-no NAFL group: the normal body weight without NAFLD (n = 1888); (2) AO-no NAFL group: AO without NAFLD (n = 259); (3) NW-with NAFL group: NAFLD without AO (n = 93); and (4) AO-with NAFL group: AO with NAFLD (n = 505). The CIMT rate of each group was compared among 4 groups and the regression analysis was further used to correct confounders. We found that the NW-with NAFL group had a significantly higher CIMT rate than the AO-no NAFL group ([.87 ± .31] versus [.72 ± .29] P < .01) and the AO-with NAFL group ([.87 ± .31] versus [.79 ± .26], P < .01). The ectopic liver fat accumulation may increase the risk of atherosclerosis. Therefore, screening NAFLD in the population with normal weight may be beneficial for the prevention of atherosclerosis at an early stage. Copyright © 2018 National Stroke Association. Published by Elsevier Inc. All rights reserved.

Effect of accessory ostia on maxillary sinus ventilation: a computational fluid dynamics (CFD) study.

PubMed

Zhu, Jian Hua; Lee, Heow Pueh; Lim, Kian Meng; Gordon, Bruce R; Wang, De Yun

2012-08-15

We evaluated, by CFD simulation, effects of accessory ostium (AO) on maxillary sinus ventilation. A three-dimensional nasal model was constructed from an adult CT scan with two left maxillary AOs (sinus I) and one right AO (sinus II), then compared to an identical control model with all AOs sealed (sinuses III and IV). Transient simulations of quiet inspiration and expiration at 15 L/min, and nasal blow at 48 L/min, were calculated for both models using low-Reynolds-number turbulent analysis. At low flows, ventilation rates in sinuses with AOs (I ≈ 0.46 L/min, II ≈ 0.54 L/min), were both more than a magnitude higher than sinuses without AOs (II I ≈ 0.019 L/min, IV ≈ 0.020 L/min). Absence of AO almost completely prevented sinus ventilation. Increased ventilation of sinuses with AOs is complex. Under high flow conditions mimicking nose blowing, in sinuses II, III, and IV, the sinus flow rate increased. In contrast, the airflow direction through sinus I reversed between inspiration and expiration, while it remained almost constant throughout the respiration cycle in sinus II. CFD simulation demonstrated that AOs markedly increase maxillary sinus airflow rates and alter sinus air circulation patterns. Whether these airflow changes impact maxillary sinus physiology or pathophysiology is unknown. Copyright © 2012 Elsevier B.V. All rights reserved.

Proton conductivity in ampullae of Lorenzini jelly

PubMed Central

Josberger, Erik E.; Hassanzadeh, Pegah; Deng, Yingxin; Sohn, Joel; Rego, Michael J.; Amemiya, Chris T.; Rolandi, Marco

2016-01-01

In 1678, Stefano Lorenzini first described a network of organs of unknown function in the torpedo ray—the ampullae of Lorenzini (AoL). An individual ampulla consists of a pore on the skin that is open to the environment, a canal containing a jelly and leading to an alveolus with a series of electrosensing cells. The role of the AoL remained a mystery for almost 300 years until research demonstrated that skates, sharks, and rays detect very weak electric fields produced by a potential prey. The AoL jelly likely contributes to this electrosensing function, yet the exact details of this contribution remain unclear. We measure the proton conductivity of the AoL jelly extracted from skates and sharks. The room-temperature proton conductivity of the AoL jelly is very high at 2 ± 1 mS/cm. This conductivity is only 40-fold lower than the current state-of-the-art proton-conducting polymer Nafion, and it is the highest reported for a biological material so far. We suggest that keratan sulfate, identified previously in the AoL jelly and confirmed here, may contribute to the high proton conductivity of the AoL jelly with its sulfate groups—acid groups and proton donors. We hope that the observed high proton conductivity of the AoL jelly may contribute to future studies of the AoL function. PMID:27386543

Expression of Allene Oxide Synthase Determines Defense Gene Activation in Tomato1

PubMed Central

Sivasankar, Sobhana; Sheldrick, Bay; Rothstein, Steven J.

2000-01-01

Allene oxide synthase (AOS; hydroperoxide dehydratase; EC 4.2.1.92) catalyzes the first step in the biosynthesis of jasmonic acid from lipoxygenase-derived hydroperoxides of free fatty acids. Using the AOS cDNA from tomato (Lycopersicon esculentum), in which the role of jasmonic acid in wound-induced defense gene activation has been best described, we examined the kinetics of AOS induction in response to wounding and elicitors, in parallel with that of the wound-inducible PIN II (proteinase inhibitor II) gene. AOS was induced in leaves by wounding, systemin, 12-oxophytodienoic acid, and methyl jasmonate. The levels of AOS mRNA started declining by 4 h after induction, whereas the levels of PIN II mRNA continued to increase up to 20 h after induction. Salicylic acid inhibited AOS and PIN II expression, and the addition of 12-oxophytodienoic acid or methyl jasmonate did not prevent the inhibition of PIN II expression in the presence of salicylic acid. Ethylene induced the expression of AOS, but the presence of ethylene alone did not produce an optimal induction of PIN II. The addition of silver thiosulfate, an ethylene action inhibitor, prevented the wound-induced expression of both AOS and PIN II. Products of hydroperoxide lyase affected neither AOS nor PIN II, but induced expression of prosystemin. Based on these results, we propose an updated model for defense gene activation in tomato. PMID:10759530

Ar-Ar Thermochronlogy of Apollo 12 Impact-Melt Breccia 12033,638-1

NASA Technical Reports Server (NTRS)

Crow, C. A.; Cassata, W. S.; Jolliff, B. L.; Ziegler, R. A.; Borg, L. E.; Shearer, C. K.

2017-01-01

We have undertaken an Ar-Ar thermochronology investigation as part of a coordinated multichronometer analysis of a single Apollo 12 impact- melt breccia to demonstrate the wide range of information that can be obtained for a single complex rock. This has implications for the age of formation, component makeup, and subsequent impact/shock and exposure history of the sample. This study also serves as a capabilities demonstration for the proposed MoonRise Mission [1]. The goal of this investigation is to elucidate the history of this sample through coordinated 40Ar*/39Ar, Sm-Nd, Rb-Sr and zircon 207Pb-206Pb ages along with geochemical and petrographic context on a relatively small (approximately 450 mg) sample. Here, we report preliminary results of the Ar-Ar thermochronology.

(Ar-39)-(Ar-40) dating of mesosiderites - Evidence for major parent body disruption less than 4 Ga ago

NASA Technical Reports Server (NTRS)

Bogard, D. D.; Jordan, J. L.; Garrison, D. H.; Mittlefehldt, D.

1990-01-01

The (Ar-39) (Ar-40) chronologies were determined for 14 different mesosiderites representing the full range of classification according to recrystallization, and these chronologies were compared with analogous data for other meteorite types and for lunar highland rocks. Results of Ar-Ar chronologies indicate the history of a degassing of Ar due to a major thermal event that occurred less than 3.9 Ga ago; this event is not the metal-silicate mixing event, which is known to have occurred earlier than 4.4 Ga ago. It is suggested that a major collisional disruption-reassembly event less than 3.9 Ga ago took place, leaving the metal-silicate breccias buried under tens of kilometers of rubble, where they cooled slowly through the Ar closure temperatures.

Adaptive optics ophthalmoscopy.

PubMed

Roorda, Austin; Duncan, Jacque L

2015-11-01

This review starts with a brief history and description of adaptive optics (AO) technology, followed by a showcase of the latest capabilities of AO systems for imaging the human retina and an extensive review of the literature on where AO is being used clinically. The review concludes with a discussion on future directions and guidance on usage and interpretation of images from AO systems for the eye.

Revisiting Age-of-Acquisition Effects in Spanish Visual Word Recognition: The Role of Item Imageability

ERIC Educational Resources Information Center

Wilson, Maximiliano A.; Cuetos, Fernando; Davies, Rob; Burani, Cristina

2013-01-01

Word age-of-acquisition (AoA) affects reading. The mapping hypothesis predicts AoA effects when input--output mappings are arbitrary. In Spanish, the orthography-to-phonology mappings required for word naming are consistent; therefore, no AoA effects are expected. Nevertheless, AoA effects have been found, motivating the present investigation of…

Functional characterization of a second pedal peptide/orcokinin‐type neuropeptide signaling system in the starfish Asterias rubens

PubMed Central

Lin, Ming; Egertová, Michaela; Zampronio, Cleidiane G.; Jones, Alexandra M.

2017-01-01

Abstract Molluscan pedal peptides (PPs) and arthropod orcokinins (OKs) are prototypes of a family of neuropeptides that have been identified in several phyla. Recently, starfish myorelaxant peptide (SMP) was identified as a PP/OK‐type neuropeptide in the starfish Patiria pectinifera (phylum Echinodermata). Furthermore, analysis of transcriptome sequence data from the starfish Asterias rubens revealed two PP/OK‐type precursors: an SMP‐type precursor (A. rubens PP‐like neuropeptide precursor 1; ArPPLNP1) and a second precursor (ArPPLNP2). We reported previously a detailed analysis of ArPPLNP1 expression in A. rubens and here we report the first functional characterization ArPPLNP2‐derived neuropeptides. Sequencing of a cDNA encoding ArPPLNP2 revealed that it comprises eleven related neuropeptides (ArPPLN2a‐k), the structures of several of which were confirmed using mass spectrometry. Analysis of the expression of ArPPLNP2 and neuropeptides derived from this precursor using mRNA in situ hybridization and immunohistochemistry revealed a widespread distribution, including expression in radial nerve cords, circumoral nerve ring, digestive system, tube feet and innervation of interossicular muscles. In vitro pharmacology revealed that the ArPPLNP2‐derived neuropeptide ArPPLN2h has no effect on the contractility of tube feet or the body wall‐associated apical muscle, contrasting with the relaxing effect of ArPPLN1b (ArSMP) on these preparations. ArPPLN2h does, however, cause dose‐dependent relaxation of cardiac stomach preparations, with greater potency/efficacy than ArPPLN1b and with similar potency/efficacy to the SALMFamide neuropeptide S2. In conclusion, there are similarities in the expression patterns of ArPPLNP1 and ArPPLNP2 but our data also indicate specialization in the roles of neuropeptides derived from these two PP/OK‐type precursors in starfish. PMID:29218721

Functional characterization of a second pedal peptide/orcokinin-type neuropeptide signaling system in the starfish Asterias rubens.

PubMed

Lin, Ming; Egertová, Michaela; Zampronio, Cleidiane G; Jones, Alexandra M; Elphick, Maurice R

2018-04-01

Molluscan pedal peptides (PPs) and arthropod orcokinins (OKs) are prototypes of a family of neuropeptides that have been identified in several phyla. Recently, starfish myorelaxant peptide (SMP) was identified as a PP/OK-type neuropeptide in the starfish Patiria pectinifera (phylum Echinodermata). Furthermore, analysis of transcriptome sequence data from the starfish Asterias rubens revealed two PP/OK-type precursors: an SMP-type precursor (A. rubens PP-like neuropeptide precursor 1; ArPPLNP1) and a second precursor (ArPPLNP2). We reported previously a detailed analysis of ArPPLNP1 expression in A. rubens and here we report the first functional characterization ArPPLNP2-derived neuropeptides. Sequencing of a cDNA encoding ArPPLNP2 revealed that it comprises eleven related neuropeptides (ArPPLN2a-k), the structures of several of which were confirmed using mass spectrometry. Analysis of the expression of ArPPLNP2 and neuropeptides derived from this precursor using mRNA in situ hybridization and immunohistochemistry revealed a widespread distribution, including expression in radial nerve cords, circumoral nerve ring, digestive system, tube feet and innervation of interossicular muscles. In vitro pharmacology revealed that the ArPPLNP2-derived neuropeptide ArPPLN2h has no effect on the contractility of tube feet or the body wall-associated apical muscle, contrasting with the relaxing effect of ArPPLN1b (ArSMP) on these preparations. ArPPLN2h does, however, cause dose-dependent relaxation of cardiac stomach preparations, with greater potency/efficacy than ArPPLN1b and with similar potency/efficacy to the SALMFamide neuropeptide S2. In conclusion, there are similarities in the expression patterns of ArPPLNP1 and ArPPLNP2 but our data also indicate specialization in the roles of neuropeptides derived from these two PP/OK-type precursors in starfish. © 2017 The Authors The Journal of Comparative Neurology Published by Wiley Periodicals, Inc.

Atmospheric River impacts in British Columbia and the Pacific Northwest on 22-24 January 2015 during the CalWater 2015 field campaign

NASA Astrophysics Data System (ADS)

Gaggini, N. G.; Spackman, J. R.; Neiman, P. J.; White, A. B.; Fairall, C. W.; Barnet, C.; Gambacorta, A.; Hughes, M.

2015-12-01

Over 30 dropsonde transects were performed across atmospheric rivers (ARs) over the eastern Pacific during CalWater 2015. An event in late January allowed first-of-its-kind coordinated dropsonde transects of an AR using the NOAA G-IV aircraft in tandem with the NOAA Ronald H. Brown (RHB), which observed the marine boundary layer during the passage of this major AR. Dropsonde data collected on 22 January 2015 sampled the early stages of the AR, when the AR began making landfall near Vancouver Island, British Columbia. At the same time the RHB collected precipitation and oceanic moisture flux measurements on the warm side of the AR. A second flight on 24 January 2015 sampled the later stages of the AR, again passing over the RHB stationed beneath the AR. During this later period, the AR axis of moisture shifted north-northeast and fanned out along the coast, affecting regions from Northern Washington to Southern Alaska. Multi-day landfalling AR conditions led to flooding in British Columbia and northern Washington. The influence of the coastal orography combined with the shift in AR orientation is examined to understand the orographic control of precipitation that triggered the flooding. In addition, cross section analysis of the AR using dropsonde and reanalysis data are used to better understand the synoptic influences, water vapor transport, and moisture evolution during the lifecycle of the AR. To gain greater insight into AR development and prolonged AR conditions that led to enhanced flooding, a comparison of aircraft and ship data from CalWater 2015 and NOAA Unique CrIS/ATMS Processing System (NUCAPS) retrievals (integrated water vapor, vertical temperature and moisture profiles, and an experimental ATMS-only rain rate product) will be compared for the 22-24 January period.

An unusual Tn21-like transposon containing an ars operon is present in highly arsenic-resistant strains of the biomining bacterium Acidithiobacillus caldus.

PubMed

Tuffin, I Marla; de Groot, Peter; Deane, Shelly M; Rawlings, Douglas E

2005-09-01

A transposon, TnAtcArs, that carries a set of arsenic-resistance genes was isolated from a strain of the moderately thermophilic, sulfur-oxidizing, biomining bacterium Acidithiobacillus caldus. This strain originated from a commercial plant used for the bio-oxidation of gold-bearing arsenopyrite concentrates. Continuous selection for arsenic resistance over many years had made the bacterium resistant to high concentrations of arsenic. Sequence analysis indicated that TnAtcArs is 12 444 bp in length and has 40 bp terminal inverted repeat sequences and divergently transcribed resolvase and transposase genes that are related to the Tn21-transposon subfamily. A series of genes consisting of arsR, two tandem copies of arsA and arsD, two ORFs (7 and 8) and arsB is situated between the resolvase and transposase genes. Although some commercial strains of At. caldus contained the arsDA duplication, when transformed into Escherichia coli, the arsDA duplication was unstable and was frequently lost during cultivation or if a plasmid containing TnAtcArs was conjugated into a recipient strain. TnAtcArs conferred resistance to arsenite and arsenate upon E. coli cells. Deletion of one copy of arsDA had no noticeable effect on resistance to arsenite or arsenate in E. coli. ORFs 7 and 8 had clear sequence similarity to an NADH oxidase and a CBS-domain-containing protein, respectively, but their deletion did not affect resistance to arsenite or arsenate in E. coli. TnAtcArs was actively transposed in E. coli, but no increase in transposition frequency in the presence of arsenic was detected. Northern hybridization and reporter gene studies indicated that although ArsR regulated the 10 kb operon containing the arsenic-resistance genes in response to arsenic, ArsR had no effect on the regulation of genes associated with transposition activity.

14-3-3η Amplifies Androgen Receptor Actions in Prostate Cancer

PubMed Central

Titus, Mark A.; Tan, Jiann-an; Gregory, Christopher W.; Ford, O. Harris; Subramanian, Romesh R.; Fu, Haian; Wilson, Elizabeth M.; Mohler, James L.; French, Frank S.

2009-01-01

Purpose Androgen receptor (AR) abundance and AR-regulated gene expression in castration-recurrent prostate cancer (CaP) are indicative of AR activation in the absence of testicular androgen. AR transactivation of target genes in castration-recurrent CaP occurs in part through mitogen signaling that amplifies the actions of AR and its coregulators. Herein we report on the role of 14-3-3η in AR action. Experimental Design and Results AR and 14-3-3η co-localized in COS cell nuclei with and without androgen and 14-3-3η promoted AR nuclear localization in the absence of androgen. 14-3-3η interacted with AR in cell-free binding and coimmunoprecipitation assays. In the recurrent human CaP cell line, CWR-R1, native endogenous AR transcriptional activation was stimulated by 14-3-3η at low DHT concentrations and was increased by EGF. Moreover, the DHT and EGF dependent increase in AR transactivation was inhibited by a dominant negative 14-3-3η. In the CWR22 CaP xenograft model, 14-3-3η expression was increased by androgen, suggesting a feed-forward mechanism that potentiates both 14-3-3η and AR actions. 14-3-3η mRNA and protein decreased following castration of tumor bearing mice and increased in tumors of castrate mice after treatment with testosterone. CWR22 tumors that recurred 5 months after castration contained 14-3-3η levels similar to the androgen-stimulated tumors removed before castration. In a human prostate tissue microarray of clinical specimens, 14-3-3η localized with AR in nuclei and the similar amounts expressed in castration-recurrent CaP, androgen-stimulated CaP and benign prostatic hyperplasia were consistent with AR activation in recurrent CaP. Conclusion 14-3-3η enhances androgen and mitogen induced AR transcriptional activity in castration-recurrent CaP. PMID:19996220

Foraging Parameters Influencing the Detection and Interpretation of Area-Restricted Search Behaviour in Marine Predators: A Case Study with the Masked Booby

PubMed Central

Sommerfeld, Julia; Kato, Akiko; Ropert-Coudert, Yan; Garthe, Stefan; Hindell, Mark A.

2013-01-01

Identification of Area-restricted search (ARS) behaviour is used to better understand foraging movements and strategies of marine predators. Track-based descriptive analyses are commonly used to detect ARS behaviour, but they may be biased by factors such as foraging trip duration or non-foraging behaviours (i.e. resting on the water). Using first-passage time analysis we tested if (I) daylight resting at the sea surface positions falsely increase the detection of ARS behaviour and (II) short foraging trips are less likely to include ARS behaviour in Masked Boobies Sula dactylatra. We further analysed whether ARS behaviour may be used as a proxy to identify important feeding areas. Depth-acceleration and GPS-loggers were simultaneously deployed on chick-rearing adults to obtain (1) location data every 4 minutes and (2) detailed foraging activity such as diving rates, time spent sitting on the water surface and in flight. In 82% of 50 foraging trips, birds adopted ARS behaviour. In 19.3% of 57 detected ARS zones, birds spent more than 70% of total ARS duration resting on the water, suggesting that these ARS zones were falsely detected. Based on generalized linear mixed models, the probability of detecting false ARS zones was 80%. False ARS zones mostly occurred during short trips in close proximity to the colony, with low or no diving activity. This demonstrates the need to account for resting on the water surface positions in marine animals when determining ARS behaviour based on foraging locations. Dive rates were positively correlated with trip duration and the probability of ARS behaviour increased with increasing number of dives, suggesting that the adoption of ARS behaviour in Masked Boobies is linked to enhanced foraging activity. We conclude that ARS behaviour may be used as a proxy to identify important feeding areas in this species. PMID:23717471

Stilbene Induced Inhibition of Androgen Receptor Dimerization: Implications for AR and ARΔLBD-Signalling in Human Prostate Cancer Cells

PubMed Central

Streicher, Wolfgang; Luedeke, Manuel; Azoitei, Anca; Zengerling, Friedemann; Herweg, Alexander; Genze, Felicitas; Schrader, Mark G.; Schrader, Andres J.; Cronauer, Marcus V.

2014-01-01

Background Advanced castration resistant prostate cancer (CRPC) is often characterized by an increase of C-terminally truncated, constitutively active androgen receptor (AR) variants. Due to the absence of a ligand binding domain located in the AR-C-terminus, these receptor variants (also termed ARΔLBD) are unable to respond to all classical forms of endocrine treatments like surgical/chemical castration and/or application of anti-androgens. Methodology In this study we tested the effects of the naturally occurring stilbene resveratrol (RSV) and (E)-4-(2, 6-Difluorostyryl)-N, N-dimethylaniline, a fluorinated dialkylaminostilbene (FIDAS) on AR- and ARΔLBD in prostate cancer cells. The ability of the compounds to modulate transcriptional activity of AR and the ARΔLBD-variant Q640X was shown by reporter gene assays. Expression of endogenous AR and ARΔLBD mRNA and protein levels were determined by qRT-PCR and Western Blot. Nuclear translocation of AR-molecules was analyzed by fluorescence microscopy. AR and ARΔLBD/Q640X homo-/heterodimer formation was assessed by mammalian two hybrid assays. Biological activity of both compounds in vivo was demonstrated using a chick chorioallantoic membrane xenograft assay. Results The stilbenes RSV and FIDAS were able to significantly diminish AR and Q640X-signalling. Successful inhibition of the Q640X suggests that RSV and FIDAS are not interfering with the AR-ligand binding domain like all currently available anti-hormonal drugs. Repression of AR and Q640X-signalling by RSV and FIDAS in prostate cancer cells was caused by an inhibition of the AR and/or Q640X-dimerization. Although systemic bioavailability of both stilbenes is very low, both compounds were also able to downregulate tumor growth and AR-signalling in vivo. Conclusion RSV and FIDAS are able to inhibit the dimerization of AR and ARΔLBD molecules suggesting that stilbenes might serve as lead compounds for a novel generation of AR-inhibitors. PMID:24887556

Clinical Utility of CLIA-Grade AR-V7 Testing in Patients With Metastatic Castration-Resistant Prostate Cancer.

PubMed

Markowski, Mark C; Silberstein, John L; Eshleman, James R; Eisenberger, Mario A; Luo, Jun; Antonarakis, Emmanuel S

2017-01-01

A splice variant of the androgen receptor, AR-V7, confers resistance to AR-targeted therapies (ATTs) but not taxane chemotherapies in patients with metastatic castration-resistant prostate cancer. Since August 2015, a clinical-grade assay to detect AR-V7 messenger RNA expression in circulating tumors cells (CTCs) has been available to providers through a Clinical Laboratory Improvement Amendments-certified laboratory at Johns Hopkins University. We contacted ordering providers of the first 150 consecutive tests by using a questionnaire-based survey to determine how the results of AR-V7 testing were used to influence clinical practice. In all, 142 (95%) of 150 questionnaires were completed by 38 providers from 29 sites across the United States and Canada. AR-V7 test results were reported either as CTC- (28%), CTC+/AR-V7- (30%), or CTC+/AR-V7+ (42%). Prevalence of AR-V7 detection increased with prior exposure to ATTs (abiraterone and enzalutamide naïve, 22%; after abiraterone or enzalutamide, 35%; after abiraterone and enzalutamide, 43%). Overall, management was affected by AR-V7 testing in 53% of the patients and even more often with CTC+/AR-V7+ results. AR-V7+ patients were commonly switched from ATT to taxane chemotherapy (43%) or were offered a clinical trial (43%); management remained unchanged in only 14% of these patients. Overall, patients who had a change in management on the basis of AR-V7 testing were significantly more likely to achieve a physician-reported 50% decline in prostate-specific antigen response on next-line therapy than those who did not change treatment (54% v 31%; P = .015). Providers used AR-V7 testing to influence clinical decision making more often than not. Physicians reported thatmenwithAR-V7+results had the most treatment changes, and such men were preferentially managed with taxane therapy or offered a clinical trial, which may have improved outcomes.

Associated reactions during a visual pursuit position tracking task in hemiplegic and quadriplegic cerebral palsy.

PubMed

Chiu, Hsiu-Ching; Halaki, Mark; O'Dwyer, Nicholas

2013-04-30

Most previous studies of associated reactions (ARs) in people with cerebral palsy have used observation scales, such as recording the degree of movement through observation. The sensitive quantitative method can detect ARs that are not amply visible. The aim of this study was to provide quantitative measures of ARs during a visual pursuit position tracking task. Twenty-three hemiplegia (H) (mean +/- SD: 21y 8m +/- 11y 10m), twelve quadriplegia (Q) (21y 5m +/- 10y 3m) and twenty-two subjects with normal development (N) (21y 2m +/- 10y 10m) participated in the study. An upper limb visual pursuit tracking task was used to study ARs. The participants were required to follow a moving target with a response cursor via elbow flexion and extension movements. The occurrence of ARs was quantified by the overall coherence between the movements of tracking and non-tracking limbs and the amount of movement due to ARs was quantified by the amplitude of movement the non-tracking limbs. The amplitude of movement of the non-tracking limb indicated that the amount of ARs was larger in the Q group than the H and N groups with no significant differences between the H and N groups. The amplitude of movement of the non-tracking limb was larger during non-dominant than dominant tracking in all three groups. Some movements in the non-tracking limb were correlated with the tracking limb (correlated ARs) and some movements that were not correlated with the tracking limb (uncorrelated ARs). The correlated ARs comprised less than 40% of the total ARs for all three groups. Correlated ARs were negatively associated with clinical evaluations, but not the uncorrelated ARs. The correlated and uncorrelated ARs appear to have different relationships with clinical evaluations, implying the effect of ARs on upper limb activities could be varied.

Foraging parameters influencing the detection and interpretation of area-restricted search behaviour in marine predators: a case study with the masked booby.

PubMed

Sommerfeld, Julia; Kato, Akiko; Ropert-Coudert, Yan; Garthe, Stefan; Hindell, Mark A

2013-01-01

Identification of Area-restricted search (ARS) behaviour is used to better understand foraging movements and strategies of marine predators. Track-based descriptive analyses are commonly used to detect ARS behaviour, but they may be biased by factors such as foraging trip duration or non-foraging behaviours (i.e. resting on the water). Using first-passage time analysis we tested if (I) daylight resting at the sea surface positions falsely increase the detection of ARS behaviour and (II) short foraging trips are less likely to include ARS behaviour in Masked Boobies Sula dactylatra. We further analysed whether ARS behaviour may be used as a proxy to identify important feeding areas. Depth-acceleration and GPS-loggers were simultaneously deployed on chick-rearing adults to obtain (1) location data every 4 minutes and (2) detailed foraging activity such as diving rates, time spent sitting on the water surface and in flight. In 82% of 50 foraging trips, birds adopted ARS behaviour. In 19.3% of 57 detected ARS zones, birds spent more than 70% of total ARS duration resting on the water, suggesting that these ARS zones were falsely detected. Based on generalized linear mixed models, the probability of detecting false ARS zones was 80%. False ARS zones mostly occurred during short trips in close proximity to the colony, with low or no diving activity. This demonstrates the need to account for resting on the water surface positions in marine animals when determining ARS behaviour based on foraging locations. Dive rates were positively correlated with trip duration and the probability of ARS behaviour increased with increasing number of dives, suggesting that the adoption of ARS behaviour in Masked Boobies is linked to enhanced foraging activity. We conclude that ARS behaviour may be used as a proxy to identify important feeding areas in this species.

Retinal imaging using adaptive optics technology☆

PubMed Central

Kozak, Igor

2014-01-01

Adaptive optics (AO) is a technology used to improve the performance of optical systems by reducing the effect of wave front distortions. Retinal imaging using AO aims to compensate for higher order aberrations originating from the cornea and the lens by using deformable mirror. The main application of AO retinal imaging has been to assess photoreceptor cell density, spacing, and mosaic regularity in normal and diseased eyes. Apart from photoreceptors, the retinal pigment epithelium, retinal nerve fiber layer, retinal vessel wall and lamina cribrosa can also be visualized with AO technology. Recent interest in AO technology in eye research has resulted in growing number of reports and publications utilizing this technology in both animals and humans. With the availability of first commercially available instruments we are making transformation of AO technology from a research tool to diagnostic instrument. The current challenges include imaging eyes with less than perfect optical media, formation of normative databases for acquired images such as cone mosaics, and the cost of the technology. The opportunities for AO will include more detailed diagnosis with description of some new findings in retinal diseases and glaucoma as well as expansion of AO into clinical trials which has already started. PMID:24843304

Scythe regulates apoptosis through modulating ubiquitin-mediated proteolysis of the Xenopus elongation factor XEF1AO

PubMed Central

Minami, Ryosuke; Shimada, Masumi; Yokosawa, Hideyoshi; Kawahara, Hiroyuki

2007-01-01

Scythe was originally identified as a novel Reaper-binding anti-apoptotic protein, although the mechanisms of its functions remain largely obscure. Our previous analysis revealed that Scythe can bind to a proteasomal subunit via N-terminal domains and that the domains are required for appropriate development of Xenopus embryos. In the present study, we show evidence that the N-terminus of Scythe interacts with XEF1AO, a maternal form of Xenopus laevis EF1A that was suggested to be a potential inducer of apoptosis in vertebrates, and that the binding enhances the poly-ubiquitin modification and subsequent degradation of XEF1AO. Scythe is required for degradation of XEF1AO, since immunodepletion of Scythe from embryonic extracts stabilized XEF1AO significantly. Furthermore, we show that apoptosis induced by accumulation of XEF1AO can be suppressed by co-expression of the full-length form of Scythe. These observations indicate that the proteolytic regulation of XEF1AO, mediated through Scythe, is essential to prevent inappropriate accumulation of XEF1AO and resulting apoptotic events during the course of Xenopus development. PMID:17428197

Virtual Reality and Augmented Reality in Plastic Surgery: A Review.

PubMed

Kim, Youngjun; Kim, Hannah; Kim, Yong Oock

2017-05-01

Recently, virtual reality (VR) and augmented reality (AR) have received increasing attention, with the development of VR/AR devices such as head-mounted displays, haptic devices, and AR glasses. Medicine is considered to be one of the most effective applications of VR/AR. In this article, we describe a systematic literature review conducted to investigate the state-of-the-art VR/AR technology relevant to plastic surgery. The 35 studies that were ultimately selected were categorized into 3 representative topics: VR/AR-based preoperative planning, navigation, and training. In addition, future trends of VR/AR technology associated with plastic surgery and related fields are discussed.

Virtual Reality and Augmented Reality in Plastic Surgery: A Review

PubMed Central

Kim, Youngjun; Kim, Hannah

2017-01-01

Recently, virtual reality (VR) and augmented reality (AR) have received increasing attention, with the development of VR/AR devices such as head-mounted displays, haptic devices, and AR glasses. Medicine is considered to be one of the most effective applications of VR/AR. In this article, we describe a systematic literature review conducted to investigate the state-of-the-art VR/AR technology relevant to plastic surgery. The 35 studies that were ultimately selected were categorized into 3 representative topics: VR/AR-based preoperative planning, navigation, and training. In addition, future trends of VR/AR technology associated with plastic surgery and related fields are discussed. PMID:28573091

A Novel Role for the Receptor of the Complement Cleavage Fragment C5a, C5aR1, in CCR5-Mediated Entry of HIV into Macrophages.

PubMed

Moreno-Fernandez, Maria E; Aliberti, Julio; Groeneweg, Sander; Köhl, Jörg; Chougnet, Claire A

2016-04-01

The complement system is an ancient pattern recognition system that becomes activated during all stages of HIV infection. Previous studies have shown that C5a can enhance the infection of monocyte-derived macrophages and T cells indirectly through the production of interleukin (IL)-6 and tumor necrosis factor (TNF)-α and the attraction of dendritic cells. C5a exerts its multiple biologic functions mainly through activation of C5a receptor 1 (C5aR1). Here, we assessed the role of C5aR1 as an enhancer of CCR5-mediated HIV infection. We determined CCR5 and C5aR1 heterodimer formation in myeloid cells and the impact of C5aR1 blockade on HIV entry and genomic integration. C5aR1/CCR5 heterodimer formation was identified by immunoprecipitation and western blotting. THP-1 cells and monocyte-derived macrophages (MDM) were infected by R5 laboratory strains or HIV pseudotyped for the vesicular stomatitis virus (VSV) envelope. Levels of integrated HIV were measured by quantitative PCR after targeting of C5aR1 by a C5aR antagonist, neutralizing C5aR1 monoclonal antibody (mAb) or hC5a. C5aR1 was also silenced by specific siRNA prior to viral entry. We found that C5aR1 forms heterodimers with the HIV coreceptor CCR5 in myeloid cells. Targeting C5aR1 significantly decreased integration by R5 viruses but not by VSV-pseudotyped viruses, suggesting that C5aR1 is critical for viral entry. The level of inhibition achieved with C5aR1-blocking reagents was comparable to that of CCR5 antagonists. Mechanistically, C5aR1 targeting decreased CCR5 expression. MDM from CCR5Δ32 homozygous subjects expressed levels of C5aR1 similar to CCR5 WT individuals, suggesting that mere C5aR1 expression is not sufficient for HIV infection. HIV appeared to preferentially enter THP-1 cells expressing high levels of both C5aR1 and CCR5. Targeted reduction of C5aR1 expression in such cells reduced HIV infection by ~50%. Our data thus suggest that C5aR1 acts as an enhancer of CCR5-mediated HIV entry into macrophages, the targeting of which may prove useful to reduce HIV infection by R5 strains.

Undercutting Studies of Protected Kapton. H Exposed to In-Space and Ground-Based Atomic Oxygen

NASA Technical Reports Server (NTRS)

Snyder, Aaron; Banks, Bruce A.; Waters, Deborah L.

2006-01-01

This study is part of a Materials International Space Station Experiment (MISSE) sequence to characterize the performance of prospective spacecraft materials when subjected to the synergistic effects of the space environment. Atomic oxygen (AO) is the most prevalent species in low earth orbit (LEO). In this environment AO is mainly responsible for the erosion of hydrocarbons and halocarbon polymers. The AO erosion rates of Kapton (DuPont) H are known and well documented. Hence, it is customary to compare the AO erosion yields of candidate materials to the commonly accepted standard of this polyimide. The purpose of this study was to provide characterization of AO degradation of SiO(x) protected Kapton H film, which was subject during MISSE 2 to undercutting erosion beneath microscopic defects in the protective film, and compare the degradation resulting from hyperthermal ram (approx.4.5 eV) LEO AO to the degradation resulting from exposure to thermal ground-based (approx.0.04 eV) AO.

Agricultural Research Service

MedlinePlus

... Durum Wheat Opens Door to Expand Food Uses ARS Research In Your State - choose - Alabama Alaska Arizona ... Media About ARS Work With Us Connect with ARS Sign up ARS Home USDA.gov Plain Writing ...

Drug safety is a barrier to the discovery and development of new androgen receptor antagonists.

PubMed

Foster, William R; Car, Bruce D; Shi, Hong; Levesque, Paul C; Obermeier, Mary T; Gan, Jinping; Arezzo, Joseph C; Powlin, Stephanie S; Dinchuk, Joseph E; Balog, Aaron; Salvati, Mark E; Attar, Ricardo M; Gottardis, Marco M

2011-04-01

Androgen receptor (AR) antagonists are part of the standard of care for prostate cancer. Despite the almost inevitable development of resistance in prostate tumors to AR antagonists, no new AR antagonists have been approved for over a decade. Treatment failure is due in part to mutations that increase activity of AR in response to lower ligand concentrations as well as to mutations that result in AR response to a broader range of ligands. The failure to discover new AR antagonists has occurred in the face of continued research; to enable progress, a clear understanding of the reasons for failure is required. Non-clinical drug safety studies and safety pharmacology assays were performed on previously approved AR antagonists (bicalutamide, flutamide, nilutamide), next generation antagonists in clinical testing (MDV3100, BMS-641988), and a pre-clinical drug candidate (BMS-501949). In addition, non-clinical studies with AR mutant mice, and EEG recordings in rats were performed. Non-clinical findings are compared to disclosures of clinical trial results. As a drug class, AR antagonists cause seizure in animals by an off-target mechanism and are found in vitro to inhibit GABA-A currents. Clinical trials of candidate next generation AR antagonists identify seizure as a clinical safety risk. Non-clinical drug safety profiles of the AR antagonist drug class create a significant barrier to the identification of next generation AR antagonists. GABA-A inhibition is a common off-target activity of approved and next generation AR antagonists potentially explaining some side effects and safety hazards of this class of drugs. Copyright © 2010 Wiley-Liss, Inc.

Steroidogenic acute regulatory protein (StAR) overexpression attenuates HFD-induced hepatic steatosis and insulin resistance.

PubMed

Qiu, Yanyan; Sui, Xianxian; Zhan, Yongkun; Xu, Chen; Li, Xiaobo; Ning, Yanxia; Zhi, Xiuling; Yin, Lianhua

2017-04-01

Non-alcoholic fatty liver disease (NAFLD) covers a wide spectrum of liver pathology. Intracellular lipid accumulation is the first step in the development and progression of NAFLD. Steroidogenic acute regulatory protein (StAR) plays an important role in the synthesis of bile acid and intracellular lipid homeostasis and cholesterol metabolism. We hypothesize that StAR is involved in non-alcoholic fatty liver disease (NAFLD) pathogenesis. The hypothesis was identified using free fatty acid (FFA)-overloaded NAFLD in vitro model and high-fat diet (HFD)-induced NAFLD mouse model transfected by recombinant adenovirus encoding StAR (StAR). StAR expression was also examined in pathology samples of patients with fatty liver by immunohistochemical staining. We found that the expression level of StAR was reduced in the livers obtained from fatty liver patients and NAFLD mice. Additionally, StAR overexpression decreased the levels of hepatic lipids and maintained the hepatic glucose homeostasis due to the activation of farnesoid x receptor (FXR). StAR overexpression attenuated the impairment of insulin signaling in fatty liver. This protective role of StAR was owing to a reduction of intracellular diacylglycerol levels and the phosphorylation of PKCε. Furthermore, FXR inactivation reversed the observed beneficial effects of StAR. The present study revealed that StAR overexpression can reduce hepatic lipid accumulation, regulate glucose metabolism and attenuate insulin resistance through a mechanism involving the activation of FXR. Our study suggests that StAR may be a potential therapeutic target for NAFLD. Copyright © 2017 Elsevier B.V. All rights reserved.

Androgen receptor signaling and mutations in prostate cancer

PubMed Central

Koochekpour, Shahriar

2010-01-01

Normal and neoplastic growth of the prostate gland are dependent on androgen receptor (AR) expression and function. Androgenic activation of the AR, in association with its coregulatory factors, is the classical pathway that leads to transcriptional activity of AR target genes. Alternatively, cytoplasmic signaling crosstalk of AR by growth factors, neurotrophic peptides, cytokines or nonandrogenic hormones may have important roles in prostate carcinogenesis and in metastatic or androgen-independent (AI) progression of the disease. In addition, cross-modulation by various nuclear transcription factors acting through basal transcriptional machinery could positively or negatively affect the AR or AR target genes expression and activity. Androgen ablation leads to an initial favorable response in a significant number of patients; however, almost invariably patients relapse with an aggressive form of the disease known as castration-resistant or hormone-refractory prostate cancer (PCa). Understanding critical molecular events that lead PCa cells to resist androgen-deprivation therapy is essential in developing successful treatments for hormone-refractory disease. In a significant number of hormone-refractory patients, the AR is overexpressed, mutated or genomically amplified. These genetic alterations maintain an active presence for a highly sensitive AR, which is responsive to androgens, antiandrogens or nonandrogenic hormones and collectively confer a selective growth advantage to PCa cells. This review provides a brief synopsis of the AR structure, AR coregulators, posttranslational modifications of AR, duality of AR function in prostate epithelial and stromal cells, AR-dependent signaling, genetic changes in the form of somatic and germline mutations and their known functional significance in PCa cells and tissues. PMID:20711217

ARS turns fifteen: la quinceañera bonita.

PubMed

Sen, Chandan K

2013-01-01

ARS was aimed at advancing the erstwhile niche field of redox biology to a more central position in research. Currently, ARS ranks first (impact factor: 8.456) in the field of redox biology. Of 8336 journals listed in Journal Citation Reports, ARS ranks 205th. The next journal in redox biology ranks 449th. ARS ranks 169th of 8336 in immediacy index. The next journal in redox biology ranks 923rd. Thus, ARS is the primary source of hot papers in redox sciences and healthcare. To grow footprint and overall impact, ARS has nearly doubled the annual publication volume from roughly 200 to 400 in one year. Because the manuscript volume represents the denominator of the impact factor calculation, such a sharp increase in volume would be predicted to a proportionally lower impact factor. Because of the robust current upward momentum, ARS will be affected less than that predicted by simple arithmetic and will maintain its top position even after such aggressive volume expansion. As another year passes, the additional manuscripts will get more time to be cited, and therefore the impact factor is expected to bounce back resulting in a much stronger journal with a substantially enhanced overall presence. ARS currently publishes 36 issues annually as two series: ARS-Discoveries, and ARS-Therapeutics. Redox biology does have the potential of major health impact. ARS-Therapeutics is the first and only forum dedicated to highlight that strength. I am grateful to the global redox village for their unreserved support to raise ARS and this fascinating field of redox research and healthcare. Antioxid. Redox Signal. 18, 1-4.

Current Allergic Rhinitis Experiences Survey (CARES): Health-care practitioners' awareness, attitudes and practices.

PubMed

Blaiss, Michael S; Fromer, Leonard M; Jacob-Nara, Juby A; Long, Randall M; Mannion, Karen M; Lauersen, Lori A

2014-01-01

Allergic rhinitis (AR) is a common health problem in the United States, with significant comorbidities and impairment of quality of life despite the availability of many prescription (Rx) and over-the-counter (OTC) medications. The health-care practitioners (HCPs) arm of the Current Allergic Rhinitis Experiences Survey (CARES) assessed HCPs' perceptions about the current management of AR. This U.S.-based national survey included 375 primary care physicians and 375 nurse practitioners/physician assistants. Participants were screened to ensure that they treat ≥15 AR sufferers per month during allergy season. The majority of HCPs (86%) agreed that AR patients can easily recognize allergy symptoms after diagnosis and that 57% of their patients come to them self-recognizing their symptoms. A total of 82% strongly agreed that AR sufferers are primarily diagnosed via history and physical and do not typically undergo diagnostic testing until after pharmacologic intervention. HCPs reported that 63-77% of AR sufferers can easily manage AR once treatment is established. According to surveyed HCPs, OTC medication should precede an Rx medication for AR management. A total of 82% HCPs considered intranasal steroids (INSs) to be the gold standard AR treatment and have minimal safety concerns about INS use. HCPs perceive that patients can easily recognize and self-manage their AR symptoms. Patient history/symptoms and physical examination are the primary methods of AR diagnosis. INSs are considered the gold standard for treatment of AR. However, most HCPs feel OTC medication should be tried before Rx medication for AR management.

Insights into arsenic multi-operons expression and resistance mechanisms in Rhodopseudomonas palustris CGA009

PubMed Central

Zhao, Chungui; Zhang, Yi; Chan, Zhuhua; Chen, Shicheng; Yang, Suping

2015-01-01

Arsenic (As) is widespread in the environment and causes numerous health problems. Rhodopseudomonas palustris has been regarded as a good model organism for studying arsenic detoxification since it was first demonstrated to methylate environmental arsenic by conversion to soluble or gaseous methylated species. However, the detailed arsenic resistance mechanisms remain unknown though there are at least three arsenic-resistance operons (ars1, ars2, and ars3) in R. palustris. In this study, we investigated how arsenic multi-operons contributed to arsenic detoxification in R. palustris. The expression of ars2 or ars3 operons increased with increasing environmental arsenite (As(III)) concentrations (up to 1.0 mM) while transcript of ars1 operon was not detected in the middle log-phase (55 h). ars2 operon was actively expressed even at the low concentration of As(III) (0.01 μM), whereas the ars3 operon was expressed at 1.0 μM of As(III), indicating that there was a differential regulation mechanism for the three arsenic operons. Furthermore, ars2 and ars3 operons were maximally transcribed in the early log-phase where ars2 operon was 5.4-fold higher than that of ars3 operon. A low level of ars1 transcript was only detected at 43 h (early log-phase). Arsenic speciation analysis demonstrated that R. palustris could reduce As(V) to As(III). Collectively, strain CGA009 detoxified arsenic by using arsenic reduction and methylating arsenic mechanism, while the latter might occur with the presence of higher concentrations of arsenic. PMID:26441915

Psycholinguistic and motor theories of apraxia of speech.

PubMed

Ziegler, Wolfram

2002-11-01

This article sketches the relationships between modern conceptions of apraxia of speech (AOS) and current models of neuromotor and neurolinguistic disorders. The first section is devoted to neurophysiological perspectives of AOS, and its relation to dysarthrias and to limb apraxia is discussed. The second section introduces the logogen model and considers AOS in relation to supramodal aspects of aphasia. In the third section, AOS with the background of psycholinguistic models of spoken language production, including the Levelt model and connectionist models, is discussed. In the fourth section, the view of AOS as a disorder of speech motor programming is discussed against the background of theories from experimental psychology. The final section considers two models of speech motor control and their relation to AOS. The article discusses the strengths and weaknesses of these approaches.

Pax6 Represses Androgen Receptor-Mediated Transactivation by Inhibiting Recruitment of the Coactivator SPBP

PubMed Central

Johnsen, Sylvia Sagen; Kaino, Katrine; Sjøttem, Eva; Johansen, Terje

2011-01-01

The androgen receptor (AR) has a central role in development and maintenance of the male reproductive system and in the etiology of prostate cancer. The transcription factor Pax6 has recently been reported to act as a repressor of AR and to be hypermethylated in prostate cancer cells. SPBP is a transcriptional regulator that previously has been shown to enhance the activity of Pax6. In this study we have identified SPBP to act as a transcriptional coactivator of AR. We also show that Pax6 inhibits SPBP-mediated enhancement of AR activity on the AR target gene probasin promoter, a repression that was partly reversed by increased expression of SPBP. Enhanced expression of Pax6 reduced the amount of SPBP associated with the probasin promoter when assayed by ChIP in HeLa cells. We mapped the interaction between both AR and SPBP, and AR and Pax6 to the DNA-binding domains of the involved proteins. Further binding studies revealed that Pax6 and SPBP compete for binding to AR. These results suggest that Pax6 represses AR activity by displacing and/or inhibiting recruitment of coactivators to AR target promoters. Understanding the mechanism for inhibition of AR coactivators can give rise to molecular targeted drugs for treatment of prostate cancer. PMID:21935435

Fitness costs associated with infections of secondary endosymbionts in the cassava whitefly species Bemisia tabaci.

PubMed

Ghosh, Saptarshi; Bouvaine, Sophie; Richardson, Simon C W; Ghanim, Murad; Maruthi, M N

2018-01-01

We investigated the dual effects of bacterial infections and diseased cassava plants on the fitness and biology of the Bemisia tabaci infesting cassava in Africa. Isofemale B. tabaci colonies of sub-Saharan Africa 1-subgroup 3 (SSA1-SG3), infected with two secondary endosymbiotic bacteria Arsenophonus and Rickettsia (AR+) and those free of AR infections (AR-), were compared for fitness parameters on healthy and East African cassava mosaic virus -Uganda variant (EACMV-UG)-infected cassava plants. The whitefly fecundity and nymph development was not affected by bacterial infections or the infection of cassava by the virus. However, emergence of adults from nymphs was 50 and 17% higher by AR- on healthy and virus-infected plants, respectively, than AR+ flies. Development time of adults also was 10 days longer in AR+ than AR-. The whiteflies were further compared for acquisition and retention of EACMV-UG. Higher proportion of AR- acquired (91.8%) and retained (87.6%) the virus than AR+ (71.8, 61.2%, respectively). Similarly, the AR- flies retained higher quantities of virus (~ninefold more) than AR+. These results indicated that bacteria-free whiteflies were superior and better transmitters of EACMV-UG, as they had higher adult emergence, quicker life cycle and better virus retention abilities than those infected with bacteria.

Inhibition of androgen receptor by decoy molecules delays progression to castration-recurrent prostate cancer.

PubMed

Myung, Jae-Kyung; Wang, Gang; Chiu, Helen H L; Wang, Jun; Mawji, Nasrin R; Sadar, Marianne D

2017-01-01

Androgen receptor (AR) is a member of the steroid receptor family and a therapeutic target for all stages of prostate cancer. AR is activated by ligand binding within its C-terminus ligand-binding domain (LBD). Here we show that overexpression of the AR NTD to generate decoy molecules inhibited both the growth and progression of prostate cancer in castrated hosts. Specifically, it was shown that lentivirus delivery of decoys delayed hormonal progression in castrated hosts as indicated by increased doubling time of tumor volume, prolonged time to achieve pre-castrate levels of serum prostate-specific antigen (PSA) and PSA nadir. These clinical parameters are indicative of delayed hormonal progression and improved therapeutic response and prognosis. Decoys reduced the expression of androgen-regulated genes that correlated with reduced in situ interaction of the AR with androgen response elements. Decoys did not reduce levels of AR protein or prevent nuclear localization of the AR. Nor did decoys interact directly with the AR. Thus decoys did not inhibit AR transactivation by a dominant negative mechanism. This work provides evidence that the AR NTD plays an important role in the hormonal progression of prostate cancer and supports the development of AR antagonists that target the AR NTD.

Inhibition of androgen receptor by decoy molecules delays progression to castration-recurrent prostate cancer

PubMed Central

Myung, Jae-Kyung; Wang, Gang; Chiu, Helen H. L.; Wang, Jun; Mawji, Nasrin R.; Sadar, Marianne D.

2017-01-01

Androgen receptor (AR) is a member of the steroid receptor family and a therapeutic target for all stages of prostate cancer. AR is activated by ligand binding within its C-terminus ligand-binding domain (LBD). Here we show that overexpression of the AR NTD to generate decoy molecules inhibited both the growth and progression of prostate cancer in castrated hosts. Specifically, it was shown that lentivirus delivery of decoys delayed hormonal progression in castrated hosts as indicated by increased doubling time of tumor volume, prolonged time to achieve pre-castrate levels of serum prostate-specific antigen (PSA) and PSA nadir. These clinical parameters are indicative of delayed hormonal progression and improved therapeutic response and prognosis. Decoys reduced the expression of androgen-regulated genes that correlated with reduced in situ interaction of the AR with androgen response elements. Decoys did not reduce levels of AR protein or prevent nuclear localization of the AR. Nor did decoys interact directly with the AR. Thus decoys did not inhibit AR transactivation by a dominant negative mechanism. This work provides evidence that the AR NTD plays an important role in the hormonal progression of prostate cancer and supports the development of AR antagonists that target the AR NTD. PMID:28306720

Multimodal actions of the phytochemical sulforaphane suppress both AR and AR-V7 in 22Rv1 cells: Advocating a potent pharmaceutical combination against castration-resistant prostate cancer.

PubMed

Khurana, Namrata; Kim, Hogyoung; Chandra, Partha K; Talwar, Sudha; Sharma, Pankaj; Abdel-Mageed, Asim B; Sikka, Suresh C; Mondal, Debasis

2017-11-01

Prostate cancer (PCa) cells expressing full-length androgen receptor (AR-FL) are susceptible to androgen deprivation therapy (ADT). However, outgrowth of castration-resistant prostate cancer (CRPC) can occur due to the expression of constitutively active (ligand-independent) AR splice variants, particularly AR-V7. We previously demonstrated that sulforaphane (SFN), an isothiocyanate phytochemical, can decrease AR-FL levels in the PCa cell lines, LNCaP and C4-2B. Here, we examined the efficacy of SFN in targeting both AR-FL and AR-V7 in the CRPC cell line, CWR22Rv1 (22Rv1). MTT cell viability, wound-heal assay, and colony forming unit (CFU) measurements revealed that 22Rv1 cells are resistant to the anti-androgen, enzalutamide (ENZ). However, co-exposure to SFN sensitized these cells to the potent anticancer effects of ENZ (P<0.05). Immunoblot analyses showed that SFN (5-20 µM) rapidly decreases both AR-FL and AR-V7 levels, and immunofluorescence microscopy (IFM) depicted decreased AR in both cytoplasm and nucleus with SFN treatment. SFN increased both ubiquitination and proteasomal activity in 22Rv1 cells. Studies using a protein synthesis inhibitor (cycloheximide) or a proteasomal inhibitor (MG132) indicated that SFN increases both ubiquitin-mediated aggregation and subsequent proteasomal-degradation of AR proteins. Previous studies reported that SFN inhibits the chaperone activity of heat-shock protein 90 (Hsp90) and induces the nuclear factor erythroid-2-like 2 (Nrf2) transcription factor. Therefore, we investigated whether the Hsp90 inhibitor, ganetespib (G) or the Nrf2 activator, bardoxolone methyl (BM) can similarly suppress AR levels in 22Rv1 cells. Low doses of G and BM, alone or in combination, decreased both AR-FL and AR-V7 levels, and combined exposure to G+BM sensitized 22Rv1 cells to ENZ. Therefore, adjunct treatment with the phytochemical SFN or a safe pharmaceutical combination of G+BM may be effective against CRPC cells, especially those expressing AR-V7.

Multimodal actions of the phytochemical sulforaphane suppress both AR and AR-V7 in 22Rv1 cells: Advocating a potent pharmaceutical combination against castration-resistant prostate cancer

PubMed Central

Khurana, Namrata; Kim, Hogyoung; Chandra, Partha K.; Talwar, Sudha; Sharma, Pankaj; Abdel-Mageed, Asim B.; Sikka, Suresh C.; Mondal, Debasis

2017-01-01

Prostate cancer (PCa) cells expressing full-length androgen receptor (AR-FL) are susceptible to androgen deprivation therapy (ADT). However, outgrowth of castration-resistant prostate cancer (CRPC) can occur due to the expression of constitutively active (ligand-independent) AR splice variants, particularly AR-V7. We previously demonstrated that sulforaphane (SFN), an isothiocyanate phytochemical, can decrease AR-FL levels in the PCa cell lines, LNCaP and C4-2B. Here, we examined the efficacy of SFN in targeting both AR-FL and AR-V7 in the CRPC cell line, CWR22Rv1 (22Rv1). MTT cell viability, wound-heal assay, and colony forming unit (CFU) measurements revealed that 22Rv1 cells are resistant to the anti-androgen, enzalutamide (ENZ). However, co-exposure to SFN sensitized these cells to the potent anticancer effects of ENZ (P<0.05). Immunoblot analyses showed that SFN (5–20 µM) rapidly decreases both AR-FL and AR-V7 levels, and immunofluorescence microscopy (IFM) depicted decreased AR in both cytoplasm and nucleus with SFN treatment. SFN increased both ubiquitination and proteasomal activity in 22Rv1 cells. Studies using a protein synthesis inhibitor (cycloheximide) or a proteasomal inhibitor (MG132) indicated that SFN increases both ubiquitin-mediated aggregation and subsequent proteasomal-degradation of AR proteins. Previous studies reported that SFN inhibits the chaperone activity of heat-shock protein 90 (Hsp90) and induces the nuclear factor erythroid-2-like 2 (Nrf2) transcription factor. Therefore, we investigated whether the Hsp90 inhibitor, ganetespib (G) or the Nrf2 activator, bardoxolone methyl (BM) can similarly suppress AR levels in 22Rv1 cells. Low doses of G and BM, alone or in combination, decreased both AR-FL and AR-V7 levels, and combined exposure to G+BM sensitized 22Rv1 cells to ENZ. Therefore, adjunct treatment with the phytochemical SFN or a safe pharmaceutical combination of G+BM may be effective against CRPC cells, especially those expressing AR-V7. PMID:28901514

Nicotine induced CpG methylation of Pax6 binding motif in StAR promoter reduces the gene expression and cortisol production

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, Tingting; Department of Pharmacology, Uniformed Services University of the Health Sciences, Bethesda, Maryland; Chen, Man

Steroidogenic acute regulatory protein (StAR) mediates the rate-limiting step in the synthesis of steroid hormones, essential to fetal development. We have reported that the StAR expression in fetal adrenal is inhibited in a rat model of nicotine-induced intrauterine growth retardation (IUGR). Here using primary human fetal adrenal cortex (pHFAC) cells and a human fetal adrenal cell line NCI-H295A, we show that nicotine inhibits StAR expression and cortisol production in a dose- and time-dependent manner, and prolongs the inhibitory effect on cells proliferating over 5 passages after termination of nicotine treatment. Methylation detection within the StAR promoter region uncovers a singlemore » site CpG methylation at nt -377 that is sensitive to nicotine treatment. Nicotine-induced alterations in frequency of this point methylation correlates well with the levels of StAR expression, suggesting an important role of the single site in regulating StAR expression. Further studies using bioinformatics analysis and siRNA approach reveal that the single CpG site is part of the Pax6 binding motif (CGCCTGA) in the StAR promoter. The luciferase activity assays validate that Pax6 increases StAR gene expression by binding to the glucagon G3-like motif (CGCCTGA) and methylation of this site blocks Pax6 binding and thus suppresses StAR expression. These data identify a nicotine-sensitive CpG site at the Pax6 binding motif in the StAR promoter that may play a central role in regulating StAR expression. The results suggest an epigenetic mechanism that may explain how nicotine contributes to onset of adult diseases or disorders such as metabolic syndrome via fetal programming. -- Highlights: Black-Right-Pointing-Pointer Nicotine-induced StAR inhibition in two human adrenal cell models. Black-Right-Pointing-Pointer Nicotine-induced single CpG site methylation in StAR promoter. Black-Right-Pointing-Pointer Persistent StAR inhibition and single CpG methylation after nicotine termination. Black-Right-Pointing-Pointer Single CpG methylation located at Pax6 binding motif regulates StAR expression.« less

Application of K-Ar Dating to the Chronology of Young Volcanic Centers

NASA Astrophysics Data System (ADS)

Lanphere, M. A.

2003-12-01

K-Ar dating and a derivative technique, 40Ar/39Ar dating, are methods of high-precision chronology applicable to young volcanic centers. Cascade volcanoes studied in detail by several USGS volcanologists, Duane Champion paleomagetist, and me include Mt. Baker, WA; Mt. Rainier, WA; Mt. Adams, WA; Mt. Hood, OR; Crater Lake, OR; and Medicine Lake, CA. For Mt. Adams using detailed geologic mapping by Hildreth and Fierstein and 74 K-Ar ages for 63 mapped units, Hildreth and Lanphere established a detailed chronology for the stratovolcano. Good agreement has been achieved for K-Ar ages and 40Ar/39Ar ages of rocks from Mt. Adams as young as 36 ka. A similar detailed chronology has been established for other Cascade volcanoes using andesites, in particular. These chronologies often take 10 years or more to develop. Major advantages of the 40Ar/39Ar technique are the ability to work with small sample sizes and the possibility to push the technique to very young ages. The Campanian Ignimbrite erupted from the Campi Flegrei crater near Naples, Italy is an example of the use of small samples. Nine incremental-heating ages were determined on samples of sanidine ranging in size from 47 mg to 67 mg. These samples yielded ages for the Campanian Ignimbrite ranging from 37.1 +/- 0.75 ka to 39.5 +/- 0.62 ka and averaging 38.1 +/- 0.8 ka. Other workers have proposed 40Ar/39Ar ages for the Campanian Ignimbrite of 37.1 +/- 0.4 ka and 39.3 +/- 0.1 ka. An example of the use of 40Ar/39Ar dating of very young samples is the Christian Era (CE) age of the Vesuvius eruption of year 79. Eight packets of sanidine weighing 213-296 mg from two localities, Casti Amanti in Pompeii and Villa Poppea in nearby Oplontis, yielded a weighted-mean incremental-heating age of 1924 +/- 66 years. The known age for the CE 79 eruption of Vesuvius is 1924 years. Earlier studies of Vesuvius by other workers yielded an 40Ar/39Ar age for the Villa Poppea locality of 1922 +/- 72 years.

40Ar/36Ar geochronology on a quadrupole mass spectrometer: Where are we going?

NASA Astrophysics Data System (ADS)

Schneider, B.; Wijbrans, J. R.; Kuiper, K. F.; Fenton, C. R.; Williams, A. J.

2009-04-01

40Ar/39Ar analysis has passed many milestones since its first application (Wänke & König, 1959). From the early all-glass Reynolds-type vacuum system to today's high quality, bakeable all-metal piping and valve systems, the evolution of ultra high vacuum systems has been considerable. Extraction systems have faced similar changes over time. Early furnaces made partially of glass were later replaced by full metal constructs containing a high temperature resistant molybdenum alloy tube and heating mechanism, sometimes contained within an insulating secondary vacuum chamber. Laser extraction techniques further refined the approach allowing very small samples or sample parts to be analyzed. The principal type of mass spectrometer used for 40Ar/36Ar geochronology is the magnetic sector instrument, which has the resolution and sensitivity necessary for measuring argon isotopes and achieving high precision over a large age range. We present 40Ar/39Ar data from basalt samples collected from a number of different locations, all obtained using the Hiden HAL Series 1000 quadrupole mass spectrometer at Vrije University, Amsterdam. We show that quadrupole technology is not only a viable option in K-Ar geochronology (Rouchon et al., 2008) but also in 40Ar/39Ar geochronology. The data was obtained from groundmass hand-picked from 200-500 um size fractions. Sample amounts of 200 to 500 mg were used for incremental heating experiments. The quality of the data is demonstrated by convergence of plateau and isochron ages, replicate analyses and by comparison to results of independent studies. Sample ages range from 40 ka to 400 ka, demonstrating the potential of quadrupole instruments for dating even very young rocks using the 40Ar/39Ar incremental heating technique. Rouchon, V., Lefevre, J.-C., Quidelleur, X., Guerin, G., Gillot, P.-Y. (2008): Nonspiked 40Ar and 36Ar quantification using a quadrupole mass spectrometer: A potential for K-Ar geochronology. International Journal of Mass Spectrometry 270, 52-61. Wänke H., König H. (1959): Eine neue Methode zur Kalium-Argon-Altersbestimmung und ihre Anwendung auf Steinmeteorite. Z. Naturforschung, 14a, 860 - 866.

Two barcodes encoded by the type-1 PDZ and by phospho-Ser312 regulate retromer/WASH-mediated sorting of the ß1-adrenergic receptor from endosomes to the plasma membrane.

PubMed

Nooh, Mohammed M; Bahouth, Suleiman W

2017-01-01

Recycling of the majority of agonist-internalized GPCR is dependent on a type I-PDZ "barcode" in their C-tail. The recycling of wild-type (WT) ß 1 -AR is also dependent on its default "type-1 PDZ barcode", but trafficking of the ß 1 -AR is inhibited when PKA or its substrate serine at position 312 (Ser 312 ) are inactivated. We tested the hypothesis that phospho-Ser 312 provided a second barcode for ß 1 -AR sorting from endosomes to the plasma membrane by determining the role of retromer/WASH complexes in ß 1 -AR trafficking. Recycling of WT ß 1 -AR or WT ß 2 -AR was dependent on targeting the retromer to endosomal membranes via SNX3 and rab7a, and on complexing the retromer to the WASH pentamer via the C-tail of FAM21 (FAM21 C ). These maneuvers however, did not inhibit the recycling of a phospho-Ser 312 ß 1 -AR mimic ((S312D) ß 1 -AR). Knockdown of the trans-acting PDZ protein sorting nexin27 (SNX27) inhibited the recycling of WT ß 1 -AR and WT ß 2 -AR, but had no effect on (S312D) ß 1 -AR∆PDZ or on phosphorylation of WT ß 1 -AR by PKA at Ser 312 . However, depletion of FKBP15, a FAM21 C -binding endosomal protein, selectively inhibited WT ß 1 -AR but not ß 2 -AR recycling, suggesting divergence might exist in GPCR trafficking roadmaps. These results indicate that two barcodes are involved in sorting WT ß 1 -AR out of early endosomes. The first and antecedent "barcode" was the "type-1 PDZ", followed by a second reversible "phospho-Ser 312 " verification "barcode". This organization allows tight regulation of ß 1 -AR density to signaling intensity in conditions associated with aberrant ß 1 -AR signaling such as in hypertension and heart failure. Copyright © 2016 Elsevier Inc. All rights reserved.

40Ar/39Ar geochronology of terrestrial pyroxene

NASA Astrophysics Data System (ADS)

Ware, Bryant; Jourdan, Fred

2018-06-01

Geochronological techniques such as U/Pb in zircon and baddeleyite and 40Ar/39Ar on a vast range of minerals, including sanidine, plagioclase, and biotite, provide means to date an array of different geologic processes. Many of these minerals, however, are not always present in a given rock, or can be altered by secondary processes (e.g. plagioclase in mafic rocks) limiting our ability to derive an isotopic age. Pyroxene is a primary rock forming mineral for both mafic and ultramafic rocks and is resistant to alteration process but attempts to date this phase with 40Ar/39Ar has been met with little success so far. In this study, we analyzed pyroxene crystals from two different Large Igneous Provinces using a multi-collector noble gas mass spectrometer (ARGUS VI) since those machines have been shown to significantly improve analytical precision compared to the previous single-collector instruments. We obtain geologically meaningful and relatively precise 40Ar/39Ar plateau ages ranging from 184.6 ± 3.9 to 182.4 ± 0.8 Ma (2σ uncertainties of ±1.8-0.4%) and 506.3 ± 3.4 Ma for Tasmanian and Kalkarindji dolerites, respectively. Those data are indistinguishable from new and/or published U-Pb and 40Ar/39Ar plagioclase ages showing that 40Ar/39Ar dating of pyroxene is a suitable geochronological tool. Scrutinizing the analytical results of the pyroxene analyses as well as comparing them to the analytical result from plagioclase of the same samples indicate pure pyroxene was dated. Numerical models of argon diffusion in plagioclase and pyroxene support these observations. However, we found that the viability of 40Ar/39Ar dating approach of pyroxene can be affected by irradiation-induced recoil redistribution between thin pyroxene exsolution lamellae and the main pyroxene crystal, hence requiring careful petrographic observations before analysis. Finally, diffusion modeling show that 40Ar/39Ar of pyroxene can be used as a powerful tool to date the formation age of mafic rocks affected by greenschist metamorphism and will likely play an important role in high temperature thermochronology.

Simpler Adaptive Optics using a Single Device for Processing and Control

NASA Astrophysics Data System (ADS)

Zovaro, A.; Bennet, F.; Rye, D.; D'Orgeville, C.; Rigaut, F.; Price, I.; Ritchie, I.; Smith, C.

The management of low Earth orbit is becoming more urgent as satellite and debris densities climb, in order to avoid a Kessler syndrome. A key part of this management is to precisely measure the orbit of both active satellites and debris. The Research School of Astronomy and Astrophysics at the Australian National University have been developing an adaptive optics (AO) system to image and range orbiting objects. The AO system provides atmospheric correction for imaging and laser ranging, allowing for the detection of smaller angular targets and drastically increasing the number of detectable objects. AO systems are by nature very complex and high cost systems, often costing millions of dollars and taking years to design. It is not unusual for AO systems to comprise multiple servers, digital signal processors (DSP) and field programmable gate arrays (FPGA), with dedicated tasks such as wavefront sensor data processing or wavefront reconstruction. While this multi-platform approach has been necessary in AO systems to date due to computation and latency requirements, this may no longer be the case for those with less demanding processing needs. In recent years, large strides have been made in FPGA and microcontroller technology, with todays devices having clock speeds in excess of 200 MHz whilst using a < 5 V power supply. AO systems using a single such device for all data processing and control may present a far simpler, cheaper, smaller and more efficient solution than existing systems. A novel AO system design based around a single, low-cost controller is presented. The objective is to determine the performance which can be achieved in terms of bandwidth and correction order, with a focus on optimisation and parallelisation of AO algorithms such as wavefront measurement and reconstruction. The AO system consists of a Shack-Hartmann wavefront sensor and a deformable mirror to correct light from a 1.8 m telescope for the purpose of imaging orbiting satellites. The microcontroller or FPGA interfaces directly with the wavefront sensor detector and deformable mirror. Wavefront slopes are calculated from each detector frame and converted into actuator commands to complete the closed loop AO control system. A particular challenge of this system is to optimise the AO algorithms to achieve a high rate (> 1kHz) with low latency (< 1ms) to achieve a good AO correction. As part of the Space Environment Cooperative Research Centre (SERC) this AO system design will be used as a demonstrator for what is possible with ground based AO corrected satellite imaging and ranging systems. The ability to directly and efficiently interface the wavefront sensor and deformable mirror is an important step in reducing the cost and complexity of an AO system. It is hoped that in the future this design can be modified for use in general AO applications, such as in 1-3 m telescopes for space surveillance, or even for amateur astronomy.

40 CFR 52.120 - Identification of plan.

Code of Federal Regulations, 2011 CFR

2011-07-01

.... (i) Incorporation by reference. (A) Arizona Revised Statutes. (1) Senate Bill 1360: Section 6: ARS 15-1444-C (added), Section 7: QRS 15-1627-F (added), Section 21: ARS 49- 542-A (amended, Section 21: ARS 49-542-E (added), Section 21: ARS 49-542-J.3.(b) (amended), and Section 23: ARS 49-550-E (added...

40 CFR 52.120 - Identification of plan.

Code of Federal Regulations, 2012 CFR

2012-07-01

.... (i) Incorporation by reference. (A) Arizona Revised Statutes. (1) Senate Bill 1360: Section 6: ARS 15-1444-C (added), Section 7: QRS 15-1627-F (added), Section 21: ARS 49- 542-A (amended, Section 21: ARS 49-542-E (added), Section 21: ARS 49-542-J.3.(b) (amended), and Section 23: ARS 49-550-E (added...

40 CFR 52.120 - Identification of plan.

Code of Federal Regulations, 2014 CFR

2014-07-01

.... (i) Incorporation by reference. (A) Arizona Revised Statutes. (1) Senate Bill 1360: Section 6: ARS 15-1444-C (added), Section 7: QRS 15-1627-F (added), Section 21: ARS 49- 542-A (amended, Section 21: ARS 49-542-E (added), Section 21: ARS 49-542-J.3.(b) (amended), and Section 23: ARS 49-550-E (added...

75 FR 61774 - Agency Information Collection Activities; Submission for OMB Review; Comment Request; Annual...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-10-06

... (ARS) information collection. While the primary purpose of the ARS is to verify or to correct the North... purposes of the ARS. The ARS seeks accurate mailing and physical location addresses of establishments as... States). The ARS constitutes an information collection within the meaning of the PRA. Under the PRA, a...

40 CFR 52.120 - Identification of plan.

Code of Federal Regulations, 2010 CFR

2010-07-01

.... (i) Incorporation by reference. (A) Arizona Revised Statutes. (1) Senate Bill 1360: Section 6: ARS 15-1444-C (added), Section 7: QRS 15-1627-F (added), Section 21: ARS 49- 542-A (amended, Section 21: ARS 49-542-E (added), Section 21: ARS 49-542-J.3.(b) (amended), and Section 23: ARS 49-550-E (added...

40 CFR 52.120 - Identification of plan.

Code of Federal Regulations, 2013 CFR

2013-07-01

.... (i) Incorporation by reference. (A) Arizona Revised Statutes. (1) Senate Bill 1360: Section 6: ARS 15-1444-C (added), Section 7: QRS 15-1627-F (added), Section 21: ARS 49- 542-A (amended, Section 21: ARS 49-542-E (added), Section 21: ARS 49-542-J.3.(b) (amended), and Section 23: ARS 49-550-E (added...

[The genetic background for the eye malformations anophthalmia and microphthalmia].

PubMed

Roos, Laura Sønderberg; Grønskov, Karen; Jensen, Hanne; Tümer, Zeynep

2012-03-12

Anophthalmia and microphthalmia (AO/MO) are rare congenital eye malformations, in which the eyeball is apparently absent or smaller than normal, which causes various degrees of visual impairment. Over 200 different AO/MO-related syndromes have been described, but the genetic background is unknown in many cases. The aim of this article is to give an overview of AO/MO, focusing on the genetic background. It is illustrated that the future identification of new AO/MO related genes will benefit in the genetic counseling of AO/MO patients, and in the understanding of eye development and congenital eye malformations.

Antioxidant-spotting in micelles and emulsions.

PubMed

Aliaga, Carolina; López de Arbina, Amaia; Pastenes, Camila; Rezende, Marcos Caroli

2018-04-15

A simple protocol is described for locating the site of action of an antioxidant (AO) in a micro-heterogeneous mixture, based on the pattern of the reactivity curve towards the AO of a series of 4-alkanoyl TEMPO radicals. The resulting cut-off curves yield information regarding the hydrophobic microenvironment surrounding the reactive AO group, and its accessibility by the probe. Convex curves are an indication of an AO located in a more hydrophilic environment, while concave plots originate from AOs in a more hydrophobic location in the micro-heterogeneous system. Copyright © 2017 Elsevier Ltd. All rights reserved.

Ar-Ar Impact Heating Ages of Eucrites and Timing of the LHB

NASA Technical Reports Server (NTRS)

Bogard, Donald; Garrison, Daniel

2009-01-01

Eucrites and howardites, more than most meteorite types, show extensive impact resetting of their Ar-39-Ar-40 (K-Ar) ages approximately equal to 3.4-4.1 Ga ago, and many specimens show some disturbance of other radiometry chronometers as well. Bogard (1995) argued that this age resetting occurred on Vesta and was produced by the same general population of objects that produced many of the lunar impact basins. The exact nature of the lunar late heavy bombardment (LHB or 'cataclysm') remains controversial, but the timing is similar to the reset ages of eucrites. Neither the beginning nor ending time of the lunar LHB is well constrained. Comparison of Ar-Ar ages of brecciated eucrites with data for the lunar LHB can resolve both the origin of these impactors and the time period over which they were delivered to the inner solar system. This abstract reports some new Ar-Ar age data for eucrites, obtained since the authors' 1995 and 2003 papers.

The role of mitochondrial fusion and StAR phosphorylation in the regulation of StAR activity and steroidogenesis.

PubMed

Castillo, Ana F; Orlando, Ulises; Helfenberger, Katia E; Poderoso, Cecilia; Podesta, Ernesto J

2015-06-15

The steroidogenic acute regulatory (StAR) protein regulates the rate-limiting step in steroidogenesis, i.e. the delivery of cholesterol from the outer (OMM) to the inner (IMM) mitochondrial membrane. StAR is a 37-kDa protein with an N-terminal mitochondrial targeting sequence that is cleaved off during mitochondrial import to yield 30-kDa intramitochondrial StAR. StAR acts exclusively on the OMM and its activity is proportional to how long it remains on the OMM. However, the precise fashion and the molecular mechanism in which StAR remains on the OMM have not been elucidated yet. In this work we will discuss the role of mitochondrial fusion and StAR phosphorylation by the extracellular signal-regulated kinases 1/2 (ERK1/2) as part of the mechanism that regulates StAR retention on the OMM and activity. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Static and Impulsive Models of Solar Active Regions

NASA Technical Reports Server (NTRS)

Patsourakos, S.; Klimchuk, James A.

2008-01-01

The physical modeling of active regions (ARs) and of the global coronal is receiving increasing interest lately. Recent attempts to model ARs using static equilibrium models were quite successful in reproducing AR images of hot soft X-ray (SXR) loops. They however failed to predict the bright EUV warm loops permeating ARs: the synthetic images were dominated by intense footpoint emission. We demonstrate that this failure is due to the very weak dependence of loop temperature on loop length which cannot simultaneously account for both hot and warm loops in the same AR. We then consider time-dependent AR models based on nanoflare heating. We demonstrate that such models can simultaneously reproduce EUV and SXR loops in ARs. Moreover, they predict radial intensity variations consistent with the localized core and extended emissions in SXR and EUV AR observations respectively. We finally show how the AR morphology can be used as a gauge of the properties (duration, energy, spatial dependence, repetition time) of the impulsive heating.

Age of the Hawaiian-Emperor bend

USGS Publications Warehouse

Dalrymple, G.B.; Clague, D.A.

1976-01-01

40Ar/39Ar age data on alkalic and tholeiitic basalts from Diakakuji and Kinmei Seamounts in the vicinity of the Hawaiian-Emperor bend indicate that these volcanoes are about 41 and 39 m.y. old, respectively. Combined with previously published age data on Yuryaku and Ko??ko Seamounts, the new data indicate that the best age for the bend is 42.0 ?? 1.4 m.y. Petrochemical data indicate that the volcanic rocks recovered from bend seamounts are indistinguishable from Hawaiian volcanic rocks, strengthening the hypothesis that the Hawaiian-Emperor bend is part of the Hawaiian volcanic chain. 40Ar/39Ar total fusion ages on altered whole-rock basalt samples are consistent with feldspar ages and with 40Ar/39Ar incremental heating data and appear to reflect the crystallization ages of the samples even though conventional K-Ar ages are significantly younger. The cause of this effect is not known but it may be due to low-temperature loss of 39Ar from nonretentive montmorillonite clays that have also lost 40Ar. ?? 1976.

Re-examining the surfaces of bone in boys and girls during adolescent growth: a 12-year mixed longitudinal pQCT study

PubMed Central

Gabel, Leigh; Nettlefold, Lindsay; Brasher, Penelope M.; Moore, Sarah; Ahamed, Yasmin; Macdonald, Heather M.; McKay, Heather A.

2016-01-01

We revisit Stanley Garn’s theory related to sex differences in endocortical and periosteal apposition during adolescence using a 12-year mixed longitudinal study design. We used peripheral quantitative computed tomography to examine bone parameters in 230 participants (110 boys, 120 girls; 11.0 yrs at baseline). We assessed total (Tt.Ar, mm2), cortical (Ct.Ar, mm2), and medullary canal area (Me.Ar, mm2), Ct.Ar/Tt.Ar, cortical bone mineral density (Ct.BMD, mg/cm3) and polar strength-strain index (SSIp, mm3) at the tibial midshaft (50% site). We used annual measures of height and chronological age to identify age at peak height velocity (APHV) for each participant. We compared annual accrual rates of bone parameters between boys and girls, aligned on APHV using a linear mixed effects model. At APHV, boys demonstrated greater Tt.Ar (Ratio: 1.27; 95% CI: [1.21, 1.32]), Ct.Ar (1.24; [1.18, 1.30]), Me.Ar (1.31; [1.22, 1.40]) and SSIp (1.36; [1.28, 1.45]), and less Ct.Ar/Tt.Ar (0.98; [0.96, 1.00]) and Ct.BMD (0.97; [0.96, 0.97]) compared with girls. Boys and girls demonstrated periosteal bone formation and net bone loss at the endocortical surface. Compared with girls, boys demonstrated greater annual accrual rates pre-APHV for Tt.Ar (1.18; [1.02, 1.34]) and Me.Ar (1.34; [1.11, 1.57]), lower annual accrual rates pre-APHV for Ct.Ar/Tt.Ar (0.56; [0.29, 0.83]) and Ct.BMD (−0.07; [−0.17, 0.04]) and similar annual accrual rates pre-APHV for Ct.Ar (1.10; [0.94, 1.26]) and SSIp (1.14; [0.98, 1.30]). Post-APHV, boys demonstrated similar annual accrual rates for Ct.Ar/Tt.Ar (1.01; [0.71, 1.31]) and greater annual accrual rates for all other bone parameters compared with girls (Ratio: 1.23 – 2.63; 95% CI: 1.11 to 3.45). Our findings support those of Garn and others of accelerated periosteal apposition during adolescence, more evident in boys than girls. However, our findings challenge the notion of greater endocortical apposition in girls, suggesting instead that girls experience diminished endocortical resorption compared with boys. PMID:26058373

Expression of beta 3-adrenoceptor mRNA in rat tissues.

PubMed

Evans, B A; Papaioannou, M; Bonazzi, V R; Summers, R J

1996-01-01

1. This study examines the expression of beta 3-adrenoceptor messenger RNA (beta 3-AR mRNA) in rat tissues to allow comparison with atypical beta-adrenoceptors determined by functional and radioligand binding techniques. 2. A reverse transcription/polymerase chain reaction protocol has been developed for determining the relative amounts of beta 3-AR mRNA in rat tissues. 3. Measurement of adipsin and uncoupling protein (UCP) mRNA was used to examine all tissues for the presence of white and brown adipose tissue which may contribute beta 3-AR mRNA. 4. The beta 3-AR mRNA is expressed at high levels in brown and white adipose tissue, stomach fundus, the longitudinal/circular smooth muscle of both colon and ileum, and colon submucosa. There was substantial expression of adipsin in colon submucosa and moderate expression in fundus, suggesting that in these regions at least some of the beta 3-AR signal may be contributed by fat. Pylorus and colon mucosa showed moderate levels of beta 3-AR mRNA with lower levels of adipsin. Ileum mucosa and submucosa showed low but readily detectable levels of beta 3-AR. 5. Expression of adipsin in rat skeletal muscles coupled to very low levels of beta 3-AR mRNA indicates that the observed beta 3-AR may be due to the presence of intrinsic fat. beta 3-AR mRNA was virtually undetectable in heart, lung and liver. These results raise the possibility that the atypical beta-AR demonstrated by functional and/or binding studies in muscle and in heart is not the beta 3-AR. 6. By use of two different sets of primers for amplification of beta 3-AR cDNA, no evidence was found for differential splicing of the mRNA in any of the tissues examined. 7. The detection of beta 3-AR mRNA in the gut mucosa and submucosa suggests that in addition to its established roles in lipolysis, thermogenesis and regulation of gut motility beta 3-AR may subserve other functions in the gastrointestinal tract. The absence of beta 3-AR mRNA in rat heart or its presence with adipsin in skeletal muscle suggests that atypical beta-adrenoceptor responses in heart and skeletal muscle are unlikely to be mediated by beta 3-AR.

The androgen receptor gene CAG polymorphism is associated with the severity of coronary artery disease in men.

PubMed

Alevizaki, M; Cimponeriu, A T; Garofallaki, M; Sarika, H L; Alevizaki, C C; Papamichael, C; Philippou, G; Anastasiou, E A; Lekakis, J P; Mavrikakis, M

2003-12-01

The role of androgens in the pathogenesis of coronary artery disease (CAD) remains controversial. The length of the polyglutamine stretch of the transactivation domain (CAG repeat) of the androgen receptor (AR) inversely affects androgen activity. The aim of this study was to investigate the effect of this polymorphism of the AR gene in the extent of CAD in male patients. The relationship of the length of the AR gene CAG repeat on the severity of CAD was examined in 131 men (36-86 years old) undergoing coronary angiography. The severity of CAD was assessed by the number (0-3) of coronary vessels with > 50% reduction in the luminal diameter. The interaction of the AR gene polymorphism with the intima media thickness (IMT) of peripheral arteries and serum levels of sex steroids, insulin and biochemical parameters were also studied. The upper quartile of CAG length (range 9-30) was > or = 23 repeats (longAR). The mean body mass index (BMI) of patients with shorter repeats (< 23; shortAR) was significantly lower than in men with longAR (26.1 vs. 27.6, respectively; P = 0.043 M-W Rank test). There was no correlation between the AR gene repeat length and serum testosterone. Oestradiol levels were significantly higher in longAR (0.19 +/- 0.08 nmol/l vs. 0.14 +/- 0.07 in shortAR, P = 0.031). This difference was independent of BMI. Men with shortAR had significant CAD (i.e. one to three arteries with stenosis) more frequently (79.5%) than men with longAR (20.5%); of the subjects with stenosis in no arteries, 56.5% had shortAR and 43.5% longAR (chi2 = 4.3, P = 0.038). This association was independent of age and BMI. The IMT of peripheral arteries, lipid parameters, basal insulin resistance, blood pressure and family history for early CAD, did not differ according to AR length. The shorter CAG repeat of the AR gene is associated with more severe CAD, which suggests a role for the sensitivity to androgens in the increased frequency of CAD in males. In addition, a protective role of endogenous oestrogen, which is higher in the longAR subgroup, can contribute to the observed difference.

ARS-Media for excel instruction manual

USDA-ARS?s Scientific Manuscript database

ARS-Media for Excel Instruction Manual is the instruction manual that explains how to use the Excel spreadsheet ARS-Media for Excel application. ARS-Media for Excel Instruction Manual is provided as a pdf file....

Publications - RDF 2015-10 | Alaska Division of Geological & Geophysical

Science.gov Websites

Keywords 40Ar/39Ar; Age Dates; Analyses; Analyses and Sampling; Analytical Lab Results; Analytical Results ; Ar-Ar; Bedrock; Bedrock Geology; Cretaceous; Early Jurassic; Eocene; Geochronology; Geology; Lab

Ar-39 - Ar-40 Evidence for an Approximately 4.26 Ga Impact Heating Event on the LL Parent Body

NASA Technical Reports Server (NTRS)

Dixon, E. T.; Bogard, D. D.; Rubin, A. E.

2003-01-01

Miller Range 99301 is a type 6, unbrecciated LL chondrite. MIL 99301 is of interest because some compositional and petrographic features suggest it experienced rather high shock grades, whereas other features suggest it is relatively unshocked. Inconsistent shock indicators could be explained if MIL 99301 was shocked but then partly annealed by heat produced by impacts on the parent body. The hypothesis that MIL 99301 experienced high temperature metamorphism (type 6) followed by a later shock event that heated, but did not melt, the constituent feldspar can be evaluated using (39)Ar-(40)Ar chronology. This is because (39)Ar-(40)Ar ages of shocked ordinary chondrites are generally <4.2 Ga, whereas (39)Ar-(40)Ar ages of unshocked meteorites are generally older, and between 4.52 - 4.38 Ga.

Analysis of the androgen receptor-regulated lncRNA landscape identifies a role for ARLNC1 in prostate cancer progression.

PubMed

Zhang, Yajia; Pitchiaya, Sethuramasundaram; Cieślik, Marcin; Niknafs, Yashar S; Tien, Jean C-Y; Hosono, Yasuyuki; Iyer, Matthew K; Yazdani, Sahr; Subramaniam, Shruthi; Shukla, Sudhanshu K; Jiang, Xia; Wang, Lisha; Liu, Tzu-Ying; Uhl, Michael; Gawronski, Alexander R; Qiao, Yuanyuan; Xiao, Lanbo; Dhanasekaran, Saravana M; Juckette, Kristin M; Kunju, Lakshmi P; Cao, Xuhong; Patel, Utsav; Batish, Mona; Shukla, Girish C; Paulsen, Michelle T; Ljungman, Mats; Jiang, Hui; Mehra, Rohit; Backofen, Rolf; Sahinalp, Cenk S; Freier, Susan M; Watt, Andrew T; Guo, Shuling; Wei, John T; Feng, Felix Y; Malik, Rohit; Chinnaiyan, Arul M

2018-06-01

The androgen receptor (AR) plays a critical role in the development of the normal prostate as well as prostate cancer. Using an integrative transcriptomic analysis of prostate cancer cell lines and tissues, we identified ARLNC1 (AR-regulated long noncoding RNA 1) as an important long noncoding RNA that is strongly associated with AR signaling in prostate cancer progression. Not only was ARLNC1 induced by the AR protein, but ARLNC1 stabilized the AR transcript via RNA-RNA interaction. ARLNC1 knockdown suppressed AR expression, global AR signaling and prostate cancer growth in vitro and in vivo. Taken together, these data support a role for ARLNC1 in maintaining a positive feedback loop that potentiates AR signaling during prostate cancer progression and identify ARLNC1 as a novel therapeutic target.

Aldose reductase mediates retinal microglia activation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chang, Kun-Che; Shieh, Biehuoy; Petrash, J. Mark, E-mail: mark.petrash@ucdenver.edu

Retinal microglia (RMG) are one of the major immune cells in charge of surveillance of inflammatory responses in the eye. In the absence of an inflammatory stimulus, RMG reside predominately in the ganglion layer and inner or outer plexiform layers. However, under stress RMG become activated and migrate into the inner nuclear layer (INL) or outer nuclear layer (ONL). Activated RMG in cell culture secrete pro-inflammatory cytokines in a manner sensitive to downregulation by aldose reductase inhibitors. In this study, we utilized CX3CR1{sup GFP} mice carrying AR mutant alleles to evaluate the role of AR on RMG activation and migrationmore » in vivo. When tested on an AR{sup WT} background, IP injection of LPS induced RMG activation and migration into the INL and ONL. However, this phenomenon was largely prevented by AR inhibitors or in AR null mice, or was exacerbated in transgenic mice that over-express AR. LPS-induced increases in ocular levels of TNF-α and CX3CL-1 in WT mice were substantially lower in AR null mice or were reduced by AR inhibitor treatment. These studies demonstrate that AR expression in RMG may contribute to the proinflammatory phenotypes common to various eye diseases such as uveitis and diabetic retinopathy. - Highlights: • AR inhibition prevents retinal microglial activation. • Endotoxin-induced ocular cytokine production is reduced in AR null mice. • Overexpression of AR spontaneously induces retinal microglial activation.« less

Nicotine Suppressed Fetal Adrenal StAR Expression via YY1 Mediated-Histone Deacetylation Modification Mechanism.

PubMed

Liu, Lian; Wang, Jian-Fei; Fan, Jie; Rao, Yi-Song; Liu, Fang; Yan, You-E; Wang, Hui

2016-09-03

Steroidogenic acute regulatory (StAR) protein plays a pivotal role in steroidogenesis. Previously, we have demonstrated that prenatal nicotine exposure suppressed fetal adrenal steroidogenesis via steroidogenic factor 1 deacetylation. This study further explored the potential role of the transcriptional repressor Yin Yang 1 (YY1) in nicotine-mediated StAR inhibition. Nicotine was subcutaneously administered (1.0 mg/kg) to pregnant rats twice per day and NCI-H295A cells were treated with nicotine. StAR and YY1 expression were analyzed by real-time PCR, immunohistochemistry, and Western blotting. Histone modifications and the interactions between the YY1 and StAR promoter were assessed using chromatin immunoprecipitation (ChIP). Prenatal nicotine exposure increased YY1 expression and suppressed StAR expression. ChIP assay showed that there was a decreasing trend for histone acetylation at the StAR promoter in fetal adrenal glands, whereas H3 acetyl-K14 at the YY1 promoter presented an increasing trend following nicotine exposure. Furthermore, in nicotine-treated NCI-H295A cells, nicotine enhanced YY1 expression and inhibited StAR expression. ChIP assay showed that histone acetylation decreased at the StAR promoter in NCI-H295A cells and that the interaction between the YY1 and StAR promoter increased. These data indicated that YY1-medicated histone deacetylation modification in StAR promoters might play an important role in the inhibitory effect of nicotine on StAR expression.

Cardiac Alpha1-Adrenergic Receptors: Novel Aspects of Expression, Signaling Mechanisms, Physiologic Function, and Clinical Importance

PubMed Central

O’Connell, Timothy D.; Jensen, Brian C.; Baker, Anthony J.

2014-01-01

Adrenergic receptors (AR) are G-protein-coupled receptors (GPCRs) that have a crucial role in cardiac physiology in health and disease. Alpha1-ARs signal through Gαq, and signaling through Gq, for example, by endothelin and angiotensin receptors, is thought to be detrimental to the heart. In contrast, cardiac alpha1-ARs mediate important protective and adaptive functions in the heart, although alpha1-ARs are only a minor fraction of total cardiac ARs. Cardiac alpha1-ARs activate pleiotropic downstream signaling to prevent pathologic remodeling in heart failure. Mechanisms defined in animal and cell models include activation of adaptive hypertrophy, prevention of cardiac myocyte death, augmentation of contractility, and induction of ischemic preconditioning. Surprisingly, at the molecular level, alpha1-ARs localize to and signal at the nucleus in cardiac myocytes, and, unlike most GPCRs, activate “inside-out” signaling to cause cardioprotection. Contrary to past opinion, human cardiac alpha1-AR expression is similar to that in the mouse, where alpha1-AR effects are seen most convincingly in knockout models. Human clinical studies show that alpha1-blockade worsens heart failure in hypertension and does not improve outcomes in heart failure, implying a cardioprotective role for human alpha1-ARs. In summary, these findings identify novel functional and mechanistic aspects of cardiac alpha1-AR function and suggest that activation of cardiac alpha1-AR might be a viable therapeutic strategy in heart failure. PMID:24368739

Accelerated hematopoietic syndrome after radiation doses bridging hematopoietic (H-ARS) and gastrointestinal (GI-ARS) acute radiation syndrome: early hematological changes and systemic inflammatory response syndrome in minipig.

PubMed

Moroni, Maria; Elliott, Thomas B; Deutz, Nicolaas E; Olsen, Cara H; Owens, Rossitsa; Christensen, Christine; Lombardini, Eric D; Whitnall, Mark H

2014-05-01

To characterize acute radiation syndrome (ARS) sequelae at doses intermediate between the bone marrow (H-ARS) and full gastrointestinal (GI-ARS) syndrome. Male minipigs, approximately 5 months old, 9-12 kg in weight, were irradiated with Cobalt-60 (total body, bilateral gamma irradiation, 0.6 Gy/min). Endpoints were 10-day survival, gastrointestinal histology, plasma citrulline, bacterial translocation, vomiting, diarrhea, vital signs, systemic inflammatory response syndrome (SIRS), febrile neutropenia (FN). We exposed animals to doses (2.2-5.0 Gy) above those causing H-ARS (1.6-2.0 Gy), and evaluated development of ARS. Compared to what was observed during H-ARS (historical data: Moroni et al. 2011a , 2011c ), doses above 2 Gy produced signs of increasingly severe pulmonary damage, faster deterioration of clinical conditions, and faster increases in levels of C-reactive protein (CRP). In the range of 4.6-5.0 Gy, animals died by day 9-10; signs of the classic GI syndrome, as measured by diarrhea, vomiting and bacterial translocation, did not occur. At doses above 2 Gy we observed transient reduction in circulating citrulline levels, and animals exhibited earlier depletion of blood elements and faster onset of SIRS and FN. An accelerated hematopoietic subsyndrome (AH-ARS) is observed at radiation doses between those producing H-ARS and GI-ARS. It is characterized by early onset of SIRS and FN, and greater lung damage, compared to H-ARS.

The novel HDAC inhibitor AR-42-induced anti-colon cancer cell activity is associated with ceramide production

DOE Office of Scientific and Technical Information (OSTI.GOV)

Xu, Weihong; Xu, Bin; Yao, Yiting

In the current study, we investigated the potential activity of AR-42, a novel histone deacetylase (HDAC) inhibitor, against colon cancer cells. Our in vitro results showed that AR-42 induced ceramide production, exerted potent anti-proliferative and pro-apoptotic activities in established (SW-620 and HCT-116 lines) and primary human colon cancer cells. Exogenously-added sphingosine 1-phosphate (S1P) suppressed AR-42-induced activity, yet a cell-permeable ceramide (C4) facilitated AR-42-induced cytotoxicity against colon cancer cells. In addition, AR-42-induced ceramide production and anti-colon cancer cell activity were inhibited by the ceramide synthase inhibitor fumonisin B1, but were exacerbated by PDMP, which is a ceramide glucosylation inhibitor. In vivo, oral administrationmore » of a single dose of AR-42 dramatically inhibited SW-620 xenograft growth in severe combined immunodeficient (SCID) mice, without inducing overt toxicities. Together, these results show that AR-42 dramatically inhibits colon cancer cell proliferation in vitro and in vivo, and ceramide production might be the key mechanism responsible for its actions. - Highlights: • AR-42 is anti-proliferative against primary/established colon cancer cells. • AR-42 induces significant apoptotic death in primary/established colon cancer cells. • Ceramide production mediates AR-42-induced cytotoxicity in colon cancer cells. • AR-42 oral administration potently inhibits SW-620 xenograft growth in SCID mice.« less

Photosynthetic and antioxidant responses of Liquidambar formosana and Schima superba seedlings to sulfuric-rich and nitric-rich simulated acid rain.

PubMed

Chen, Juan; Wang, Wen-Hua; Liu, Ting-Wu; Wu, Fei-Hua; Zheng, Hai-Lei

2013-03-01

To study whether differential responses occur in photosynthesis and antioxidant system for seedlings of Liquidambar formosana, an acid rain (AR)-sensitive tree species and Schima superba, an AR-tolerant tree species treated with three types of pH 3.0 simulated AR (SiAR) including sulfuric-rich (S-SiAR), nitric-rich (N-SiAR), sulfate and nitrate mixed (SN-SiAR), we investigated the changes of leaf necrosis, chlorophyll content, soluble protein and proline content, photosynthesis and chlorophyll fluorescence characteristics, reactive oxygen species production, membrane lipid peroxidation, small molecular antioxidant content, antioxidant enzyme activities and related protein expressions. Our results showed that SiAR significantly caused leaf necrosis, inhibited photosynthesis, induced superoxide radical and hydrogen peroxide generation, aggravated membrane lipid peroxidation, changed antioxidant enzyme activities, modified related protein expressions such as Cu/Zn superoxide dismutase (SOD), l-ascorbate peroxidase (APX, EC 1. 11. 1. 11), glutathione S transferase (GST, EC 2. 5. 1. 18) and Rubisco large subunit (RuBISCO LSU), altered non-protein thiols (NPT) and glutathione (GSH) content in leaves of L. formosana and S. superba. Taken together, we concluded that the damages caused by SiAR in L. formosana were more severe and suffered from more negative impacts than in S. superba. S-SiAR induced more serious damages for the plants than did SN-SiAR and N-SiAR. Crown Copyright © 2013. Published by Elsevier Masson SAS. All rights reserved.

Modeling Truncated AR Expression in a Natural Androgen Responsive Environment and Identification of RHOB as a Direct Transcriptional Target

PubMed Central

Tsai, Hui-Chi; Boucher, David L.; Martinez, Anthony; Tepper, Clifford G.; Kung, Hsing-Jien

2012-01-01

Recent studies identifying putative truncated androgen receptor isoforms with ligand-independent activity have shed new light on the acquisition of androgen depletion independent (ADI) growth of prostate cancer. In this study, we present a model system in which a C-terminally truncated variant of androgen receptor (TC-AR) is inducibly expressed in LNCaP, an androgen-dependent cell line, which expresses little truncated receptor. We observed that when TC-AR is overexpressed, the endogenous full length receptor (FL-AR) is transcriptionally downmodulated. This in essence allows us to “replace” FL-AR with TC-AR and compare their individual properties in exactly the same genetic and cellular background, which has not been performed before. We show that the TC-AR translocates to the nucleus, activates transcription of AR target genes in the absence of DHT and is sufficient to confer ADI growth to the normally androgen dependent LNCaP line. We also show that while there is significant overlap in the genes regulated by FL- and TC-AR there are also differences in the respective suites of target genes with each AR form regulating genes that the other does not. Among the genes uniquely activated by TC-AR is RHOB which is shown to be involved in the increased migration and morphological changes observed in LN/TC-AR, suggesting a role of RHOB in the regulation of androgen-independent behavior of prostate cancer cells. PMID:23209612

Nicotine Suppressed Fetal Adrenal StAR Expression via YY1 Mediated-Histone Deacetylation Modification Mechanism

PubMed Central

Liu, Lian; Wang, Jian-Fei; Fan, Jie; Rao, Yi-Song; Liu, Fang; Yan, You-E; Wang, Hui

2016-01-01

Steroidogenic acute regulatory (StAR) protein plays a pivotal role in steroidogenesis. Previously, we have demonstrated that prenatal nicotine exposure suppressed fetal adrenal steroidogenesis via steroidogenic factor 1 deacetylation. This study further explored the potential role of the transcriptional repressor Yin Yang 1 (YY1) in nicotine-mediated StAR inhibition. Nicotine was subcutaneously administered (1.0 mg/kg) to pregnant rats twice per day and NCI-H295A cells were treated with nicotine. StAR and YY1 expression were analyzed by real-time PCR, immunohistochemistry, and Western blotting. Histone modifications and the interactions between the YY1 and StAR promoter were assessed using chromatin immunoprecipitation (ChIP). Prenatal nicotine exposure increased YY1 expression and suppressed StAR expression. ChIP assay showed that there was a decreasing trend for histone acetylation at the StAR promoter in fetal adrenal glands, whereas H3 acetyl-K14 at the YY1 promoter presented an increasing trend following nicotine exposure. Furthermore, in nicotine-treated NCI-H295A cells, nicotine enhanced YY1 expression and inhibited StAR expression. ChIP assay showed that histone acetylation decreased at the StAR promoter in NCI-H295A cells and that the interaction between the YY1 and StAR promoter increased. These data indicated that YY1-medicated histone deacetylation modification in StAR promoters might play an important role in the inhibitory effect of nicotine on StAR expression. PMID:27598153

Adaptive optics ophthalmoscopy

PubMed Central

Roorda, Austin; Duncan, Jacque L.

2016-01-01

This review starts with a brief history and description of adaptive optics (AO) technology, followed by a showcase of the latest capabilities of AO systems for imaging the human retina and an extensive review of the literature on where AO is being used clinically. The review concludes with a discussion on future directions and guidance on usage and interpretation of images from AO systems for the eye. PMID:26973867

Assessing the Treatment Effects in Apraxia of Speech: Introduction and Evaluation of the Modified Diadochokinesis Test

ERIC Educational Resources Information Center

Hurkmans, Joost; Jonkers, Roel; Boonstra, Anne M.; Stewart, Roy E.; Reinders-Messelink, Heleen A.

2012-01-01

Background: The number of reliable and valid instruments to measure the effects of therapy in apraxia of speech (AoS) is limited. Aims: To evaluate the newly developed Modified Diadochokinesis Test (MDT), which is a task to assess the effects of rate and rhythm therapies for AoS in a multiple baseline across behaviours design. Methods: The…

A rethinking on the benefits and drawbacks of common antioxidants and a proposal to look for the antioxidants in allium products as ideal agents: a review.

PubMed

Augusti, K T; Jose, Regi; Sajitha, G R; Augustine, Paul

2012-01-01

This review article on the beneficial uses of Allium antioxidants tries to give some answers to the recent doubts raised by Singh et al. (Ind J Clin Biochem 25(3):225-243, 2010) against the claim of some researchers that Antioxidants (AOs) are miraculous molecules. Many people still believe that vitamins like A, C and E are the only true AOs that play important role in the corrections of metabolic derangements in life style diseases and hence all their faults are attributed to the failures of AOs as a class. This is quite unfair as there are many other natural AOs that do equal or even better AO action than the vitamins. Such is the case with the Allium S-alkyl sulfoxide aminoacids and their breakdown products viz, the various poly sulfides and their oxides e.g. allicin and ajoene type compounds which trap electrons mainly. It is true that antioxidant vitamins and β-carotene a precursor of Vitamin A bring about problems as prooxidant or as agents that block some metabolic pathways and gene expression. Again the argument that AOs cannot improve the level of antioxidant enzymes like SOD, catalase and glutathione Px is also not universal. Actually allium AOs can even spare the use of antioxidant vitamins in the body and enhance the action of antioxidant enzymes and supply of ATP and other nutrients to the tissues as the former are good vasodialators and promoters of membrane permeability. The use of AOs should be selective and moderate. Allium AOs satisfy the role of ideal AOs based on many of their invivo and invitro actions reported by the author and others. Their metabolits can regenerate them and recycle them for a sufficient time in the body. They have non antioxidant effects also such as antiplatelet, fibrinolytic, antiinflammatory, immunomodulatory, antiageing actions etc. Plant derived AOs may be more beneficial and better tolerated in their partially purified forms rather than in their absolutely purified forms as the accompanying principles have some protective and regulatory effects in general. This and other aspects of allium AOs are discussed in the paper.

Cloning and Functional Analysis of the Promoter of an Ascorbate Oxidase Gene from Gossypium hirsutum

PubMed Central

Xin, Shan; Tao, Chengcheng; Li, Hongbin

2016-01-01

Apoplastic ascorbate oxidase (AO) plays significant roles in plant cell growth. However, the mechanism of underlying the transcriptional regulation of AO in Gossypium hirsutum remains unclear. Here, we obtained a 1,920-bp promoter sequence from the Gossypium hirsutum ascorbate oxidase (GhAO1) gene, and this GhAO1 promoter included a number of known cis-elements. Promoter activity analysis in overexpressing pGhAO1::GFP-GUS tobacco (Nicotiana benthamiana) showed that the GhAO1 promoter exhibited high activity, driving strong reporter gene expression in tobacco trichomes, leaves and roots. Promoter 5’-deletion analysis demonstrated that truncated GhAO1 promoters with serial 5’-end deletions had different GUS activities. A 360-bp fragment was sufficient to activate GUS expression. The P-1040 region had less GUS activity than the P-720 region, suggesting that the 320-bp region from nucleotide -720 to -1040 might include a cis-element acting as a silencer. Interestingly, an auxin-responsive cis-acting element (TGA-element) was uncovered in the promoter. To analyze the function of the TGA-element, tobacco leaves transformed with promoters with different 5’ truncations were treated with indole-3-acetic acid (IAA). Tobacco leaves transformed with the promoter regions containing the TGA-element showed significantly increased GUS activity after IAA treatment, implying that the fragment spanning nucleotides -1760 to -1600 (which includes the TGA-element) might be a key component for IAA responsiveness. Analyses of the AO promoter region and AO expression pattern in Gossypium arboreum (Ga, diploid cotton with an AA genome), Gossypium raimondii (Gr, diploid cotton with a DD genome) and Gossypium hirsutum (Gh, tetraploid cotton with an AADD genome) indicated that AO promoter activation and AO transcription were detected together only in D genome/sub-genome (Gr and Gh) cotton. Taken together, these results suggest that the 1,920-bp GhAO1 promoter is a functional sequence with a potential effect on fiber cell development, mediated by TGA-element containing sequences, via the auxin-signaling pathway. PMID:27597995

Cloning and Functional Analysis of the Promoter of an Ascorbate Oxidase Gene from Gossypium hirsutum.

PubMed

Xin, Shan; Tao, Chengcheng; Li, Hongbin

2016-01-01

Apoplastic ascorbate oxidase (AO) plays significant roles in plant cell growth. However, the mechanism of underlying the transcriptional regulation of AO in Gossypium hirsutum remains unclear. Here, we obtained a 1,920-bp promoter sequence from the Gossypium hirsutum ascorbate oxidase (GhAO1) gene, and this GhAO1 promoter included a number of known cis-elements. Promoter activity analysis in overexpressing pGhAO1::GFP-GUS tobacco (Nicotiana benthamiana) showed that the GhAO1 promoter exhibited high activity, driving strong reporter gene expression in tobacco trichomes, leaves and roots. Promoter 5'-deletion analysis demonstrated that truncated GhAO1 promoters with serial 5'-end deletions had different GUS activities. A 360-bp fragment was sufficient to activate GUS expression. The P-1040 region had less GUS activity than the P-720 region, suggesting that the 320-bp region from nucleotide -720 to -1040 might include a cis-element acting as a silencer. Interestingly, an auxin-responsive cis-acting element (TGA-element) was uncovered in the promoter. To analyze the function of the TGA-element, tobacco leaves transformed with promoters with different 5' truncations were treated with indole-3-acetic acid (IAA). Tobacco leaves transformed with the promoter regions containing the TGA-element showed significantly increased GUS activity after IAA treatment, implying that the fragment spanning nucleotides -1760 to -1600 (which includes the TGA-element) might be a key component for IAA responsiveness. Analyses of the AO promoter region and AO expression pattern in Gossypium arboreum (Ga, diploid cotton with an AA genome), Gossypium raimondii (Gr, diploid cotton with a DD genome) and Gossypium hirsutum (Gh, tetraploid cotton with an AADD genome) indicated that AO promoter activation and AO transcription were detected together only in D genome/sub-genome (Gr and Gh) cotton. Taken together, these results suggest that the 1,920-bp GhAO1 promoter is a functional sequence with a potential effect on fiber cell development, mediated by TGA-element containing sequences, via the auxin-signaling pathway.

Reference intervals of aortic pulse wave velocity assessed with an oscillometric device in healthy children and adolescents from Argentina.

PubMed

Alejandro, Díaz; Yanina, Zócalo; Daniel, Bia; Franco, Sabino; Victoria, Rodríguez; Edmundo, Cabrera FIscher

2018-03-09

Age-related reference intervals (RIs) of aortic pulse wave velocity (Ao-PWV) obtained from a large healthy population are lacking in South America. The aims of this study were to determine Ao-PWV RIs in a cohort of healthy children and adolescents from Argentina and to generate year-to-year percentile curves. Ao-PWV was measured in 1000 healthy subjects non-exposed to traditional cardiovascular risk factors (Age: 10-22 y. o., 56% males). First, we evaluated if RIs for males and females were necessaries (correlation and covariate analysis). Second, mean (M) and standard deviation (SD) age-related equations were obtained for cf-PWV, using parametric regression methods based on fractional polynomials. Third, age-specific (year to year) percentiles curves (for all, males and females children and adolescents) were generated using the standard normal distribution. They were, age-specific 1st, 2.5th, 5th, 10th, 25th, 50th, 75th, 90th, 95th, 97.5th and 99th percentile curves and values. After covariate analysis (i.e., adjusting by age, jugulum-symphysis distance, body weight and height), specific RIs for males and females of children and adolescents were evidenced as necessaries. The equations were For all subjects: Ao-PWV_Mean = 4.98 + 12.86x10 -5 Age 3 . Ao-PWV_SD = 0.47 + 21.00x10 -6 Age 3 . For girls: Ao-PWV_Mean = 5.07 + 10.23x10 -5 Age 3 . Ao-PWV_SD = 0.50 + 10.00x10 -6 Age 3 . For boys: Ao-PWV_Mean = 4.87 + 15.81x10 -5 Age 3 . Ao-PWV_SD = 0.46 + 22.34x10 -6 Age 3 . Our study provides the largest database to-date concerning Ao-PWV in healthy children and adolescents in Argentina. Age-related equations (M and SD values) for Ao-PWV are reported by the first time. Specific RIs and percentiles of Ao-PWV are now available according to age and sex for an Argentinian population.

Variability of age at onset in siblings with familial Alzheimer disease.

PubMed

Gómez-Tortosa, Estrella; Barquero, M Sagrario; Barón, Manuel; Sainz, M Jose; Manzano, Sagrario; Payno, Maria; Ros, Raquel; Almaraz, Carmen; Gómez-Garré, Pilar; Jiménez-Escrig, Adriano

2007-12-01

Variability of age at onset (AO) of Alzheimer disease (AD) among members of the same family is important as a biological clue and because of its clinical effects. To evaluate which clinical variables influence the discrepancy in AO among affected relatives with familial AD. Clinical genetic project of Spanish kindred with AD conducted by 4 academic hospitals in Madrid, Spain. Age at onset of AD in 162 families and discrepancy in AO in intragenerational and intergenerational affected pairs were analyzed in relation to age, sex, maternal or paternal transmission, pattern of inheritance, and apolipoprotein E genotype. Maternal transmission of AD was significantly more frequent than paternal transmission (P < .001). In 27% of the affected individuals, AO occurred before the patient was 65 years old. Discrepancy in AO among siblings was within 5 years in 44% of the families, 6 to 10 years in 29%, and more than 10 years in 27% (range, 0-22). This discrepancy was independent of the sex of the sibling pairs and was significantly lower with maternal transmission of AD (P = .02). Segregation analysis showed no differences in the inheritance pattern between families with low (< or =5 years) or high (>5 years) AO discrepancy. Age at onset in carriers of the apolipoprotein E epsilon4 allele was slightly younger. However, among siblings, an extra apolipoprotein E epsilon4 allele was not consistently associated with earlier onset of AD. Eighty percent of patients, independent of sex or mode of transmission, were already affected at their parents' reported AO. There is a wide discrepancy in AO in affected siblings that is not clearly explained by a single clinical variable or apolipoprotein E genotype. The interaction of many factors probably determines AO in each affected individual. However, maternal transmission of AD seems to result in a similar AO in offspring, and the risk of developing dementia after the parent's reported AO decreases significantly.

Reference values of aortic pulse wave velocity in the elderly.

PubMed

Alecu, Cosmin; Labat, Carlos; Kearney-Schwartz, Anna; Fay, Renaud; Salvi, Paolo; Joly, Laure; Lacolley, Patrick; Vespignani, Hervé; Benetos, Athanase

2008-11-01

Increased aortic pulse wave velocity (AoPWV) is an independent predictor of cardiovascular morbidity and mortality. There are, however, no generally accepted limits for defining the normal or reference values. The aim of the present study was to define reference values for AoPWV. AoPWV was assessed using applanation tonometry (PulsePen device) in a community living ambulatory population of 455 individuals aged 60-75 years. AoPWV was studied in a group of 206 individuals without hypertension or diabetes, called the 'reference-values group' (RVG), and in a group of 249 individuals with hypertension or diabetes, called the hypertension-diabetes group (HDG). The 95th percentile of the samples was used to determine the upper limit of AoPWV reference values. Mean AoPWV was 8.7+/-2.3 m/s in the RVG and 10.2+/-2.5 m/s in the hypertension-diabetes group (P<0.0001). In the RVG, median AoPWV in the three age subgroups was 8.0 m/s (7.6-8.5) in the 60-64-, 8.0 m/s (7.5-9.0) in the 65-69- and 9.0 m/s (7.9-9.5) in the 70-75-year-old group (NS among groups). In the entire RVG, the upper bounds of the 75th and the 95th percentile of the sample's AoPWV were 10 and 13 m/s, respectively, with no difference between sexes. In elderly individuals of 60-75 years, an AoPWV value below 10 m/s, measured with the PulsePen device, can be considered as a normal value. Values of 10-13 m/s can be considered as 'high normal' or 'borderline', whereas an AoPWV above 13 m/s is frankly elevated. This study provides, for the first time in the elderly, reference values of AoPWV.

Initial accomplishments of the Environmental Control and Life Support System (ECLSS) atmosphere revitalization (AR) predevelopment operational system test (POST) for the Space Station Freedom (SSF)

NASA Technical Reports Server (NTRS)

Dunn, Kevin H.; Bulgajewski, Peter J.

1992-01-01

Initial results of the integrated AR POST conducted by Boeing at Marshall Space Flight Center in 1992 are presented. The three baselined ECLSS Man Tended Capability AR assemblies were integrated and operated in a closed door chamber in which the internal atmosphere was monitored. The test provides a prerequisite checkout of the AR subsystem in preparation for longer duration tests in which the AR subsystem will be integrated with the Water Recovery Management subsystem. The integrated AR POST will serve as an early test bed to evaluate the integration of the space station ECLSS AR subsystem during design maturation.

Correlation of echo-Doppler aortic valve regurgitation index with angiographic aortic regurgitation severity.

PubMed

Chen, Ming; Luo, Huai; Miyamoto, Takashi; Atar, Shaul; Kobal, Sergio; Rahban, Masoud; Brasch, Andrea V; Makkar, Rajendra; Neuman, Yoram; Naqvi, Tasneem Z; Tolstrup, Kirsten; Siegel, Robert J

2003-09-01

We assessed aortic regurgitation (AR) severity by utilizing multiple echo-Doppler variables in comparison with AR severity by aortic root angiography. Patients were divided into 3 groups: mild, moderate, and severe. An AR index (ARI) was developed, comprising 5 echocardiographic parameters: ratio of color AR jet height to left ventricular outlet flow diameter, AR signal density from continuous-wave Doppler, pressure half-time, left ventricular end-diastolic diameter, and aortic root diameter. There was a strong correlation between AR severity by angiography and the calculated echo-Doppler ARI (r = 0.84, p = 0.0001). As validated by aortic angiography, the ARI is an accurate reflection of AR severity.

75 FR 38557 - Application Nos. and Proposed Exemptions; D-11489, Morgan Stanley & Co., Incorporated; L-11609...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-07-02

...; (b) The term ``Auction Rate Security'' or ``ARS'' means a security: (1) That is either a debt... Securities (ARS). The applicant describes ARS and the arrangement by which ARS are bought and sold as follows. ARS are securities (issued as debt or preferred stock) with an interest rate or dividend that is reset...

ACTH Action on StAR Biology

PubMed Central

Clark, Barbara J.

2016-01-01

Adrenocorticotropin hormone (ACTH) produced by the anterior pituitary stimulates glucocorticoid synthesis by the adrenal cortex. The first step in glucocorticoid synthesis is the delivery of cholesterol to the mitochondrial matrix where the first enzymatic reaction in the steroid hormone biosynthetic pathway occurs. A key response of adrenal cells to ACTH is activation of the cAMP-protein kinase A (PKA) signaling pathway. PKA activation results in an acute increase in expression and function of the Steroidogenic Acute Regulatory protein (StAR). StAR plays an essential role in steroidogenesis- it controls the hormone-dependent movement of cholesterol across the mitochondrial membranes. Currently StAR's mechanism of action remains a major unanswered question in the field. However, some insight may be gained from understanding the mechanism(s) controlling the PKA-dependent phosphorylation of StAR at S194/195 (mouse/human StAR), a modification that is required for function. This mini-review provides a background on StAR's biology with a focus on StAR phosphorylation. The model for StAR translation and phosphorylation at the outer mitochondrial membrane, the location for StAR function, is presented to highlight a unifying theme emerging from diverse studies. PMID:27999527

ACTH Action on StAR Biology.

PubMed

Clark, Barbara J

2016-01-01

Adrenocorticotropin hormone (ACTH) produced by the anterior pituitary stimulates glucocorticoid synthesis by the adrenal cortex. The first step in glucocorticoid synthesis is the delivery of cholesterol to the mitochondrial matrix where the first enzymatic reaction in the steroid hormone biosynthetic pathway occurs. A key response of adrenal cells to ACTH is activation of the cAMP-protein kinase A (PKA) signaling pathway. PKA activation results in an acute increase in expression and function of the Steroidogenic Acute Regulatory protein (StAR). StAR plays an essential role in steroidogenesis- it controls the hormone-dependent movement of cholesterol across the mitochondrial membranes. Currently StAR's mechanism of action remains a major unanswered question in the field. However, some insight may be gained from understanding the mechanism(s) controlling the PKA-dependent phosphorylation of StAR at S194/195 (mouse/human StAR), a modification that is required for function. This mini-review provides a background on StAR's biology with a focus on StAR phosphorylation. The model for StAR translation and phosphorylation at the outer mitochondrial membrane, the location for StAR function, is presented to highlight a unifying theme emerging from diverse studies.

Stromal androgen receptor roles in the development of normal prostate, benign prostate hyperplasia, and prostate cancer.

PubMed

Wen, Simeng; Chang, Hong-Chiang; Tian, Jing; Shang, Zhiqun; Niu, Yuanjie; Chang, Chawnshang

2015-02-01

The prostate is an androgen-sensitive organ that needs proper androgen/androgen receptor (AR) signals for normal development. The progression of prostate diseases, including benign prostate hyperplasia (BPH) and prostate cancer (PCa), also needs proper androgen/AR signals. Tissue recombination studies report that stromal, but not epithelial, AR plays more critical roles via the mesenchymal-epithelial interactions to influence the early process of prostate development. However, in BPH and PCa, much more attention has been focused on epithelial AR roles. However, accumulating evidence indicates that stromal AR is also irreplaceable and plays critical roles in prostate disease progression. Herein, we summarize the roles of stromal AR in the development of normal prostate, BPH, and PCa, with evidence from the recent results of in vitro cell line studies, tissue recombination experiments, and AR knockout animal models. Current evidence suggests that stromal AR may play positive roles to promote BPH and PCa progression, and targeting stromal AR selectively with AR degradation enhancer, ASC-J9, may allow development of better therapies with fewer adverse effects to battle BPH and PCa. Copyright © 2015 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Voltammetric Response of Alizarin Red S-Confined Film-Coated Electrodes to Diol and Polyol Compounds: Use of Phenylboronic Acid-Modified Poly(ethyleneimine) as Film Component.

PubMed

Takahashi, Shigehiro; Suzuki, Iwao; Ojima, Takuto; Minaki, Daichi; Anzai, Jun-Ichi

2018-01-22

Alizarin red S (ARS) was confined in layer-by-layer (LbL) films composed of phenylboronic acid-modified poly(ethyleneimine) (PBA-PEI) and carboxymethylcellulose (CMC) to study the voltammetric response to diol and polyol compounds. The LbL film-coated gold (Au) electrode and quartz slide were immersed in an ARS solution to uptake ARS into the film. UV-visible absorption spectra of ARS-confined LbL film suggested that ARS formed boronate ester (ARS-PBS) in the film. The cyclic voltammetry of the ARS-confined LbL film-coated electrodes exhibited oxidation peaks at -0.50 and -0.62 V, which were ascribed to the oxidation reactions of ARS-PBS and free ARS, respectively, in the LbL film. The peak current at -0.62 V increased upon the addition of diol or polyol compounds such as L-dopa, glucose, and sorbitol into the solution, depending on the concentration, whereas the peak current at -0.50 V decreased. The results suggest a possible use of ARS-confined PBA-PEI/CMC LbL film-coated Au electrodes for the construction of voltammetric sensors for diol and polyol compounds.

Androgen Receptor (AR) in Cardiovascular Diseases

PubMed Central

Huang, Chiung-Kuei; Lee, Soo Ok; Chang, Eugene; Pang, Haiyan; Chang, Chawnshang

2016-01-01

Cardiovascular diseases (CVDs) are still the highest leading cause of death worldwide. Several risk factors have been linked to CVDs, including smoking, diabetes, hyperlipidemia, and gender among others. Sex hormones, especially the androgen and its receptor, androgen receptor (AR), have been linked to many diseases with a clear gender difference. Here, we summarize androgen/AR effects on CVDs, including hypertension, stroke, atherosclerosis, abdominal aortic aneurysm (AAA), myocardial hypertrophy, and heart failure, as well as metabolic syndrome/diabetes and their impacts on CVDs. Androgen/AR signaling exacerbates hypertension and anti-androgens may suppress hypertension. Androgen/AR signaling plays dual roles in strokes, depending on different kinds of factors, but generally males have a higher incidence of strokes than females. Androgen and AR differentially modulate atherosclerosis. Androgen deficiency causes elevated lipid accumulation to enhance atherosclerosis, but targeting AR in selective cells without altering serum androgen levels would suppress atherosclerosis progression. Androgen/AR signaling is crucial in AAA development and progression, and targeting androgen/AR profoundly restricts AAA progression. Men have increased cardiac hypertrophy as compared to age-matched women that may be due to androgens. Finally, androgen/AR plays important roles in contributing to obesity and insulin/leptin resistance to increase the metabolic syndrome. PMID:26769913

Effects of alkylresorcinols on volume and structure of yeast-leavened bread.

PubMed

Andersson, Annica Am; Landberg, Rikard; Söderman, Thomas; Hedkvist, Sofie; Katina, Kati; Juvonen, Riikka; Holopainen, Ulla; Lehtinen, Pekka; Aman, Per

2011-01-30

Alkylresorcinols (AR) are amphiphilic phenolic compounds found in high amounts in wheat, durum wheat and rye, with different homologue composition for each cereal. The effect of different amounts of added AR from these cereals on bread volume, height, porosity and microstructure was studied. Breads with added rye bran (with high levels of AR) or acetone-extracted rye bran (with low levels of AR) were also baked, as well as breads with finely milled forms of each of these brans. Breads with high amounts of added AR, irrespective of AR homologue composition, had a lower volume, a more compact structure and an adverse microstructure compared with breads with no or low levels of added AR. AR were also shown to inhibit the activity of baker's yeast. There was no difference in bread volume and porosity between bread baked with rye bran and acetone-extracted rye bran or with brans of different particle size. Irrespective of homologue composition, AR had a negative effect on wheat bread properties when added in high amounts as purified extracts from wheat, durum wheat and rye. Natural levels of AR in rye bran, however, did not affect the volume and porosity of yeast-leavened wheat breads. 2010 Society of Chemical Industry.

40Ar/39Ar and K-Ar data bearing on the metamorphic and tectonic history of western New England.

USGS Publications Warehouse

Sutter, J.F.; Ratcliffe, N.M.; Mukasa, S.B.

1985-01-01

40Ar/39Ar ages of coexisting biotite and hornblende from Proterozoic Y gneisses of the Berkshire and Green Mt massifs, as well as 40Ar/39Ar and K/Ar mineral and whole-rock ages from Palaeozoic metamorphic rocks, suggest that the thermal peaks for the dominant metamorphic recrystallization in western New England occurred 465 + or - 5 m.y. (Taconian). 40Ar/39Ar age data from a poorly-defined terrain along the eastern strip of the area suggests that the area has been retrograded during a metamorphism that peaked at least 376 + or - 5 m.y. (Acadian). Available age and petrological data from western New England indicate the presence of at least three separate metamorphic-structure domains of Taconic age: 1) a small area of relict high-P and low-T metamorphism, 2) a broad area of normal Barrovian metamorphism from chlorite to garnet grade characterized by a gentle metamorphic gradient and, 3) a rather narrow belt of steep-gradient, Barrovian series metamorphic rocks. Areas of maximum metamorphic intensity within the last domain coincide with areas of maximum crustal thickening in the later stage of Taconic orogeny. -L.di H

Antibiotic Resistome: Improving Detection and Quantification Accuracy for Comparative Metagenomics.

PubMed

Elbehery, Ali H A; Aziz, Ramy K; Siam, Rania

2016-04-01

The unprecedented rise of life-threatening antibiotic resistance (AR), combined with the unparalleled advances in DNA sequencing of genomes and metagenomes, has pushed the need for in silico detection of the resistance potential of clinical and environmental metagenomic samples through the quantification of AR genes (i.e., genes conferring antibiotic resistance). Therefore, determining an optimal methodology to quantitatively and accurately assess AR genes in a given environment is pivotal. Here, we optimized and improved existing AR detection methodologies from metagenomic datasets to properly consider AR-generating mutations in antibiotic target genes. Through comparative metagenomic analysis of previously published AR gene abundance in three publicly available metagenomes, we illustrate how mutation-generated resistance genes are either falsely assigned or neglected, which alters the detection and quantitation of the antibiotic resistome. In addition, we inspected factors influencing the outcome of AR gene quantification using metagenome simulation experiments, and identified that genome size, AR gene length, total number of metagenomics reads and selected sequencing platforms had pronounced effects on the level of detected AR. In conclusion, our proposed improvements in the current methodologies for accurate AR detection and resistome assessment show reliable results when tested on real and simulated metagenomic datasets.

Effects of mixing on resolved and unresolved scales on stratospheric age of air

NASA Astrophysics Data System (ADS)

Dietmüller, Simone; Garny, Hella; Plöger, Felix; Jöckel, Patrick; Cai, Duy

2017-06-01

Mean age of air (AoA) is a widely used metric to describe the transport along the Brewer-Dobson circulation. We seek to untangle the effects of different processes on the simulation of AoA, using the chemistry-climate model EMAC (ECHAM/MESSy Atmospheric Chemistry) and the Chemical Lagrangian Model of the Stratosphere (CLaMS). Here, the effects of residual transport and two-way mixing on AoA are calculated. To do so, we calculate the residual circulation transit time (RCTT). The difference of AoA and RCTT is defined as aging by mixing. However, as diffusion is also included in this difference, we further use a method to directly calculate aging by mixing on resolved scales. Comparing these two methods of calculating aging by mixing allows for separating the effect of unresolved aging by mixing (which we term aging by diffusion in the following) in EMAC and CLaMS. We find that diffusion impacts AoA by making air older, but its contribution plays a minor role (order of 10 %) in all simulations. However, due to the different advection schemes of the two models, aging by diffusion has a larger effect on AoA and mixing efficiency in EMAC, compared to CLaMS. Regarding the trends in AoA, in CLaMS the AoA trend is negative throughout the stratosphere except in the Northern Hemisphere middle stratosphere, consistent with observations. This slight positive trend is neither reproduced in a free-running nor in a nudged simulation with EMAC - in both simulations the AoA trend is negative throughout the stratosphere. Trends in AoA are mainly driven by the contributions of RCTT and aging by mixing, whereas the contribution of aging by diffusion plays a minor role.

Contemporary experience with surgical treatment of aortic valve disease in children.

PubMed

Khan, Muhammad S; Samayoa, Andres X; Chen, Diane W; Petit, Christopher J; Fraser, Charles D

2013-09-01

Surgical treatment of aortic valve (AoV) disease in childhood involves complex decisions particularly in very small patients. There is no consensus regarding the optimum surgical option. The objective of this review was to analyze a contemporary experience of AoV surgery in a large children's hospital. A retrospective review of children (aged ≤ 18 years) undergoing AoV repair or replacement from June 1995 to December 2011 was carried out. A total of 285 AoV operations (97 repairs, 188 replacements) were performed on 241 patients. Hospital survival for repair was 98% and for replacements was 97%. At follow-up of repairs, there were 16 (17%) reoperations and 3 (3%) late deaths. Follow-up of AoV replacements demonstrated 31 (16%) reoperations (homograft 27, autograft 3, mechanical 1) and 8 (4%) late deaths (homograft 5, autograft 2, mechanical 1). Freedom from reintervention or death (FRD) was found to be lower in repairs for infants (P = .048) and truncal valves (P < .05). For AoV replacements, infants and patients who had concomitant CHD or homografts (P < .0001) had lower FRD. Cox regression analysis for AoV replacements identified infants and homograft root replacements at a higher risk for death/reoperation. AoV repairs and replacements were generally found to be associated with low death and reoperation rates at long-term follow-up. Infants had a lower freedom from reintervention or death after either an AoV repair or replacement, although truncal valve repairs and AoV replacement in patients with concomitant CHD were associated with lower valve survival. Among the valve options, homograft root replacement had a higher risk of death/reoperation and lowest freedom from reintervention or death. Copyright © 2013 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.

Three Weeks of Anti-orthostatic Suspension had no Effect on Immune Status in a Specific-Pathogen-Free Enfvironment

NASA Astrophysics Data System (ADS)

Jang, Tae Young; Chang, Geun Uck; Kim, Kyu-Sung; Heo, Min-Jeong; Jung, Ah-Yeoun; Kim, Young Hyo

2015-09-01

Anti-Orthostatic Suspension (AOS) is a well-known murine ground-based model of simulated microgravity. However, because no commercial equipment is available for AOS in Specific-Pathogen-Free (SPF) laboratories no previous study has been conducted to examine the effect of AOS on allergic immunity. Accordingly, we developed an AOS cage suitable for SPF conditions, and evaluate its reliability and the effect of 3 weeks of AOS on immunity in a mouse model. An AOS cage were developed using stainless steel components. Fourteen female BALB/c mice were allocated to Group A (control group, n=7) or Group B (AOS, n=7). Body weights and thickness of posterior thigh muscles were measured before and after 3 weeks of AOS, and serum IgE and the titers of cytokines (IL-4, IL-5, IL-10, IL-13, and IFN- γ) in bronchoalveolar lavage (BAL) fluid were compared, as were lung histologic findings. The SPF condition was successfully maintained. No significant difference in weight gain was observed between groups A (0.9 ±1.0 g) and B (0.8 ±1.1 g, P>0.05) after the 3-week experimental period. The mean thickness of posterior thigh muscles in Group B was significantly lower than in Group A (0.7 ±0.2 versus -0.4 ±0.3 mm, P =0.001). However, group serum IgE titers, and IL-4, IL-5, IL-10, IL-13, and IFN- γ titers in BAL fluid were non-significantly different. No intergroup difference was found by histopathologic examinations of lungs. In conclusion, using AOS equipment in a SPF laboratory, immune status was not found to be significantly affected by 3 weeks AOS in healthy mice.

SoAx: A generic C++ Structure of Arrays for handling particles in HPC codes

NASA Astrophysics Data System (ADS)

Homann, Holger; Laenen, Francois

2018-03-01

The numerical study of physical problems often require integrating the dynamics of a large number of particles evolving according to a given set of equations. Particles are characterized by the information they are carrying such as an identity, a position other. There are generally speaking two different possibilities for handling particles in high performance computing (HPC) codes. The concept of an Array of Structures (AoS) is in the spirit of the object-oriented programming (OOP) paradigm in that the particle information is implemented as a structure. Here, an object (realization of the structure) represents one particle and a set of many particles is stored in an array. In contrast, using the concept of a Structure of Arrays (SoA), a single structure holds several arrays each representing one property (such as the identity) of the whole set of particles. The AoS approach is often implemented in HPC codes due to its handiness and flexibility. For a class of problems, however, it is known that the performance of SoA is much better than that of AoS. We confirm this observation for our particle problem. Using a benchmark we show that on modern Intel Xeon processors the SoA implementation is typically several times faster than the AoS one. On Intel's MIC co-processors the performance gap even attains a factor of ten. The same is true for GPU computing, using both computational and multi-purpose GPUs. Combining performance and handiness, we present the library SoAx that has optimal performance (on CPUs, MICs, and GPUs) while providing the same handiness as AoS. For this, SoAx uses modern C++ design techniques such template meta programming that allows to automatically generate code for user defined heterogeneous data structures.

The impact of climate change on the expansion of Ixodes persulcatus habitat and the incidence of tick-borne encephalitis in the north of European Russia

PubMed Central

Tokarevich, Nikolay K.; Tronin, Andrey A.; Blinova, Olga V.; Buzinov, Roman V.; Boltenkov, Vitaliy P.; Yurasova, Elena D.; Nurse, Jo

2011-01-01

Background The increase in tick-borne encephalitis (TBE) incidence is observed in recent decades in a number of subarctic countries. The reasons of it are widely discussed in scientific publications. The objective of this study was to understand if the climate change in Arkhangelsk Oblast (AO) situated in the north of European subarctic zone of Russia has real impact on the northward expansion of Ixodid ticks and stipulates the increase in TBE incidence. Methods This study analyzes: TBE incidence in AO and throughout Russia, the results of Ixodid ticks collecting in a number of sites in AO, and TBE virus prevalence in those ticks, the data on tick bite incidence in AO, and meteorological data on AO mean annual air temperatures and precipitations. Results It is established that in recent years TBE incidence in AO tended to increase contrary to its apparent decrease nationwide. In last 10 years, there was nearly 50-fold rise in TBE incidence in AO when compared with 1980–1989. Probably, the increase both in mean annual air temperatures and temperatures during tick active season resulted in the northward expansion of Ixodes Persulcatus, main TBE virus vector. The Ixodid ticks expansion is confirmed both by the results of ticks flagging from the surface vegetation and by the tick bite incidence in the population of AO locations earlier free from ticks. Our mathematical (correlation and regression) analysis of available data revealed a distinct correlation between TBE incidence and the growth of mean annual air temperatures in AO in 1990–2009. Conclusion Not ruling out other factors, we conclude that climate change contributed much to the TBE incidence increase in AO. PMID:22028678

Aerobic biodegradation of amphoteric amine-oxide-based surfactants: Effect of molecular structure, initial surfactant concentration and pH.

PubMed

Ríos, Francisco; Lechuga, Manuela; Fernández-Serrano, Mercedes; Fernández-Arteaga, Alejandro

2017-03-01

The present study was designed to provide information regarding the effect of the molecular structure of amphoteric amine-oxide-based surfactants and the initial surfactant concentration on their ultimate biodegradation. Moreover, given this parameter's pH-dependence, the effect of pH was also investigated. Three amine-oxide-based surfactants with structural differences in their hydrophobic alkyl chain were tested: Lauramine oxide (AO-R 12 ), Myristamine oxide (AO-R 14 ) and Cocamidopropylamine oxide (AO-Cocoamido). We studied the ultimate biodegradation using the Modified OECD Screening Test at initial surfactant concentrations ranged from 5 to 75 mg L -1 and at pH levels from 5 to 7.4. The results demonstrate that at pH 7.4, amine-oxide-based surfactants are readily biodegradable. In this study, we concluded that ω-oxidation can be assumed to be the main biodegradation pathway of amine-oxides and that differences in the biodegradability between them can be explained by the presence of an amide group in the alkyl chain of AO-Cocoamido; the CN fission of the amide group slows down their mineralization process. In addition, the increase in the concentration of the surfactant from 5 to 75 mg L -1 resulted in an increase in the final biodegradation of AO-R 12 and AO-R 14 . However, in the case of AO-Cocoamido, a clear relationship between the concentration and biodegradation cannot be stated. Conversely, the biodegradability of AO-R 12 and AO-R 14 was considerably lower in an acid condition than at a pH of 7.4, whereas AO-Cocoamido reached similar percentages in acid conditions and at a neutral pH. However, microorganisms required more time to acclimate. Copyright © 2016 Elsevier Ltd. All rights reserved.

Minimal clinically important difference and the effect of clinical variables on the ankle osteoarthritis scale in surgically treated end-stage ankle arthritis.

PubMed

Coe, Marcus P; Sutherland, Jason M; Penner, Murray J; Younger, Alastair; Wing, Kevin J

2015-05-20

There is much debate regarding the best outcome tool for use in foot and ankle surgery, specifically in patients with ankle arthritis. The Ankle Osteoarthritis Scale (AOS) is a validated, disease-specific score. The goals of this study were to investigate the clinical performance of the AOS and to determine a minimal clinically important difference (MCID) for it, using a large cohort of 238 patients undergoing surgery for end-stage ankle arthritis. Patients treated with total ankle arthroplasty or ankle arthrodesis were prospectively followed for a minimum of two years at a single site. Data on demographics, comorbidities, AOS score, Short Form-36 results, and the relationship between expectations and satisfaction were collected at baseline (preoperatively), at six and twelve months, and then yearly thereafter. A linear regression analysis examined the variables affecting the change in AOS scores between baseline and the two-year follow-up. An MCID in the AOS change score was then determined by employing an anchor question, which asked patients to rate their relief from symptoms after surgery. Surgical treatment of end-stage ankle arthritis resulted in a mean improvement (and standard deviation) of 31.2 ± 22.7 points in the AOS score two years after surgery. The MCID of the AOS change score was a mean of 28.0 ± 17.9 points. The change in AOS score was significantly affected by the preoperative AOS score, smoking, back pain, and age. Patients undergoing arthroplasty or arthrodesis for end-stage ankle arthritis experienced a mean improvement in AOS score that was greater than the estimated MCID (31.2 versus 28.0 points). Copyright © 2015 by The Journal of Bone and Joint Surgery, Incorporated.

Intestinal microbial variation may predict early acute rejection after liver transplantation in rats.

PubMed

Ren, Zhigang; Jiang, Jianwen; Lu, Haifeng; Chen, Xinhua; He, Yong; Zhang, Hua; Xie, Haiyang; Wang, Weilin; Zheng, Shusen; Zhou, Lin

2014-10-27

Acute rejection (AR) remains a life-threatening complication after orthotopic liver transplantation (OLT) and there are few available diagnostic biomarkers clinically for AR. This study aims to identify intestinal microbial profile and explore potential application of microbial profile as a biomarker for AR after OLT. The OLT models in rats were established. Hepatic graft histology, ultrastructure, function, and intestinal barrier function were tested. Ileocecal contents were collected for intestinal microbial analysis. Hepatic graft suffered from the ischemia-reperfusion (I/R) injury on day 1, initial AR on day 3, and severe AR on day 7 after OLT. Real-time quantitative polymerase chain reaction results showed that genus Faecalibacterium prausnitzii and Lactobacillus were decreased, whereas Clostridium bolteae was increased during AR. Notably, cluster analysis of denaturing gradient gel electrophoresis (DGGE) profiles showed the 7AR and 3AR groups clustered together with 73.4% similarity, suggesting that intestinal microbiota was more sensitive than hepatic function in responding to AR. Microbial diversity and species richness were decreased during AR. Phylogenetic tree analysis showed that most of the decreased key bacteria belonged to phylum Firmicutes, whereas increased key bacteria belonged to phylum Bacteroidetes. Moreover, intestinal microvilli loss and tight junction damage were noted, and intestinal barrier dysfunction during AR presented a decrease of fecal secretory immunoglobulin A (sIgA) and increase of blood bacteremia, endotoxin, and tumor necrosis factor-α. We dynamically detail intestinal microbial characterization and find a high sensitivity of microbial change during AR after OLT, suggesting that intestinal microbial variation may predict AR in early phase and become an assistant therapeutic target to improve rejection after OLT.

Identification of an AR Mutation-Negative Class of Androgen Insensitivity by Determining Endogenous AR Activity.

PubMed

Hornig, N C; Ukat, M; Schweikert, H U; Hiort, O; Werner, R; Drop, S L S; Cools, M; Hughes, I A; Audi, L; Ahmed, S F; Demiri, J; Rodens, P; Worch, L; Wehner, G; Kulle, A E; Dunstheimer, D; Müller-Roßberg, E; Reinehr, T; Hadidi, A T; Eckstein, A K; van der Horst, C; Seif, C; Siebert, R; Ammerpohl, O; Holterhus, P-M

2016-11-01

Only approximately 85% of patients with a clinical diagnosis complete androgen insensitivity syndrome and less than 30% with partial androgen insensitivity syndrome can be explained by inactivating mutations in the androgen receptor (AR) gene. The objective of the study was to clarify this discrepancy by in vitro determination of AR transcriptional activity in individuals with disorders of sex development (DSD) and male controls. Quantification of DHT-dependent transcriptional induction of the AR target gene apolipoprotein D (APOD) in cultured genital fibroblasts (GFs) (APOD assay) and next-generation sequencing of the complete coding and noncoding AR locus. The study was conducted at a university hospital endocrine research laboratory. GFs from 169 individuals were studied encompassing control males (n = 68), molecular defined DSD other than androgen insensitivity syndrome (AIS; n = 18), AR mutation-positive AIS (n = 37), and previously undiagnosed DSD including patients with a clinical suspicion of AIS (n = 46). There were no interventions. DHT-dependent APOD expression in cultured GF and AR mutation status in 169 individuals was measured. The APOD assay clearly separated control individuals (healthy males and molecular defined DSD patients other than AIS) from genetically proven AIS (cutoff < 2.3-fold APOD-induction; 100% sensitivity, 93.3% specificity, P < .0001). Of 46 DSD individuals with no AR mutation, 17 (37%) fell below the cutoff, indicating disrupted androgen signaling. AR mutation-positive AIS can be reliably identified by the APOD assay. Its combination with next-generation sequencing of the AR locus uncovered an AR mutation-negative, new class of androgen resistance, which we propose to name AIS type II. Our data support the existence of cellular components outside the AR affecting androgen signaling during sexual differentiation with high clinical relevance.

Coagulation factor VII is regulated by androgen receptor in breast cancer.

PubMed

Naderi, Ali

2015-02-01

Androgen receptor (AR) is widely expressed in breast cancer; however, there is limited information on the key molecular functions and gene targets of AR in this disease. In this study, gene expression data from a cohort of 52 breast cancer cell lines was analyzed to identify a network of AR co-expressed genes. A total of 300 genes, which were significantly enriched for cell cycle and metabolic functions, showed absolute correlation coefficients (|CC|) of more than 0.5 with AR expression across the dataset. In this network, a subset of 35 "AR-signature" genes were highly co-expressed with AR (|CC|>0.6) that included transcriptional regulators PATZ1, NFATC4, and SPDEF. Furthermore, gene encoding coagulation factor VII (F7) demonstrated the closest expression pattern with AR (CC=0.716) in the dataset and factor VII protein expression was significantly associated to that of AR in a cohort of 209 breast tumors. Moreover, functional studies demonstrated that AR activation results in the induction of factor VII expression at both transcript and protein levels and AR directly binds to a proximal region of F7 promoter in breast cancer cells. Importantly, AR activation in breast cancer cells induced endogenous factor VII activity to convert factor X to Xa in conjunction with tissue factor. In summary, F7 is a novel AR target gene and AR activation regulates the ectopic expression and activity of factor VII in breast cancer cells. These findings have functional implications in the pathobiology of thromboembolic events and regulation of factor VII/tissue factor signaling in breast cancer. Copyright © 2014 Elsevier Inc. All rights reserved.

A NEW METHOD TO QUANTIFY AND REDUCE THE NET PROJECTION ERROR IN WHOLE-SOLAR-ACTIVE-REGION PARAMETERS MEASURED FROM VECTOR MAGNETOGRAMS

DOE Office of Scientific and Technical Information (OSTI.GOV)

Falconer, David A.; Tiwari, Sanjiv K.; Moore, Ronald L.

Projection errors limit the use of vector magnetograms of active regions (ARs) far from the disk center. In this Letter, for ARs observed up to 60° from the disk center, we demonstrate a method for measuring and reducing the projection error in the magnitude of any whole-AR parameter that is derived from a vector magnetogram that has been deprojected to the disk center. The method assumes that the center-to-limb curve of the average of the parameter’s absolute values, measured from the disk passage of a large number of ARs and normalized to each AR’s absolute value of the parameter atmore » central meridian, gives the average fractional projection error at each radial distance from the disk center. To demonstrate the method, we use a large set of large-flux ARs and apply the method to a whole-AR parameter that is among the simplest to measure: whole-AR magnetic flux. We measure 30,845 SDO /Helioseismic and Magnetic Imager vector magnetograms covering the disk passage of 272 large-flux ARs, each having whole-AR flux >10{sup 22} Mx. We obtain the center-to-limb radial-distance run of the average projection error in measured whole-AR flux from a Chebyshev fit to the radial-distance plot of the 30,845 normalized measured values. The average projection error in the measured whole-AR flux of an AR at a given radial distance is removed by multiplying the measured flux by the correction factor given by the fit. The correction is important for both the study of the evolution of ARs and for improving the accuracy of forecasts of an AR’s major flare/coronal mass ejection productivity.« less

Coral calcifying fluid aragonite saturation states derived from Raman spectroscopy

NASA Astrophysics Data System (ADS)

DeCarlo, Thomas M.; D'Olivo, Juan P.; Foster, Taryn; Holcomb, Michael; Becker, Thomas; McCulloch, Malcolm T.

2017-11-01

Quantifying the saturation state of aragonite (ΩAr) within the calcifying fluid of corals is critical for understanding their biomineralization process and sensitivity to environmental changes including ocean acidification. Recent advances in microscopy, microprobes, and isotope geochemistry enable the determination of calcifying fluid pH and [CO32-], but direct quantification of ΩAr (where ΩAr = [CO32-][Ca2+]/Ksp) has proved elusive. Here we test a new technique for deriving ΩAr based on Raman spectroscopy. First, we analysed abiogenic aragonite crystals precipitated under a range of ΩAr from 10 to 34, and we found a strong dependence of Raman peak width on ΩAr with no significant effects of other factors including pH, Mg/Ca partitioning, and temperature. Validation of our Raman technique for corals is difficult because there are presently no direct measurements of calcifying fluid ΩAr available for comparison. However, Raman analysis of the international coral standard JCp-1 produced ΩAr of 12.3 ± 0.3, which we demonstrate is consistent with published skeletal Mg/Ca, Sr/Ca, B/Ca, δ11B, and δ44Ca data. Raman measurements are rapid ( ≤ 1 s), high-resolution ( ≤ 1 µm), precise (derived ΩAr ± 1 to 2 per spectrum depending on instrument configuration), accurate ( ±2 if ΩAr < 20), and require minimal sample preparation, making the technique well suited for testing the sensitivity of coral calcifying fluid ΩAr to ocean acidification and warming using samples from natural and laboratory settings. To demonstrate this, we also show a high-resolution time series of ΩAr over multiple years of growth in a Porites skeleton from the Great Barrier Reef, and we evaluate the response of ΩAr in juvenile Acropora cultured under elevated CO2 and temperature.

Artemisinin disrupts androgen responsiveness of human prostate cancer cells by stimulating the 26S proteasome-mediated degradation of the androgen receptor protein.

PubMed

Steely, Andrea M; Willoughby, Jamin A; Sundar, Shyam N; Aivaliotis, Vasiliki I; Firestone, Gary L

2017-10-01

Androgen receptor (AR) expression and activity is highly linked to the development and progression of prostate cancer and is a target of therapeutic strategies for this disease. We investigated whether the antimalarial drug artemisinin, which is a sesquiterpene lactone isolated from the sweet wormwood plant Artemisia annua, could alter AR expression and responsiveness in cultured human prostate cancer cell lines. Artemisinin treatment induced the 26S proteasome-mediated degradation of the receptor protein, without altering AR transcript levels, in androgen-responsive LNCaP prostate cancer cells or PC-3 prostate cancer cells expressing exogenous wild-type AR. Furthermore, artemisinin stimulated AR ubiquitination and AR receptor interactions with the E3 ubiquitin ligase MDM2 in LNCaP cells. The artemisinin-induced loss of AR protein prevented androgen-responsive cell proliferation and ablated total AR transcriptional activity. The serine/threonine protein kinase AKT-1 was shown to be highly associated with artemisinin-induced proteasome-mediated degradation of AR protein. Artemisinin treatment activated AKT-1 enzymatic activity, enhanced receptor association with AKT-1, and induced AR serine phosphorylation. Treatment of LNCaP cells with the PI3-kinase inhibitor LY294002, which inhibits the PI3-kinase-dependent activation of AKT-1, prevented the artemisinin-induced AR degradation. Furthermore, in transfected receptor-negative PC-3 cells, artemisinin failed to stimulate the degradation of an altered receptor protein (S215A/S792A) with mutations in its two consensus AKT-1 serine phosphorylation sites. Taken together, our results indicate that artemisinin induces the degradation of AR protein and disrupts androgen responsiveness of human prostate cancer cells, suggesting that this natural compound represents a new potential therapeutic molecule that selectively targets AR levels.

The Development of Adultoid Reproductives and Brachypterous Neotenic Reproductives From the Last Instar Nymphs in Reticulitermes labralis (Isoptera: Rhinotermitidae): A Comparative Study

PubMed Central

Su, Xiao Hong; Xue, Wei; Liu, He; Chen, Jiao Ling; Zhang, Xiao Jing; Xing, Lian Xi; Liu, Ming Hua

2015-01-01

Secondary reproductives develop primarily from nymphs. However, they have been rarely studied; in particular, the development of adultoid reproductives (AR) with floppy wings is still unclear. In this study, the change in juvenile hormone (JH) levels, vitellogenin gene expression, and oogenesis during the development of AR and brachypterous neotenic reproductives (BN) from the last instar nymphs of Reticulitermes labralis are investigated and compared. The results showed that the AR derived from the last instar nymphs by molting, and they were more similar to neotenic reproductives in morphology. In addition, the paired AR were not able to survive in the absence of workers. In R. labralis, the process of the last instar nymphs developing into AR and BN took an increase in JH level as a starting point. The JH level of the last instar nymphs molting into BN was approximately 1.5-fold higher than that of the AR. Additionally, The JHIII level of BN peaked on day 5, and that of AR peaked on day 10, which induced the onset of vitellogenesis in BN and AR, respectively. After molting, the vitellogenin gene expression levels of both BN and AR initially increased and then declined, and the expression levels in the BN were significantly higher than those in the AR. In addition, the oocytes of BN matured earlier than those of the AR, and the number of eggs laid by the BN was higher than the number laid by the AR. Our results demonstrate that, in R. labralis, the last instar nymphs can develop into AR, which are significantly different from BN in their development. PMID:26494776

Dhofar 378 Martian shergottite: Evidence of early shock melting

NASA Astrophysics Data System (ADS)

Park, Jisun; Bogard, Donald D.; Mikouchi, Takashi; McKay, Gordon A.

2008-08-01

Shock heating of the Dhofar 378 (Dho 378) Martian shergottite produced melting, vesiculation, and flow of the plagioclase, which upon cooling recrystallized into complex textures. Heating experiments on the similar Zagami shergottite indicate that Dho 378 was shock heated to 1000-1100°C and was cooled at ~2.5°C/h. An 39Ar-40Ar analysis of Dho 378 plagioclase indicates different Ar diffusion domains and K/Ca ratios. The lower-temperature phase defines an Ar-Ar isochron age of 141 +/- 32 Ma. The higher-temperature phase released more 40Ar but does not define an age. The meteorite's thermal history was examined by constructing a generic model to compare cooling rates for objects of different sizes against fractional diffusion loss of Ar for different cooling times. Using gas diffusion parameter values measured for Dho 378, this model indicates that it is improbable that the major shock heating event occurred at the time that Dho 378 was ejected from Mars ~3 Ma ago. Rather, we suggest that the time of shock heating is probably given by its Ar-Ar age. For Dho 378 to cool sufficiently fast not to lose most of its 40Ar ~3 Ma ago would require it to have been ejected into space as an impossibly small object. Larger and more reasonable Mars ejection sizes indicate that Dho 378 should have lost most of its 40Ar. On the basis of plagioclase texture and Ar data, we suggest that a major impact event ~141 Ma ago melted Dho 378 plagioclase, degassed most of its 40Ar, and deposited it in crater ejecta to cool. A smaller and later impact ejected it into space ~3 Ma ago.

Intestinal Microbial Variation May Predict Early Acute Rejection after Liver Transplantation in Rats

PubMed Central

Ren, Zhigang; Jiang, Jianwen; Lu, Haifeng; Chen, Xinhua; He, Yong; Zhang, Hua; Xie, Haiyang; Wang, Weilin; Zheng, Shusen; Zhou, Lin

2014-01-01

Background Acute rejection (AR) remains a life-threatening complication after orthotopic liver transplantation (OLT) and there are few available diagnostic biomarkers clinically for AR. This study aims to identify intestinal microbial profile and explore potential application of microbial profile as a biomarker for AR after OLT. Methods The OLT models in rats were established. Hepatic graft histology, ultrastructure, function, and intestinal barrier function were tested. Ileocecal contents were collected for intestinal microbial analysis. Results Hepatic graft suffered from the ischemia-reperfusion (I/R) injury on day 1, initial AR on day 3, and severe AR on day 7 after OLT. Real-time quantitative polymerase chain reaction results showed that genus Faecalibacterium prausnitzii and Lactobacillus were decreased, whereas Clostridium bolteae was increased during AR. Notably, cluster analysis of denaturing gradient gel electrophoresis (DGGE) profiles showed the 7AR and 3AR groups clustered together with 73.4% similarity, suggesting that intestinal microbiota was more sensitive than hepatic function in responding to AR. Microbial diversity and species richness were decreased during AR. Phylogenetic tree analysis showed that most of the decreased key bacteria belonged to phylum Firmicutes, whereas increased key bacteria belonged to phylum Bacteroidetes. Moreover, intestinal microvilli loss and tight junction damage were noted, and intestinal barrier dysfunction during AR presented a decrease of fecal secretory immunoglobulin A (sIgA) and increase of blood bacteremia, endotoxin, and tumor necrosis factor-α. Conclusion We dynamically detail intestinal microbial characterization and find a high sensitivity of microbial change during AR after OLT, suggesting that intestinal microbial variation may predict AR in early phase and become an assistant therapeutic target to improve rejection after OLT. PMID:25321166

Atmospheric Rivers in VR-CESM: Historical Comparison and Future Projections

NASA Astrophysics Data System (ADS)

McClenny, E. E.; Ullrich, P. A.

2016-12-01

Atmospheric rivers (ARs) are responsible for most of the horizontal vapor transport from the tropics, and bring upwards of half the annual precipitation to midlatitude west coasts. The difference between a drought year and a wet year can come down to 1-2 ARs. Such few events transform an otherwise arid region into one which supports remarkable biodiversity, productive agriculture, and booming human populations. It follows that such a sensitive hydroclimate feature would demand priority in evaluating end-of-century climate runs, and indeed, the AR subfield has grown significantly over the last decade. However, results tend to vary wildly from study to study, raising questions about how to best approach ARs in models. The disparity may result from any number of issues, including the ability for a model to properly resolve a precipitating AR, to the formulation and application of an AR detection algorithm. ARs pose a unique problem in global climate models (GCMs) computationally and physically, because the GCM horizontal grid must be fine enough to resolve coastal mountain range topography and force orographic precipitation. Thus far, most end-of-century projections on ARs have been performed on models whose grids are too coarse to resolve mountain ranges, causing authors to draw conclusions on AR intensity from water vapor content or transport alone. The use of localized grid refinement in the Variable Resolution version of NCAR's Community Earth System Model (VR-CESM) has succeeded in resolving AR landfall. This study applies an integrated water vapor AR detection algorithm to historical and future projections from VR-CESM, with historical ARs validated against NASA's Modern Era Retrospective-Analysis for Research and Applications. Results on end-of-century precipitating AR frequency, intensity, and landfall location will be discussed.

Novel Nine-Exon AR Transcripts (Exon 1/Exon 1b/Exons 2-8) in Normal and Cancerous Breast and Prostate Cells.

PubMed

Hu, Dong Gui; McKinnon, Ross A; Hulin, Julie-Ann; Mackenzie, Peter I; Meech, Robyn

2016-12-27

Nearly 20 different transcripts of the human androgen receptor (AR) are reported with two currently listed as Refseq isoforms in the NCBI database. Isoform 1 encodes wild-type AR (type 1 AR) and isoform 2 encodes the variant AR45 (type 2 AR). Both variants contain eight exons: they share common exons 2-8 but differ in exon 1 with the canonical exon 1 in isoform 1 and the variant exon 1b in isoform 2. Splicing of exon 1 or exon 1b is reported to be mutually exclusive. In this study, we identified a novel exon 1b (1b/TAG) that contains an additional TAG trinucleotide upstream of exon 1b. Moreover, we identified AR transcripts in both normal and cancerous breast and prostate cells that contained either exon 1b or 1b/TAG spliced between the canonical exon 1 and exon 2, generating nine-exon AR transcripts that we have named isoforms 3a and 3b. The proteins encoded by these new AR variants could regulate androgen-responsive reporters in breast and prostate cancer cells under androgen-depleted conditions. Analysis of type 3 AR-GFP fusion proteins showed partial nuclear localization in PC3 cells under androgen-depleted conditions, supporting androgen-independent activation of the AR. Type 3 AR proteins inhibited androgen-induced growth of LNCaP cells. Microarray analysis identified a small set of type 3a AR target genes in LNCaP cells, including genes known to modulate growth and proliferation of prostate cancer ( PCGEM1 , PEG3 , EPHA3 , and EFNB2 ) or other types of human cancers ( TOX3 , ST8SIA4 , and SLITRK3 ), and genes that are diagnostic/prognostic biomarkers of prostate cancer ( GRINA3 , and BCHE ).

Androgen receptor polyglutamine repeat length (AR-CAGn) modulates the effect of testosterone on androgen-associated somatic traits in Filipino young adult men.

PubMed

Ryan, Calen P; Georgiev, Alexander V; McDade, Thomas W; Gettler, Lee T; Eisenberg, Dan T A; Rzhetskaya, Margarita; Agustin, Sonny S; Hayes, M Geoffrey; Kuzawa, Christopher W

2017-06-01

The androgen receptor (AR) mediates expression of androgen-associated somatic traits such as muscle mass and strength. Within the human AR is a highly variable glutamine short-tandem repeat (AR-CAGn), and CAG repeat number has been inversely correlated to AR transcriptional activity in vitro. However, evidence for an attenuating effect of long AR-CAGn on androgen-associated somatic traits has been inconsistent in human populations. One possible explanation for this lack of consistency is that the effect of AR-CAGn on AR bioactivity in target tissues likely varies in relation to circulating androgen levels. We tested whether relationships between AR-CAGn and several androgen-associated somatic traits (waist circumference, lean mass, arm muscle area, and grip strength) were modified by salivary (waking and pre-bed) and circulating (total) testosterone (T) levels in young adult males living in metropolitan Cebu, Philippines (n = 675). When men's waking T was low, they had a reduction in three out of four androgen-associated somatic traits with lengthening AR-CAGn (p < .1), consistent with in vitro research. However, when waking T was high, we observed the opposite effect-lengthening AR-CAGn was associated with an increase in these same somatic traits. Our finding that longer AR-CAGn predicts greater androgen-associated trait expression among high-T men runs counter to in vitro work, but is generally consistent with the few prior studies to evaluate similar interactions in human populations. Collectively, these results raise questions about the applicability of findings derived from in vitro AR-CAGn studies to the receptor's role in maintaining androgen-associated somatic traits in human populations. © 2017 Wiley Periodicals, Inc.

AR Signaling in Breast Cancer.

PubMed

Rahim, Bilal; O'Regan, Ruth

2017-02-24

Androgen receptor (AR, a member of the steroid hormone receptor family) status has become increasingly important as both a prognostic marker and potential therapeutic target in breast cancer. AR is expressed in up to 90% of estrogen receptor (ER) positive breast cancer, and to a lesser degree, human epidermal growth factor 2 (HER2) amplified tumors. In the former, AR signaling has been correlated with a better prognosis given its inhibitory activity in estrogen dependent disease, though conversely has also been shown to increase resistance to anti-estrogen therapies such as tamoxifen. AR blockade can mitigate this resistance, and thus serves as a potential target in ER-positive breast cancer. In HER2 amplified breast cancer, studies are somewhat conflicting, though most show either no effect or are associated with poorer survival. Much of the available data on AR signaling is in triple-negative breast cancer (TNBC), which is an aggressive disease with inferior outcomes comparative to other breast cancer subtypes. At present, there are no approved targeted therapies in TNBC, making study of the AR signaling pathway compelling. Gene expression profiling studies have also identified a luminal androgen receptor (LAR) subtype that is dependent on AR signaling in TNBC. Regardless, there seems to be an association between AR expression and improved outcomes in TNBC. Despite lower pathologic complete response (pCR) rates with neoadjuvant therapy, patients with AR-expressing TNBC have been shown to have a better prognosis than those that are AR-negative. Clinical studies targeting AR have shown somewhat promising results. In this paper we review the literature on the biology of AR in breast cancer and its prognostic and predictive roles. We also present our thoughts on therapeutic strategies.

A Whole Blood Assay for AR-V7 and ARv567es in Patients with Prostate Cancer.

PubMed

Liu, Xichun; Ledet, Elisa; Li, Dongying; Dotiwala, Ary; Steinberger, Allie; Feibus, Allison; Li, Jianzhuo; Qi, Yanfeng; Silberstein, Jonathan; Lee, Benjamin; Dong, Yan; Sartor, Oliver; Zhang, Haitao

2016-12-01

Most prostate cancer mortality can be attributed to metastatic castration resistant prostate cancer, an advanced stage that remains incurable despite recent advances. The AR (androgen receptor) signaling axis remains active in castration resistant prostate cancer. Recent studies suggest that expression of the AR-V (AR splice variant) AR-V7 may underlie resistance to abiraterone and enzalutamide. However, controversy exists over the optimal assay. Our objective was to develop a fast and sensitive assay for AR-Vs in patients. Two approaches were assessed in this study. The first approach was based on depletion of leukocytes and the second one used RNA purified directly from whole blood preserved in PAXgene® tubes. Transcript expression was analyzed by quantitative reverse transcription-polymerase chain reaction. Through a side-by-side comparison we found that the whole blood approach was suitable to detect AR-Vs. The specificity of the assay was corroborated in a cancer-free cohort. Using the PAXgene assay samples from a cohort of 46 patients with castration resistant prostate cancer were analyzed. Overall, AR-V7 and AR v567es were detected in 67.53% and 29.87% of samples, respectively. Statistical analysis revealed a strong association of AR-V positivity with a history of second line hormonal therapies. To our knowledge this is the first study to demonstrate that PAXgene preserved whole blood can be used to obtain clinically relevant information regarding the expression of 2 AR-Vs. These data on a castration resistant prostate cancer cohort support a role for AR-Vs in resistance to therapies targeting the AR ligand-binding domain. Copyright © 2016 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

AR Signaling in Breast Cancer

PubMed Central

Rahim, Bilal; O’Regan, Ruth

2017-01-01

Androgen receptor (AR, a member of the steroid hormone receptor family) status has become increasingly important as both a prognostic marker and potential therapeutic target in breast cancer. AR is expressed in up to 90% of estrogen receptor (ER) positive breast cancer, and to a lesser degree, human epidermal growth factor 2 (HER2) amplified tumors. In the former, AR signaling has been correlated with a better prognosis given its inhibitory activity in estrogen dependent disease, though conversely has also been shown to increase resistance to anti-estrogen therapies such as tamoxifen. AR blockade can mitigate this resistance, and thus serves as a potential target in ER-positive breast cancer. In HER2 amplified breast cancer, studies are somewhat conflicting, though most show either no effect or are associated with poorer survival. Much of the available data on AR signaling is in triple-negative breast cancer (TNBC), which is an aggressive disease with inferior outcomes comparative to other breast cancer subtypes. At present, there are no approved targeted therapies in TNBC, making study of the AR signaling pathway compelling. Gene expression profiling studies have also identified a luminal androgen receptor (LAR) subtype that is dependent on AR signaling in TNBC. Regardless, there seems to be an association between AR expression and improved outcomes in TNBC. Despite lower pathologic complete response (pCR) rates with neoadjuvant therapy, patients with AR-expressing TNBC have been shown to have a better prognosis than those that are AR-negative. Clinical studies targeting AR have shown somewhat promising results. In this paper we review the literature on the biology of AR in breast cancer and its prognostic and predictive roles. We also present our thoughts on therapeutic strategies. PMID:28245550

Combination treatment with docetaxel and histone deacetylase inhibitors downregulates androgen receptor signaling in castration-resistant prostate cancer.

PubMed

Park, Sang Eun; Kim, Ha-Gyeong; Kim, Dong Eun; Jung, Yoo Jung; Kim, Yunlim; Jeong, Seong-Yun; Choi, Eun Kyung; Hwang, Jung Jin; Kim, Choung-Soo

2018-04-01

Backgrounds Since most patients with castration-resistant prostate cancer (CRPC) develop resistance to its standard therapy docetaxel, many studies have attempted to identify novel combination treatment to meet the large clinical unmet need. In this study, we examined whether histone deacetylase inhibitors (HDACIs) enhanced the effect of docetaxel on AR signaling in CRPC cells harboring AR and its splice variants. Methods HDACIs (vorinostat and CG200745) were tested for their ability to enhance the effects of docetaxel on cell viability and inhibition of AR signaling in CRPC 22Rv1 and VCaP cells by using CellTiter-Glo™ Luminescent cell viability assay, synergy index analysis and Western blotting. The nuclear localization of AR was examined via immunocytochemical staining in 22Rv1 cells and primary tumor cells from a patient with CRPC. Results Combination treatment with HDACIs (vorinostat or CG200745) and docetaxel synergistically inhibited the growth of 22Rv1 and VCaP cells. Consistently, the combination treatment decreased the levels of full-length AR (AR-FL), AR splice variants (AR-Vs), prostate-specific antigen (PSA), and anti-apoptotic Bcl-2 proteins more efficiently compared with docetaxel or vorinostat alone. Moreover, the combination treatment accelerated the acetylation and bundling of tubulin, which significantly inhibited the nuclear accumulation of AR in 22Rv1 cells. The cytoplasmic colocalization of AR-FL and AR-V7 with microtubule bundles increased after combination treatment in primary tumor cells from a patient with CRPC. Conclusions The results suggested that docetaxel, in combination with HDACIs, suppressed the expression and nuclear translocation of AR-FL and AR-Vs and showed synergistic anti-proliferative effect in CRPC cells. This combination therapy may be useful for the treatment of patients with CRPC.

Selective Gene Regulation by Androgen Receptor in Prostate Cancer

DTIC Science & Technology

2012-10-01

empty vector, wt AR, AR-E255K and AR- R753Q cells were transfected with an ARE- responsive reporter and renilla as control. Cells were treated with...empty vector (empty), wild-type AR (WT), AR-E255K or AR-R753Q were transfected with ARE-luciferase and renilla . Cells were treated with 0 or 1 nm...R1881, harvested after 24 hrs to read luciferase and renilla actiivity. % G ro w th (D ay 5 / D ay 1 ) Vector WTAR E255KR753Q 600 700 800 900

Noninvasive Detection of AR-FL/AR V7 as a Predictive Biomarker for Therapeutic Resistance in Men with Metastatic Castration-Resistant Prostate Cancer

DTIC Science & Technology

2016-10-01

AWARD NUMBER: W81XWH-15-2-0050 TITLE: Noninvasive Detection of AR -FL/ AR -V7 as a Predictive Biomarker for Therapeutic Resistance in Men with...report are those of the author(s) and should not be construed as an official Department of the Army position, policy or decision unless so designated...Detection of AR -FL/ AR -V7 as a Predictive Biomarker for Therapeutic Resistance in Men with Metastatic Castration-Resistant Prostate Cancer 5c. PROGRAM

Noninvasive Detection of AR-FL/AR-V7 as a Predictive Biomarker for Therapeutic Resistance in Men with Metastatic Castration-Resistant Prostate Cancer

DTIC Science & Technology

2016-10-01

AWARD NUMBER: W81XWH-15-2-0052 TITLE: Noninvasive Detection of AR -FL/ AR -V7 as a Predictive Biomarker for Therapeutic Resistance in Men with...DISTRIBUTION STATEMENT: Distribution Statement A: unlimited distribution The views, opinions and/or findings contained in this report are those of the...COVERED 30 Sep 2015 - 29 Sep 2016 4. TITLE AND SUBTITLE Noninvasive Detection of AR -FL/ AR -V7 as a Predictive Biomarker for Therapeutic Resistance in

Noninvasive Detection of AR-FL/AR-V7 as a Predictive Biomarker for Therapeutic Resistance in Men with Metastatic Castration-Resistant Prostate Cancer

DTIC Science & Technology

2017-10-01

AWARD NUMBER: W81XWH-15-2-0050 TITLE: Noninvasive Detection of AR -FL/ AR -V7 as a Predictive Biomarker for Therapeutic Resistance in Men with...report are those of the author(s) and should not be construed as an official Department of the Army position, policy or decision unless so designated by...Detection of AR -FL/ AR -V7 as a Predictive Biomarker for Therapeutic Resistance in Men with Metastatic Castration- Resistant Prostate Cancer 5c. PROGRAM

Telephone system operations evaluation : before AOS implementation

DOT National Transportation Integrated Search

1999-01-01

This study provides a detailed baseline analysis of telephone system performance before AOS : implementation. By the time of the preparation of this report, the phone system component of : AOS had not been implemented.

Adaptive optics at the Subaru telescope: current capabilities and development

NASA Astrophysics Data System (ADS)

Guyon, Olivier; Hayano, Yutaka; Tamura, Motohide; Kudo, Tomoyuki; Oya, Shin; Minowa, Yosuke; Lai, Olivier; Jovanovic, Nemanja; Takato, Naruhisa; Kasdin, Jeremy; Groff, Tyler; Hayashi, Masahiko; Arimoto, Nobuo; Takami, Hideki; Bradley, Colin; Sugai, Hajime; Perrin, Guy; Tuthill, Peter; Mazin, Ben

2014-08-01

Current AO observations rely heavily on the AO188 instrument, a 188-elements system that can operate in natural or laser guide star (LGS) mode, and delivers diffraction-limited images in near-IR. In its LGS mode, laser light is transported from the solid state laser to the launch telescope by a single mode fiber. AO188 can feed several instruments: the infrared camera and spectrograph (IRCS), a high contrast imaging instrument (HiCIAO) or an optical integral field spectrograph (Kyoto-3DII). Adaptive optics development in support of exoplanet observations has been and continues to be very active. The Subaru Coronagraphic Extreme-AO (SCExAO) system, which combines extreme-AO correction with advanced coronagraphy, is in the commissioning phase, and will greatly increase Subaru Telescope's ability to image and study exoplanets. SCExAO currently feeds light to HiCIAO, and will soon be combined with the CHARIS integral field spectrograph and the fast frame MKIDs exoplanet camera, which have both been specifically designed for high contrast imaging. SCExAO also feeds two visible-light single pupil interferometers: VAMPIRES and FIRST. In parallel to these direct imaging activities, a near-IR high precision spectrograph (IRD) is under development for observing exoplanets with the radial velocity technique. Wide-field adaptive optics techniques are also being pursued. The RAVEN multi-object adaptive optics instrument was installed on Subaru telescope in early 2014. Subaru Telescope is also planning wide field imaging with ground-layer AO with the ULTIMATE-Subaru project.

A multispectroscopic and molecular docking investigation of the binding interaction between serum albumins and acid orange dye

NASA Astrophysics Data System (ADS)

Naveenraj, Selvaraj; Solomon, Rajadurai Vijay; Mangalaraja, Ramalinga Viswanathan; Venuvanalingam, Ponnambalam; Asiri, Abdullah M.; Anandan, Sambandam

2018-03-01

The interaction of Acid Orange 10 (AO10) with bovine serum albumin (BSA) was investigated comparatively with that of human serum albumin (HSA) using multispectroscopic techniques for understanding their toxic mechanism. Further, density functional theory calculations and docking studies have been carried out to gain more insights into the nature of interactions existing between AO10 and serum albumins. The fluorescence results suggest that AO10 quenched the fluorescence of BSA through the combination of static and dynamic quenching mechanism. The same trend was followed in the interaction of AO10 with HSA. In addition to the type of quenching mechanism, the fluorescence spectroscopic results suggest that the binding occurs near the tryptophan moiety of serum albumins and the binding. AO10 has more binding affinity towards BSA than HSA. An AO10-Trp model has been created to explicitly understand the Csbnd Htbnd π interactions from Bader's quantum theory of atoms in molecules analysis which confirmed that AO10 bind more strongly with BSA than that of HSA due to the formation of three hydrogen bonds with BSA whereas it forms two hydrogen bonds in the case of HSA. These obtained results provide an in-depth understanding of the interaction of the acid azo dye AO10 with serum albumins. This interaction study provides insights into the underlying reasons for toxicity of AO10 relevant to understand its effect on bovids and humans during the blood transportation process.

Cytochrome P450-Dependent Metabolism of Oxylipins in Tomato. Cloning and Expression of Allene Oxide Synthase and Fatty Acid Hydroperoxide Lyase1

PubMed Central

Howe, Gregg A.; Lee, Gyu In; Itoh, Aya; Li, Lei; DeRocher, Amy E.

2000-01-01

Allene oxide synthase (AOS) and fatty acid hydroperoxide lyase (HPL) are plant-specific cytochrome P450s that commit fatty acid hydroperoxides to different branches of oxylipin metabolism. Here we report the cloning and characterization of AOS (LeAOS) and HPL (LeHPL) cDNAs from tomato (Lycopersicon esculentum). Functional expression of the cDNAs in Escherichia coli showed that LeAOS and LeHPL encode enzymes that metabolize 13- but not 9-hydroperoxide derivatives of C18 fatty acids. LeAOS was active against both 13S-hydroperoxy-9(Z),11(E),15(Z)-octadecatrienoic acid (13-HPOT) and 13S-hydroperoxy-9(Z),11(E)-octadecadienoic acid, whereas LeHPL showed a strong preference for 13-HPOT. These results suggest a role for LeAOS and LeHPL in the metabolism of 13-HPOT to jasmonic acid and hexenal/traumatin, respectively. LeAOS expression was detected in all organs of the plant. In contrast, LeHPL expression was predominant in leaves and flowers. Damage inflicted to leaves by chewing insect larvae led to an increase in the local and systemic expression of both genes, with LeAOS showing the strongest induction. Wound-induced expression of LeAOS also occurred in the def-1 mutant that is deficient in octadecanoid-based signaling of defensive proteinase inhibitor genes. These results demonstrate that tomato uses genetically distinct signaling pathways for the regulation of different classes of wound responsive genes. PMID:10859201

Partial degradation of levofloxacin for biodegradability improvement by electro-Fenton process using an activated carbon fiber felt cathode.

PubMed

Gong, Yuexiang; Li, Jiuyi; Zhang, Yanyu; Zhang, Meng; Tian, Xiujun; Wang, Aimin

2016-03-05

Solutions of 500 mL 200 mg L(-1) fluoroquinolone antibiotic levofloxacin (LEVO) have been degraded by anodic oxidation (AO), AO with electrogenerated H2O2 (AO-H2O2) and electro-Fenton (EF) processes using an activated carbon fiber (ACF) felt cathode from the point view of not only LEVO disappearance and mineralization, but also biodegradability enhancement. The LEVO decay by EF process followed a pseudo-first-order reaction with an apparent rate constant of 2.37×10(-2)min(-1), which is much higher than that of AO or AO-H2O2 processes. The LEVO mineralization also evidences the order EF>AO-H2O2>AO. The biodegradability (BOD5/COD) increased from 0 initially to 0.24, 0.09, and 0.03 for EF, AO-H2O2 and AO processes after 360 min treatment, respectively. Effects of several parameters such as current density, initial pH and Fe(2+) concentration on the EF degradation have also been examined. Three carboxylic acids including oxalic, formic and acetic acid were detected, as well as the released inorganic ions NH4(+), NO3(-) and F(-). At last, an ultra-performance liquid chromatography coupled with time-of-flight mass spectrometry was used to identify about eight aromatic intermediates formed in 60 min of EF treatment, and a plausible mineralization pathway for LEVO by EF treatment was proposed. Copyright © 2015 Elsevier B.V. All rights reserved.

Constraints on Earth degassing history from the argon isotope composition of Devonian atmosphere

NASA Astrophysics Data System (ADS)

Stuart, F. M.; Mark, D.

2012-04-01

The primordial and radiogenic isotopes of the noble gases combine to make them a powerful tool for determining the time and tempo of the outgassing of the Earth's interior. The outgassing history of the Earth is largely constrained from measurements of the isotopic composition of He, Ne, Ar and Xe in samples of modern mantle, crust and atmosphere. There have been few unequivocal measurement of the isotopic composition of noble gases in ancient atmosphere. We have re-visited whether ancient Ar is trapped in the ~400 Ma Rhynie chert [1]. We have analysed samples of pristine Rhynie chert using the ARGUS multi-collector mass spectrometer calibrated against the new determination of atmospheric Ar isotope ratios [2]. 40Ar/36Ar ratios are low, with many lower than the modern air value (298.8). Importantly these are accompanied by atmospheric 38Ar/36Ar ratios indicating that the low 40Ar/36Ar are not due to mass fractionation. We conclude that the Rhynie chert has captured Devonian atmosphere-derived Ar. The data indicate that the Devonian atmosphere 40Ar/36Ar was at least 3 % lower than the modern air value. Thus the Earth's atmosphere has accumulated at least 5 ± 0.2 x 1016 moles of 40Ar in the last 400 million years, at an average rate of 1.24 ± 0.06 x 108 mol 40Ar/year. This overlaps the rate determined from ice cores for the last 800,000 years [3] and implies that there has been no resolvable temporal change in Earth outgassing rate since mid-Palaeozoic times. The new data require the Earth outgassed early, and suggests that pristine samples of Archaean and Proterozoic chert may prove useful as palaeo-atmosphere tracers. [1] G. Turner, J. Geol. Soc. London 146, 147-154 (1989) [2] D. Mark, F.M. Stuart, M. de Podesta, Geochim. Cosmochim. Acta 75, 7494-7501 [3] M. Bender et al., Proc. Nat. Acad. Sci. 105, 8232-8237 (2008)

Differential unroofing within the central metasedimentary Belt of the Grenville Orogen: constraints from 40Ar/39Ar thermochronology

USGS Publications Warehouse

Cosca, M.A.; Essene, E.J.; Kunk, Michael J.; Sutter, J.F.

1992-01-01

An 40Ar/39Ar thermochronological investigation of upper greenschist to granulite facies gneiss, amphibolite and marble was conducted in the Central Metasedimentary Belt (CMB), Ontario, to constrain its cooling history. Incremental 40Ar/39Ar release spectra indicate that substantial differential unroofing occurred in the CMB between ??? 1000 and ??? 600 Ma. A consistent pattern of significantly older hornblende and phlogopite 40Ar/3Ar cooling ages on the southeast sides of major northeast striking shear zones is interpreted to reflect late displacement due to extensional deformation. Variations in hornblende 40Ar/39Ar age plateaus exceeding 200 Ma occur over distances less than 50 km with major age discontinuities occurring across the Robertson Lake shear zone and the Sharbot Lake mylonite zone which separate the Sharbot Lake terrane from the Elzevir and Frontenac terranes. Extensional displacements of up to 14 km are inferred between the Frontenac and Elzevir terranes of the CMB. No evidence for significant post argon-closure vertical displacement is indicated in the vicinity of the Perth Road mylonite within the Frontenac terrane. Variations of nearly 100 Ma in phlogopite 40Ar/39Ar plateau ages occur in undeformed marble on either side of the Bancroft Shear Zone. Phlogopites from sheared and mylonitized marble within the shear zone yield 40Ar/39Ar diffusional loss profiles, but have older geologically meaningless ages thought to reflect incorporation of excess argon. By ??? 900 Ma, southeast directed extension was occurring throughout the CMB, possibly initiated along previous zones of compressional shearing. An easterly migration of active zones of extension is inferred, possibly related to an earlier, overall easterly migration of active zones of regional thrusting and easterly migration of an ancient subduction zone. The duration of extensional shearing is not well constrained, but must have ceased before ??? 600 Ma as required by the deposition of overlying undeformed Cambrian and/or Ordovician sedimentary rocks. ?? 1992 Springer-Verlag.

Expectations for methodology and translation of animal research: a survey of health care workers.

PubMed

Joffe, Ari R; Bara, Meredith; Anton, Natalie; Nobis, Nathan

2015-05-07

Health care workers (HCW) often perform, promote, and advocate use of public funds for animal research (AR); therefore, an awareness of the empirical costs and benefits of animal research is an important issue for HCW. We aim to determine what health-care-workers consider should be acceptable standards of AR methodology and translation rate to humans. After development and validation, an e-mail survey was sent to all pediatricians and pediatric intensive care unit nurses and respiratory-therapists (RTs) affiliated with a Canadian University. We presented questions about demographics, methodology of AR, and expectations from AR. Responses of pediatricians and nurses/RTs were compared using Chi-square, with P < .05 considered significant. Response rate was 44/114(39%) (pediatricians), and 69/120 (58%) (nurses/RTs). Asked about methodological quality, most respondents expect that: AR is done to high quality; costs and difficulty are not acceptable justifications for low quality; findings should be reproducible between laboratories and strains of the same species; and guidelines for AR funded with public money should be consistent with these expectations. Asked about benefits of AR, most thought that there are sometimes/often large benefits to humans from AR, and disagreed that "AR rarely produces benefit to humans." Asked about expectations of translation to humans (of toxicity, carcinogenicity, teratogenicity, and treatment findings), most: expect translation >40% of the time; thought that misleading AR results should occur <21% of the time; and that if translation was to occur <20% of the time, they would be less supportive of AR. There were few differences between pediatricians and nurses/RTs. HCW have high expectations for the methodological quality of, and the translation rate to humans of findings from AR. These expectations are higher than the empirical data show having been achieved. Unless these areas of AR significantly improve, HCW support of AR may be tenuous.

Mechanistic Study on Cu(II)-Catalyzed Oxidative Cross-Coupling Reaction between Arenes and Boronic Acids under Aerobic Conditions.

PubMed

Zhang, Qian; Liu, Yang; Wang, Ting; Zhang, Xinhao; Long, Chao; Wu, Yun-Dong; Wang, Mei-Xiang

2018-04-25

Substantial attention has been given to modern organocopper chemistry in recent years since copper salts are naturally abundant, cheap, and less toxic in comparison to precious metals. Copper salts also exhibit versatility in catalyzing and mediating carbon-carbon and carbon-heteroatom bond forming reactions. Despite the wide applications of copper salts in catalysis, reaction mechanisms have remained elusive. Using azacalix[1]arene[3]pyridine, an arene-embedded macrocycle, and its isolated and structurally well-defined ArCu(II) and ArCu(III) compounds as molecular tools, we now report an in-depth experimental and computational study on the mechanism of a Cu(II)-catalyzed oxidative cross-coupling reaction between arenes and boronic acids with air as the oxidant. Stoichiometric reaction of organocopper compounds with p-tolylboronic acid validated arylcopper(II) rather than arylcopper(III) as a reactive organometallic intermediate. XPS, EPR, 1 H NMR, HRMS, and UV-vis spectroscopic evidence along with the isolation and quantification of all products and copper speciation, combined with computational analysis of the electronic structure and energetics of the transient intermediates, suggested a reaction sequence involving electrophilic metalation of arene by Cu(II), transmetalation of arylboronate to ArCu(II), the redox reaction between the resulting ArCu(II)Ar' and ArCu(II) to form respectively ArCu(III)Ar' and ArCu(I), and finally reductive elimination of ArCu(III)Ar'. Under aerobic catalytic conditions, all Cu(I) ions released from reductive elimination of ArCu(III)Ar' and from protolysis of ArCu(I) were oxidized by oxygen to regenerate Cu(II) species that enters into the next catalytic cycle. The unraveled reactivity of arylcopper(II) compounds and the catalytic cycle would enrich our knowledge of modern organocopper chemistry and provide useful information in the design of copper-catalyzed reactions.

Arsenic biotransformation potential of microbial arsH responses in the biogeochemical cycling of arsenic-contaminated groundwater.

PubMed

Chang, Jin-Soo; Yoon, In-Ho; Kim, Kyoung-Woong

2018-01-01

ArsH encodes an oxidoreductase, an NAD(P)H-dependent mononucleotide reductase, with an unknown function, frequently within an ars operon, and is widely distributed in bacteria. Novel arsenite-oxidizing bacteria have been isolated from arsenic-contaminated groundwater and surface soil in Vietnam. We found that ArsH gene activity, with arsenite oxidase in the periplasm; it revealed arsenic oxidation potential of the arsH system. Batch experiment results revealed Citrobacter freundii strain VTan4 (DQ481466) and Pseudomonas putida strain VTw33 (DQ481482) completely oxidized 1 mM of arsenite to arsenate within 30-50 h. High concentrations of arsenic were detected in groundwater and surrounding soil obtained from Vinh Tru village in Ha Nam province (groundwater: 11.0 μg/L to 37.0 μg/L; and soil: 2.5 mg/kg, 390.1 mg/kg), respectively. An arsH gene encoding an organoarsenical oxidase protein was observed in arsenite-oxidizing Citrobacter freundii strain VTan4 (DQ481466), whereas arsB, arsH, and arsH were detected in Pseudomonas putida strain VTw33 (DQ481482). arsH gene in bacteria was first reported from Vietnam for resistance and arsenite oxidase. We proposed that residues, Ser 43, Arg 45, Ser 48, and Tyr 49 are required for arsenic binding and activation of arsH. The ars-mediated biotransformation strongly influenced potential arsenite oxidase enzyme of the operon encoding a homogeneous arsH. Results suggest that the further study of arsenite-oxidizing bacteria may lead to a better understanding of arsenite oxidase responses, such as those of arsH, that may be applied to control biochemical properties; for example, speciation, detoxification, bioremediation, biotransformation, and mobilization of arsenic in contaminated groundwater. Copyright © 2017 Elsevier Ltd. All rights reserved.

The Long Non-Coding RNA XIST Interacted with MiR-124 to Modulate Bladder Cancer Growth, Invasion and Migration by Targeting Androgen Receptor (AR).

PubMed

Xiong, Yaoyao; Wang, Long; Li, Yuan; Chen, Minfeng; He, Wei; Qi, Lin

2017-01-01

Long non-coding RNA (lncRNA) X-inactive specific transcript (XIST) is involved in the progression of several tumors. The interaction between lncRNA and miRNA or miRNA's target genes is reported to play crucial roles in malignancy. In addition, Androgen receptor (AR) is considered to be involved in bladder cancer progression. In this study, we investigated the role of XIST in human bladder cancer and its interaction with miR-124 and AR. XIST and AR expression was detected in bladder tumor samples and cell lines. Effects of XIST and AR on bladder cancer cells growth, invasion and migration were analyzed. Bioinformatic analysis and luciferase assays were used to identify the interaction among XIST, AR and miR-124. The correlations of miR-124 with XIST and AR in bladder cancer samples were statistically analyzed. XIST and AR were upregulated in bladder cancer tissues and positively correlated. Higher XIST and AR expression were related to poorer TNM stage of bladder cancer. XIST knockdown reduced bladder cancer cells' proliferation, invasion and migration. While this inhibitory effect could be partially restored by AR overexpression. XIST inhibited miR-124 expression by directly targeting. Moreover, miR-124 could bind to the 3'UTR of AR to regulate its expression. MiR-124 inhibition partially restored the XIST knockdown-induced reduction of AR, c-myc, p27, MMP13 and MMP9 expression. In bladder cancer tissues, miR-124 level was inversely correlated with the expression of XIST and AR, respectively. These findings indicated that XIST might be an oncogenic lncRNA that promoted the bladder cancer growth, invasion and migration via miR-124 dependent AR regulation. © 2017 The Author(s). Published by S. Karger AG, Basel.

CgA1AR-1 acts as an alpha-1 adrenergic receptor in oyster Crassostrea gigas mediating both cellular and humoral immune response.

PubMed

Liu, Zhaoqun; Zhou, Zhi; Wang, Lingling; Qiu, Limei; Zhang, Huan; Wang, Hao; Song, Linsheng

2016-11-01

We have now cloned an alpha-1 adrenergic receptor (A1AR) from the cDNA library of oyster Crassostrea gigas, designating as CgA1AR-1. The full length of CgA1AR-1 was 1149 bp and it encodes a protein of 382 amino acids containing a 7 transmembrane domain, whose putative topology was similar to the A1ARs in higher organisms and shared similarity of 19% with mammalian A1ARs according to the phylogenic analysis. After cell transfection of CgA1AR-1 into HEK293T cells and the incubation with its specific agonist norepinephrine (NE), the concentration of second messenger Ca 2+ increased significantly (p < 0.05). But, this increasing of Ca 2+ could be inhibited by adding A1AR antagonist DOX. Tissue distribution assays using qRT-PCR suggested that CgA1AR-1 mRNA was ubiquitously expressed in all the major tissues of oyster. LPS stimulation could induce the up-regulation of CgA1AR-1 mRNA in haemocytes from 12 h to 24 h post stimulation. Moreover, the blocking of CgA1AR-1 by DOX before LPS stimulation affected the mRNA expression of oyster TNF (CGI_10005109 and CGI_10006440) in haemocytes, resulting in the rise of haemocyte phagocytic rate and apoptosis index. In addition to cellular immunity, CgA1AR-1 was also involved in humoral immunity of oyster. Inhibition of CgA1AR-1 with DOX could repress the up-regulation of LZY and SOD activities caused by LPS stimulation. These results suggested that CgA1AR-1 acted as an α-1 adrenergic receptor in cetacholaminergic neuroendocrine-immune network mediating both cellular and humoral immune response. Copyright © 2016 Elsevier Ltd. All rights reserved.

Branched Chain RNA In Situ Hybridization for Androgen Receptor Splice Variant AR-V7 as a Prognostic Biomarker for Metastatic Castration-Sensitive Prostate Cancer.

PubMed

Saylor, Philip J; Lee, Richard J; Arora, Kshitij S; Deshpande, Vikram; Hu, Rong; Olivier, Kara; Meneely, Erika; Rivera, Miguel N; Ting, David T; Wu, Chin-Lee; Miyamoto, David T

2017-01-15

The androgen receptor (AR) mRNA splice variant AR-V7 has emerged as a predictive biomarker for response to AR-targeted therapies. There are currently no commercially available assays to detect AR splice variants. The branched chain RNA in situ hybridization (ISH) platform enables the highly sensitive detection of RNA transcripts in formalin-fixed, paraffin-embedded (FFPE) tissues. We designed a branched chain RNA ISH probe to target the unique cryptic exon CE3 of AR-V7 using multiple tiling probes. This automated ISH assay was applied to tumor tissue from two distinct clinical cohorts that we hypothesized would differ in AR-V7 status. We detected AR-V7 in all tumor samples from men with metastatic castration-resistant prostate cancer with tissue obtained after disease progression despite at least one subsequent line of hormonal therapy (abiraterone, enzalutamide, or bicalutamide; n = 12). We detected AR-V7 in just one tumor from men who had undergone prostatectomy for localized adenocarcinoma (n = 30; Gleason 4 + 5 = 9 in the AR-V7-positive sample). Given the apparent distinction between the above groups by AR-V7 signal, we analyzed pretreatment AR-V7 status as a predictive and prognostic biomarker in men with treatment-naïve metastatic disease. Patients with metastases but without detectable AR-V7 RNA at baseline had significantly longer overall survival (log-rank P = 0.044) and a trend toward superior progression-free survival (log-rank P = 0.055). Within an institutional cohort, the RNA ISH assay identified AR-V7 within FFPE tissue and may have prognostic value in metastatic castration-sensitive prostate cancer. These preliminary findings warrant further study in larger cohorts. Clin Cancer Res; 23(2); 363-9. ©2016 AACR. ©2016 American Association for Cancer Research.

Protein arginine methyltransferase 5 functions as an epigenetic activator of the androgen receptor to promote prostate cancer cell growth.

PubMed

Deng, X; Shao, G; Zhang, H-T; Li, C; Zhang, D; Cheng, L; Elzey, B D; Pili, R; Ratliff, T L; Huang, J; Hu, C-D

2017-03-02

Protein arginine methyltransferase 5 (PRMT5) is an emerging epigenetic enzyme that mainly represses transcription of target genes via symmetric dimethylation of arginine residues on histones H4R3, H3R8 and H2AR3. Accumulating evidence suggests that PRMT5 may function as an oncogene to drive cancer cell growth by epigenetic inactivation of several tumor suppressors. Here, we provide evidence that PRMT5 promotes prostate cancer cell growth by epigenetically activating transcription of the androgen receptor (AR) in prostate cancer cells. Knockdown of PRMT5 or inhibition of PRMT5 by a specific inhibitor reduces the expression of AR and suppresses the growth of multiple AR-positive, but not AR-negative, prostate cancer cells. Significantly, knockdown of PRMT5 in AR-positive LNCaP cells completely suppresses the growth of xenograft tumors in mice. Molecular analysis reveals that PRMT5 binds to the proximal promoter region of the AR gene and contributes mainly to the enriched symmetric dimethylation of H4R3 in the same region. Mechanistically, PRMT5 is recruited to the AR promoter by its interaction with Sp1, the major transcription factor responsible for AR transcription, and forms a complex with Brg1, an ATP-dependent chromatin remodeler, on the proximal promoter region of the AR gene. Furthermore, PRMT5 expression in prostate cancer tissues is significantly higher than that in benign prostatic hyperplasia tissues, and PRMT5 expression correlates positively with AR expression at both the protein and mRNA levels. Taken together, our results identify PRMT5 as a novel epigenetic activator of AR in prostate cancer. Given that inhibiting AR transcriptional activity or androgen synthesis remains the major mechanism of action for most existing anti-androgen agents, our findings also raise an interesting possibility that targeting PRMT5 may represent a novel approach for prostate cancer treatment by eliminating AR expression.

An analysis of dormancy, ABA responsiveness, after-ripening and pre-harvest sprouting in hexaploid wheat (Triticum aestivum L.) caryopses.

PubMed

Gerjets, Tanja; Scholefield, Duncan; Foulkes, M John; Lenton, John R; Holdsworth, Michael J

2010-01-01

Embryo and caryopsis dormancy, abscisic acid (ABA) responsiveness, after-ripening (AR), and the disorder pre-harvest sprouting (PHS) were investigated in six genetically related wheat varieties previously characterized as resistant, intermediate, or susceptible to PHS. Timing of caryopsis AR differed between varieties; AR occurred before harvest ripeness in the most PHS-susceptible, whereas AR was slowest in the most PHS-resistant. Whole caryopses of all varieties showed little ABA-responsiveness during AR; PHS-susceptible varieties were responsive at the beginning of the AR period whereas PHS-resistant showed some responsiveness throughout. Isolated embryos showed relatively little dormancy during grain-filling and most varieties exhibited a window of decreased ABA-responsiveness around the period of maximum dry matter accumulation (physiological maturity). Susceptibility to PHS was assessed by overhead misting of either isolated ears or whole plants during AR; varieties were clearly distinguished using both methods. These analyses allowed an investigation of the interactions between the different components of seed development, compartments, and environment for the six varieties. There was no direct relationship between speed of caryopsis AR and embryo dormancy or ABA-responsiveness during seed maturation. However, the velocity of AR of a variety was closely associated with the degree of susceptibility to PHS during AR suggesting that these characters are developmentally linked. Investigation of genetic components of AR may therefore aid breeding approaches to reduce susceptibility to PHS.

Molecular identification of arsenic-resistant estuarine bacteria and characterization of their ars genotype.

PubMed

Sri Lakshmi Sunita, M; Prashant, S; Bramha Chari, P V; Nageswara Rao, S; Balaravi, Padma; Kavi Kishor, P B

2012-01-01

In the present study, 44 arsenic-resistant bacteria were isolated through serial dilutions on agar plate with concentrations ≥0.05 mM of sodium arsenite and ≥10 mM of sodium arsenate from Mandovi and Zuari--estuarine water systems. The ars genotype characterization in 36 bacterial isolates (resistant to 100 mM of sodium arsenate) revealed that only 17 isolates harboured the arsA (ATPase), B (arsenite permease) and C (arsenate reductase) genes on the plasmid DNA. The arsA, B and C genes were individually detected using PCR in 16, 9 and 13 bacterial isolates respectively. Molecular identification of the 17 isolates bearing the ars genotype was carried using 16S rDNA sequencing. A 1300 bp full length arsB gene encoding arsenite efflux pump and a 409 bp fragment of arsC gene coding for arsenate reductase were isolated from the genera Halomonas and Acinetobacter. Phylogenetic analysis of arsB and arsC genes indicated their close genetic relationship with plasmid borne ars genes of E. coli and arsenate reductase of plant origin. The putative arsenate reductase gene isolated from Acinetobacter species complemented arsenate resistance in E. coli WC3110 and JM109 validating its function. This study dealing with isolation of native arsenic-resistant bacteria and characterization of their ars genes might be useful to develop efficient arsenic detoxification strategies for arsenic contaminated aquifers.

Inhibition of androgen receptor and β-catenin activity in prostate cancer

PubMed Central

Lee, Eugine; Madar, Aviv; David, Gregory; Garabedian, Michael J.; DasGupta, Ramanuj; Logan, Susan K.

2013-01-01

Androgen receptor (AR) is the major therapeutic target in aggressive prostate cancer. However, targeting AR alone can result in drug resistance and disease recurrence. Therefore, simultaneous targeting of multiple pathways could in principle be an effective approach to treating prostate cancer. Here we provide proof-of-concept that a small-molecule inhibitor of nuclear β-catenin activity (called C3) can inhibit both the AR and β-catenin–signaling pathways that are often misregulated in prostate cancer. Treatment with C3 ablated prostate cancer cell growth by disruption of both β-catenin/T-cell factor and β-catenin/AR protein interaction, reflecting the fact that T-cell factor and AR have overlapping binding sites on β-catenin. Given that AR interacts with, and is transcriptionally regulated by β-catenin, C3 treatment also resulted in decreased occupancy of β-catenin on the AR promoter and diminished AR and AR/β-catenin target gene expression. Interestingly, C3 treatment resulted in decreased AR binding to target genes accompanied by decreased recruitment of an AR and β-catenin cofactor, coactivator-associated arginine methyltransferase 1 (CARM1), providing insight into the unrecognized function of β-catenin in prostate cancer. Importantly, C3 inhibited tumor growth in an in vivo xenograft model and blocked renewal of bicalutamide-resistant sphere-forming cells, indicating the therapeutic potential of this approach. PMID:24019458

BCAS2 promotes prostate cancer cells proliferation by enhancing AR mRNA transcription and protein stability

PubMed Central

Kuo, P-C; Huang, C-W; Lee, C-I; Chang, H-W; Hsieh, S-W; Chung, Y-P; Lee, M-S; Huang, C-S; Tsao, L-P; Tsao, Y-P; Chen, S-L

2015-01-01

Background: We showed previously that breast carcinoma amplified sequence 2 (BCAS2) functions as a negative regulator of p53. We also found that BCAS2 is a potential AR-associated protein. AR is essential for the growth and survival of prostate carcinoma. Therefore we characterised the correlation between BCAS2 and AR. Methods: Protein interactions were examined by GST pull-down assay and co-immunoprecipitation. Clinical prostate cancer (PCa) specimens were evaluated by immunohistochemical assay. AR transcriptional activity and LNCaP cell growth were assessed by luciferase assay and MTT assay, respectively. Results: BCAS2 expression was significantly increased in PCa. BCAS2 stabilised AR protein through both hormone-dependent and -independent manners. There are at least two mechanisms for BCAS2-mediated AR protein upregulation: One is p53-dependent. The p53 is suppressed by BCAS2 that results in increasing AR mRNA and protein expression. The other is via p53-independent inhibition of proteasome degradation. As BCAS2 can form a complex with AR and HSP90, it may function with HSP90 to stabilise AR protein from being degraded by proteasome. Conclusions: In this study, we show that BCAS2 is a novel AR-interacting protein and characterise the correlation between BCAS2 and PCa. Thus we propose that BCAS2 could be a diagnostic marker and therapeutic target for PCa. PMID:25461807

ID4 promotes AR expression and blocks tumorigenicity of PC3 prostate cancer cells.

PubMed

Komaragiri, Shravan Kumar; Bostanthirige, Dhanushka H; Morton, Derrick J; Patel, Divya; Joshi, Jugal; Upadhyay, Sunil; Chaudhary, Jaideep

2016-09-09

Deregulation of tumor suppressor genes is associated with tumorigenesis and the development of cancer. In prostate cancer, ID4 is epigenetically silenced and acts as a tumor suppressor. In normal prostate epithelial cells, ID4 collaborates with androgen receptor (AR) and p53 to exert its tumor suppressor activity. Previous studies have shown that ID4 promotes tumor suppressive function of AR whereas loss of ID4 results in tumor promoter activity of AR. Previous study from our lab showed that ectopic ID4 expression in DU145 attenuates proliferation and promotes AR expression suggesting that ID4 dependent AR activity is tumor suppressive. In this study, we examined the effect of ectopic expression of ID4 on highly malignant prostate cancer cell, PC3. Here we show that stable overexpression of ID4 in PC3 cells leads to increased apoptosis and decreased cell proliferation and migration. In addition, in vivo studies showed a decrease in tumor size and volume of ID4 overexpressing PC3 cells, in nude mice. At the molecular level, these changes were associated with increased androgen receptor (AR), p21, and AR dependent FKBP51 expression. At the mechanistic level, ID4 may regulate the expression or function of AR through specific but yet unknown AR co-regulators that may determine the final outcome of AR function. Copyright © 2016 Elsevier Inc. All rights reserved.

Small molecule screening reveals a transcription-independent pro-survival function of androgen receptor in castration-resistant prostate cancer

PubMed Central

Narizhneva, Natalia V.; Tararova, Natalia D.; Ryabokon, Petro; Shyshynova, Inna; Prokvolit, Anatoly; Komarov, Pavel G.; Purmal, Andrei A.; Gudkov, Andrei V.; Gurova, Katerina V.

2010-01-01

In prostate cancer (PCa) patients, initial responsiveness to androgen deprivation therapy is frequently followed by relapse due to development of treatment-resistant androgen-independent PCa. This is typically associated with acquisition of mutations in AR that allow activity as a transcription factor in the absence of ligand, indicating that androgen-independent PCa remains dependent on AR function. Our strategy to effectively target AR in androgen-independent PCa involved using a cell-based readout to isolate small molecules that inhibit AR transactivation function through mechanisms other than modulation of ligand binding. A number of the identified inhibitors were toxic to AR-expressing PCa cells regardless of their androgen dependence. Among these, some only suppressed PCa cell growth (ARTIS), while others induced cell death (ARTIK). ARTIK, but not ARTIS, compounds caused disappearance of AR protein from treated cells. siRNA against AR behaved like ARTIK compounds, while a dominant negative AR mutant that prevents AR-mediated transactivation but does not eliminate the protein showed only a growth suppressive effect. These observations reveal a transcription-independent function of AR that is essential for PCa cell viability and, therefore, is an ideal target for anti-PCa treatment. Indeed, several of the identified AR inhibitors demonstrated in vivo efficacy in mouse models of PCa and are candidates for pharmacologic optimization. PMID:19946220

Characterization of karyopherins in androgen receptor intracellular trafficking in the yeast model

PubMed Central

Nguyen, Minh M; Harmon, Robert M; Wang, Zhou

2014-01-01

Background: Mechanisms regulating androgen receptor (AR) subcellular localization represent an essential component of AR signaling. Karyopherins are a family of nucleocytoplasmic trafficking factors. In this paper, we used the yeast model to study the effects of karyopherins on the subcellular localization of the AR. Methods: Yeast mutants deficient in different nuclear transport factors were transformed with various AR based, GFP tagged constructs and their localization was monitored using microscopy. Results: We showed that yeast can mediate androgen-induced AR nuclear localization and that in addition to the import factor, Importinα/β, this process required the import karyopherin Sxm1. We also showed that a previously identified nuclear export sequence (NESAR) in the ligand binding domain of AR does not appear to rely on karyopherins for cytoplasmic localization. Conclusions: These results suggest that while AR nuclear import relies on karyopherin activity, AR nuclear export and/or cytoplasmic localization may require other undefined mechanisms. PMID:25031696

Sequence Complexity of Amyloidogenic Regions in Intrinsically Disordered Human Proteins

PubMed Central

Das, Swagata; Pal, Uttam; Das, Supriya; Bagga, Khyati; Roy, Anupam; Mrigwani, Arpita; Maiti, Nakul C.

2014-01-01

An amyloidogenic region (AR) in a protein sequence plays a significant role in protein aggregation and amyloid formation. We have investigated the sequence complexity of AR that is present in intrinsically disordered human proteins. More than 80% human proteins in the disordered protein databases (DisProt+IDEAL) contained one or more ARs. With decrease of protein disorder, AR content in the protein sequence was decreased. A probability density distribution analysis and discrete analysis of AR sequences showed that ∼8% residue in a protein sequence was in AR and the region was in average 8 residues long. The residues in the AR were high in sequence complexity and it seldom overlapped with low complexity regions (LCR), which was largely abundant in disorder proteins. The sequences in the AR showed mixed conformational adaptability towards α-helix, β-sheet/strand and coil conformations. PMID:24594841

Te Ao Kori as Expressive Movement in Aotearoa New Zealand Physical Education Teacher Education (PETE): A Narrative Account

ERIC Educational Resources Information Center

Legge, Maureen

2011-01-01

A unique aspect of Aotearoa/New Zealand physical education is the inclusion of Maori culture in the form of te ao kori. Te ao kori translates to mean the world of movement and is represented by the interpretation of indigenous movement, games and pastimes. Participation in te ao kori means the sports-based normative frame of reference for physical…

Considerations for point-of-care diagnostics: evaluation of acridine orange staining and postprocessing methods for a three-part leukocyte differential test

NASA Astrophysics Data System (ADS)

Powless, Amy J.; Conley, Roxanna J.; Freeman, Karan A.; Muldoon, Timothy J.

2017-03-01

There exists a broad range of techniques that can be used to classify and count white blood cells in a point-of-care (POC) three-part leukocyte differential test. Improvements in lenses, light sources, and cameras for image-based POC systems have renewed interest in acridine orange (AO) as a contrast agent, whereby subpopulations of leukocytes can be differentiated by colorimetric analysis of AO fluorescence emission. We evaluated the effect on test accuracy using different AO staining and postprocessing methods in the context of an image-based POC colorimetric cell classification scheme. Thirty blood specimens were measured for percent cell counts using our POC system and a conventional hematology analyzer for comparison. Controlling the AO concentration used during whole-blood staining, the incubation time with AO, and the colorimetric ratios among the three population of leukocytes yielded a percent deviation of 0.706%, -1.534%, and -0.645% for the lymphocytes, monocytes, and granulocytes, respectively. Overall, we demonstrated that a redshift in AO fluorescence was observed at elevated AO concentrations, which lead to reproducible inaccuracy of cell counts. This study demonstrates there is a need for a strict control of the AO staining and postprocessing methods to improve test accuracy in these POC systems.