Serotonin and brain function: a tale of two receptors

PubMed Central

Carhart-Harris, RL; Nutt, DJ

2017-01-01

Previous attempts to identify a unified theory of brain serotonin function have largely failed to achieve consensus. In this present synthesis, we integrate previous perspectives with new and older data to create a novel bipartite model centred on the view that serotonin neurotransmission enhances two distinct adaptive responses to adversity, mediated in large part by its two most prevalent and researched brain receptors: the 5-HT1A and 5-HT2A receptors. We propose that passive coping (i.e. tolerating a source of stress) is mediated by postsynaptic 5-HT1AR signalling and characterised by stress moderation. Conversely, we argue that active coping (i.e. actively addressing a source of stress) is mediated by 5-HT2AR signalling and characterised by enhanced plasticity (defined as capacity for change). We propose that 5-HT1AR-mediated stress moderation may be the brain’s default response to adversity but that an improved ability to change one’s situation and/or relationship to it via 5-HT2AR-mediated plasticity may also be important – and increasingly so as the level of adversity reaches a critical point. We propose that the 5-HT1AR pathway is enhanced by conventional 5-HT reuptake blocking antidepressants such as the selective serotonin reuptake inhibitors (SSRIs), whereas the 5-HT2AR pathway is enhanced by 5-HT2AR-agonist psychedelics. This bipartite model purports to explain how different drugs (SSRIs and psychedelics) that modulate the serotonergic system in different ways, can achieve complementary adaptive and potentially therapeutic outcomes. PMID:28858536

Induction of an adaptive response in human blood lymphocytes exposed to radiofrequency fields: influence of the universal mobile telecommunication system (UMTS) signal and the specific absorption rate.

PubMed

Zeni, Olga; Sannino, Anna; Romeo, Stefania; Massa, Rita; Sarti, Maurizio; Reddy, Abishek B; Prihoda, Thomas J; Vijayalaxmi; Scarfì, Maria Rosaria

2012-08-30

The induction of an adaptive response (AR) was examined in human peripheral blood lymphocytes exposed to non-ionizing radiofrequency fields (RF). Cells from nine healthy human volunteers were stimulated for 24h with phytohaemagglutinin and then exposed for 20h to an adaptive dose (AD) of a 1950MHz RF UMTS (universal mobile telecommunication system) signal used for mobile communications, at different specific absorption rates (SAR) of 1.25, 0.6, 0.3, and 0.15W/kg. This was followed by treatment of the cells at 48h with a challenge dose (CD) of 100ng/ml mitomycin C (MMC). Lymphocytes were collected at the end of the 72h total culture period. The cytokinesis-block method was used to record the frequency of micronuclei (MN) as genotoxicity end-point. When lymphocytes from six donors were pre-exposed to RF at 0.3W/kg SAR and then treated with MMC, these cells showed a significant reduction in the frequency of MN, compared with the cells treated with MMC alone; this result is indicative of induction of AR. The results from our earlier study indicated that lymphocytes that were stimulated for 24h, exposed for 20h to a 900MHz RF GSM (global system for mobile communication) signal at 1.25W/kg SAR and then treated with 100ng/ml MMC, also exhibited AR. These overall data suggest that the induction of AR depends on RF frequency, type of the signal and SAR. Further characterization of RF-induced AR is in progress. Copyright © 2012 Elsevier B.V. All rights reserved.

Cross-cultural adaptation and psychometric analysis of the Arabic version of the oxford knee score in adult male with knee osteoarthritis.

PubMed

Alghadir, Ahmad H; Al-Eisa, Einas S; Anwer, Shahnawaz

2017-05-15

There are varieties of self-assessment questionnaire used for the evaluation of pain, functional disability, and health related quality of life in individuals with knee osteoarthritis (OA). The present study intended to adapt and translate the oxford knee score into the Arabic and investigated its psychometric properties in adult male with knee OA. Ninety-seven adult male (mean age 57.55 ± 11.49 years) with knee OA participated. Patients were requested to complete the adapted Arabic version of the Oxford knee score (OKS-Ar), reduced "Western Ontario and McMaster Universities Index (WOMAC)", and the Visual analogue scale (VAS). Patients were requested to complete 2 nd form of OKS-Ar at least 1 week apart to assess the reproducibility of the score. The OKS was adapted and translated into Arabic by two independent Arabic native speakers (one rehabilitation professional having experience of knee OA patients and another one a trained translator) according to the international guidelines. All the participants completed the 2 nd form of OKS-Ar (Response rate 100%). Reliability and internal consistency was high with an ICC of 0.97, and the Cronbach's alpha coefficient of 0.987, respectively. A significant relationship between the OKS-Ar and the WOMAC and VAS scores confirmed the construct validity (p < 0.001). The standard error of measurement (SEM) and the minimum detectable change (MDC) were 2.2 and 6.2, respectively. The adapted Arabic version of the OKS demonstrated acceptable psychometric properties, including reliability, internal consistency, and the validity. The present study indicates that the OKS-Ar is a suitable questionnaire to measure pain and physical function in the Arabic speaking adult male patients with knee OA.

An Audience Response System Strategy to Improve Student Motivation, Attention, and Feedback

PubMed Central

Black, Esther P.; Rohr, Jürgen

2009-01-01

Objective To implement an audience response system (ARS) to improve student motivation and attention during lectures and provide immediate feedback to the instructor concerning student understanding of lecture content in a Physiological Chemistry/Molecular Biology course. Design Students used ARS devices to respond to strategically placed questions throughout physiological chemistry/molecular biology lectures. The instructor inserted 6 to 7 questions that promoted student/class interactivity into each of several 50-minute lectures to focus students' attention and provide feedback on students' comprehension of material. Assessment Ninety-eight percent of first-year pharmacy (P1) students (n = 109) reported that strategically placed ARS questions throughout lectures helped them maintain attention. Reports from an independent focus group indicated that students favored this strategy. Furthermore, ARS feedback helped the instructor gauge student comprehension and adjust lectures accordingly. Conclusions Focused, strategically placed ARS questions throughout lectures may help students maintain attention and stay motivated to learn. Feedback from these questions also allows instructors to adapt lectures to address areas of deficiency. PMID:19513159

An audience response system strategy to improve student motivation, attention, and feedback.

PubMed

Cain, Jeff; Black, Esther P; Rohr, Jürgen

2009-04-07

To implement an audience response system (ARS) to improve student motivation and attention during lectures and provide immediate feedback to the instructor concerning student understanding of lecture content in a Physiological Chemistry/Molecular Biology course. Students used ARS devices to respond to strategically placed questions throughout physiological chemistry/molecular biology lectures. The instructor inserted 6 to 7 questions that promoted student/class interactivity into each of several 50-minute lectures to focus students' attention and provide feedback on students' comprehension of material. Ninety-eight percent of first-year pharmacy (P1) students (n = 109) reported that strategically placed ARS questions throughout lectures helped them maintain attention. Reports from an independent focus group indicated that students favored this strategy. Furthermore, ARS feedback helped the instructor gauge student comprehension and adjust lectures accordingly. Focused, strategically placed ARS questions throughout lectures may help students maintain attention and stay motivated to learn. Feedback from these questions also allows instructors to adapt lectures to address areas of deficiency.

COMET-AR User's Manual: COmputational MEchanics Testbed with Adaptive Refinement

NASA Technical Reports Server (NTRS)

Moas, E. (Editor)

1997-01-01

The COMET-AR User's Manual provides a reference manual for the Computational Structural Mechanics Testbed with Adaptive Refinement (COMET-AR), a software system developed jointly by Lockheed Palo Alto Research Laboratory and NASA Langley Research Center under contract NAS1-18444. The COMET-AR system is an extended version of an earlier finite element based structural analysis system called COMET, also developed by Lockheed and NASA. The primary extensions are the adaptive mesh refinement capabilities and a new "object-like" database interface that makes COMET-AR easier to extend further. This User's Manual provides a detailed description of the user interface to COMET-AR from the viewpoint of a structural analyst.

ArControl: An Arduino-Based Comprehensive Behavioral Platform with Real-Time Performance.

PubMed

Chen, Xinfeng; Li, Haohong

2017-01-01

Studying animal behavior in the lab requires reliable delivering stimulations and monitoring responses. We constructed a comprehensive behavioral platform (ArControl: Arduino Control Platform) that was an affordable, easy-to-use, high-performance solution combined software and hardware components. The hardware component was consisted of an Arduino UNO board and a simple drive circuit. As for software, the ArControl provided a stand-alone and intuitive GUI (graphical user interface) application that did not require users to master scripts. The experiment data were automatically recorded with the built in DAQ (data acquisition) function. The ArControl also allowed the behavioral schedule to be entirely stored in and operated on the Arduino chip. This made the ArControl a genuine, real-time system with high temporal resolution (<1 ms). We tested the ArControl, based on strict performance measurements and two mice behavioral experiments. The results showed that the ArControl was an adaptive and reliable system suitable for behavioral research.

ArControl: An Arduino-Based Comprehensive Behavioral Platform with Real-Time Performance

PubMed Central

Chen, Xinfeng; Li, Haohong

2017-01-01

Studying animal behavior in the lab requires reliable delivering stimulations and monitoring responses. We constructed a comprehensive behavioral platform (ArControl: Arduino Control Platform) that was an affordable, easy-to-use, high-performance solution combined software and hardware components. The hardware component was consisted of an Arduino UNO board and a simple drive circuit. As for software, the ArControl provided a stand-alone and intuitive GUI (graphical user interface) application that did not require users to master scripts. The experiment data were automatically recorded with the built in DAQ (data acquisition) function. The ArControl also allowed the behavioral schedule to be entirely stored in and operated on the Arduino chip. This made the ArControl a genuine, real-time system with high temporal resolution (<1 ms). We tested the ArControl, based on strict performance measurements and two mice behavioral experiments. The results showed that the ArControl was an adaptive and reliable system suitable for behavioral research. PMID:29321735

Fifth IPCC Assessment Report Now Out

NASA Astrophysics Data System (ADS)

Kundzewicz, Zbigniew W.

2014-01-01

The Fifth Assessment Report (AR5) of the Intergovernmental Panel on Climate Change (IPCC) is now available. It provides policymakers with an assessment of information on climate change, its impacts and possible response options (adaptation and mitigation). Summaries for policymakers of three reports of IPCC working groups and of the Synthesis Report have now been approved by IPCC plenaries. This present paper reports on the most essential findings in AR5. It briefly informs on the contents of reports of all IPCC working groups. It discusses the physical science findings, therein observed changes (ubiquitous warming, shrinking cryosphere, sea level rise, changes in precipitation and extremes, and biogeochemical cycles). It deals with the drivers of climate change, progress in climate system understanding (evaluation of climate models, quantification of climate system responses), and projections for the future. It reviews impacts, adaptation and vulnerability, including observed changes, key risks, key reasons for concern, sectors and systems, and managing risks and building resilience. Finally, mitigation of climate change is discussed, including greenhouse gas emissions in the past, present and future, and mitigation in sectors. It is hoped that the present article will encourage the readership of this journal to dive into the AR5 report that provides a wealth of useful information.

A C-Type Cytochrome and a Transcriptional Regulator Responsible for Enhanced Extracellular Electron Transfer in Geobacter Sulfurreducens Revealed by Adaptive Evolution

DTIC Science & Technology

2010-01-01

dance of pgcA transcripts, consistent with increased expression of pgcA in the adapted strains. One of the mutations doubled the rate of Fe(III) oxide...sequenced bacterial genomes. BMC Genomics 8: 274. Herring, C.D., Raghunathan, A., Honisch, C., Patel, T., Apple- bee , M.K., Joyce, A.R., et al. (2006

Disrupting Androgen Receptor Signaling Induces Snail-Mediated Epithelial-Mesenchymal Plasticity in Prostate Cancer.

PubMed

Miao, Lu; Yang, Lin; Li, Rui; Rodrigues, Daniel N; Crespo, Mateus; Hsieh, Jer-Tsong; Tilley, Wayne D; de Bono, Johann; Selth, Luke A; Raj, Ganesh V

2017-06-01

Epithelial-to-mesenchymal plasticity (EMP) has been linked to metastasis, stemness, and drug resistance. In prostate cancer, EMP has been associated with both suppression and activation of the androgen receptor (AR) signaling. Here we investigated the effect of the potent AR antagonist enzalutamide on EMP in multiple preclinical models of prostate cancer and patient tissues. Enzalutamide treatment significantly enhanced the expression of EMP drivers (ZEB1, ZEB2, Snail, Twist, and FOXC2) and mesenchymal markers (N-cadherin, fibronectin, and vimentin) in prostate cancer cells, enhanced prostate cancer cell migration, and induced prostate cancer transformation to a spindle, fibroblast-like morphology. Enzalutamide-induced EMP required concomitant suppression of AR signaling and activation of the EMP-promoting transcription factor Snail, as evidenced by both knockdown and overexpression studies. Supporting these findings, AR signaling and Snail expression were inversely correlated in C4-2 xenografts, patient-derived castration-resistant metastases, and clinical samples. For the first time, we elucidate a mechanism explaining the inverse relationship between AR and Snail. Specifically, we found that AR directly repressed SNAI1 gene expression by binding to specific AR-responsive elements within the SNAI1 promoter. Collectively, our findings demonstrate that de-repression of Snail and induction of EMP is an adaptive response to enzalutamide with implications for therapy resistance. Cancer Res; 77(11); 3101-12. ©2017 AACR . ©2017 American Association for Cancer Research.

A Co-Opted Hormonal Cascade Activates Dormant Adventitious Root Primordia upon Flooding in Solanum dulcamara.

PubMed

Dawood, Thikra; Yang, Xinping; Visser, Eric J W; Te Beek, Tim A H; Kensche, Philip R; Cristescu, Simona M; Lee, Sangseok; Floková, Kristýna; Nguyen, Duy; Mariani, Celestina; Rieu, Ivo

2016-04-01

Soil flooding is a common stress factor affecting plants. To sustain root function in the hypoxic environment, flooding-tolerant plants may form new, aerenchymatous adventitious roots (ARs), originating from preformed, dormant primordia on the stem. We investigated the signaling pathway behind AR primordium reactivation in the dicot species Solanum dulcamara Transcriptome analysis indicated that flooding imposes a state of quiescence on the stem tissue, while increasing cellular activity in the AR primordia. Flooding led to ethylene accumulation in the lower stem region and subsequently to a drop in abscisic acid (ABA) level in both stem and AR primordia tissue. Whereas ABA treatment prevented activation of AR primordia by flooding, inhibition of ABA synthesis was sufficient to activate them in absence of flooding. Together, this reveals that there is a highly tissue-specific response to reduced ABA levels. The central role for ABA in the response differentiates the pathway identified here from the AR emergence pathway known from rice (Oryza sativa). Flooding and ethylene treatment also induced expression of the polar auxin transporter PIN2, and silencing of this gene or chemical inhibition of auxin transport inhibited primordium activation, even though ABA levels were reduced. Auxin treatment, however, was not sufficient for AR emergence, indicating that the auxin pathway acts in parallel with the requirement for ABA reduction. In conclusion, adaptation of S. dulcamara to wet habitats involved co-option of a hormonal signaling cascade well known to regulate shoot growth responses, to direct a root developmental program upon soil flooding. © 2016 American Society of Plant Biologists. All Rights Reserved.

A Co-Opted Hormonal Cascade Activates Dormant Adventitious Root Primordia upon Flooding in Solanum dulcamara1[OPEN

PubMed Central

Dawood, Thikra; Kensche, Philip R.; Cristescu, Simona M.; Mariani, Celestina

2016-01-01

Soil flooding is a common stress factor affecting plants. To sustain root function in the hypoxic environment, flooding-tolerant plants may form new, aerenchymatous adventitious roots (ARs), originating from preformed, dormant primordia on the stem. We investigated the signaling pathway behind AR primordium reactivation in the dicot species Solanum dulcamara. Transcriptome analysis indicated that flooding imposes a state of quiescence on the stem tissue, while increasing cellular activity in the AR primordia. Flooding led to ethylene accumulation in the lower stem region and subsequently to a drop in abscisic acid (ABA) level in both stem and AR primordia tissue. Whereas ABA treatment prevented activation of AR primordia by flooding, inhibition of ABA synthesis was sufficient to activate them in absence of flooding. Together, this reveals that there is a highly tissue-specific response to reduced ABA levels. The central role for ABA in the response differentiates the pathway identified here from the AR emergence pathway known from rice (Oryza sativa). Flooding and ethylene treatment also induced expression of the polar auxin transporter PIN2, and silencing of this gene or chemical inhibition of auxin transport inhibited primordium activation, even though ABA levels were reduced. Auxin treatment, however, was not sufficient for AR emergence, indicating that the auxin pathway acts in parallel with the requirement for ABA reduction. In conclusion, adaptation of S. dulcamara to wet habitats involved co-option of a hormonal signaling cascade well known to regulate shoot growth responses, to direct a root developmental program upon soil flooding. PMID:26850278

Affect regulation, brain development, and behavioral/emotional health in adolescence.

PubMed

Dahl, R E

2001-01-01

This paper addresses the importance of affect regulation (AR) in relation to a broad range of behavioral and emotional health problems that emerge during adolescence. AR is defined as the adaptive modulation of emotional experience to serve a goal or purpose. This conceptualization of AR emphasizes the use of cognitive skills to guide, inhibit, or modify emotion and behavior, including the expression of emotional responses, in learned, strategic ways-skills that ultimately underpin adult levels of social maturity and the ability to show "responsible" behavior across a range of emotional situations. Neurobehavioral systems that subserve these AR skills include areas of the inferior and orbital prefrontal cortex (PFC), with rich interconnections to several limbic structures and other cortical areas, including the dorsolateral PFC. Adolescence represents an important developmental period in the functional maturation of adult AR skills; it is also a critical time in the development of clinical disorders of AR (eg, rates of depression increase dramatically and gender differences in depression emerge). Maturational changes in AR that occur during adolescence-particularly with respect to the role of emotions influencing responsible decision making-are also relevant to understanding key aspects of the developmental pathways of some behavioral health problems, such as alcohol use and nicotine dependence. A strong case is made for developmental research in affective neuroscience aimed at this important maturational period, particularly the kind of transdisciplinary research leading toward mechanistic understanding of the development of adolescent-onset disorders. Improving understanding in these areas could ultimately lead to the development of early interventions in targeted high-risk populations, and has enormous clinical and social policy relevance.

Throwing enhances humeral shaft cortical bone properties in pre-pubertal baseball players: a 12-month longitudinal pilot study.

PubMed

Weatherholt, Alyssa M; Warden, Stuart J

2018-06-01

To explore throwing athletes as a prospective, within-subject controlled model for studying the response of the skeleton to exercise. Male pre-pubertal throwing athletes (n=12; age=10.3±0.6 yrs) had distal humerus cortical volumetric bone mineral density (Ct.vBMD), cortical bone mineral content (Ct.BMC), total area (Tt.Ar), cortical area (Ct.Ar), medullary area (Me.Ar), cortical thickness (Ct.Th) and polar moment of inertia (IP) assessed within their throwing (exercised) and nonthrowing (control) arms by peripheral quantitative computed tomography at baseline and 12 months. Throwing-to-nonthrowing arm percent differences (i.e. bilateral asymmetry) were compared over time. Over 12 months, the throwing arm gained 4.3% (95% Cl=1.1% to 7.5%), 2.9% (95% Cl=0.3% to 5.4%), 3.9% (95% Cl=0.7% to 7.0%), and 8.2% (95% Cl=2.0% to 6.8%) more Ct.BMC, Ct.Ar, Tt.Ar, and I P than the nonthrowing arm, respectively (all p<0.05). There was no significant effect of throwing on Ct.vBMD, Ct.Th and Me.Ar (all p=0.18-0.82). Throwing induced surface-specific cortical bone adaptation at the distal humeral diaphysis that contributed to a gain in estimated strength. These longitudinal pilot data support the utility of throwing athletes as a within-subject controlled model to explore factors influencing exercise-induced bone adaptation during the critical growing years.

Relieved residual damage in the hematopoietic system of mice rescued by radiation-induced adaptive response (Yonezawa Effect)

PubMed Central

Wang, Bing; Tanaka, Kaoru; Ninomiya, Yasuharu; Maruyama, Kouichi; VarèS, Guillaume; Eguchi-Kasai, Kiyomi; Nenoi, Mitsuru

2013-01-01

Existence of adaptive response (AR) was previously demonstrated in C57BL/6J mice. Irradiations were performed by delivering a priming low dose of X-rays (0.50 Gy) in combination with a challenge high dose of accelerated carbon or neon ion particles. AR was characterized by significantly decreased mortality in the 30-day survival test. This mouse AR model (‘Yonezawa Effect’) was originally established by using X-rays as both the priming and challenge irradiations. The underlying mechanism was due to radio-resistance occurring in blood-forming tissues. In this study, we verified the existence of AR and further investigated residual damage in the hematopoietic system in surviving animals. Results showed that the priming low dose of X-rays could relieve the detrimental effects on the hematopoietic system. We observed both an improvement in the blood platelet count and the ratio of polychromatic erythrocytes (PCEs) to the sum of PCEs and normochromatic erythrocytes (NCEs) and a marked reduction of the incidences of micronucleated PCEs and micronucleated NCEs. These findings suggest that the priming low dose of low linear energy transfer (LET) X-rays induced a protective effect on the hematopoietic system, which may play an important role in both rescue from acute lethal damage (mouse killing) and prevention of late detrimental consequences (residual anhematopoiesis and delayed genotoxic effects) caused by exposure to a high challenge dose from low-LET (X-ray) or high-LET (carbon and neon ion) irradiations. These findings provide new knowledge of the characterization of the Yonezawa Effect by providing new insight into the mechanistic study of AR in vivo. PMID:22923746

A Combined Proteomic and Transcriptomic Analysis on Sulfur Metabolism Pathways of Arabidopsis thaliana under Simulated Acid Rain

PubMed Central

Wang, Wenhua; Simon, Martin; Wu, Feihua; Hu, Wenjun; Chen, Juan B.; Zheng, Hailei

2014-01-01

With rapid economic development, most regions in southern China have suffered acid rain (AR) pollution. In our study, we analyzed the changes in sulfur metabolism in Arabidopsis under simulated AR stress which provide one of the first case studies, in which the systematic responses in sulfur metabolism were characterized by high-throughput methods at different levels including proteomic, genomic and physiological approaches. Generally, we found that all of the processes related to sulfur metabolism responded to AR stress, including sulfur uptake, activation and also synthesis of sulfur-containing amino acid and other secondary metabolites. Finally, we provided a catalogue of the detected sulfur metabolic changes and reconstructed the coordinating network of their mutual influences. This study can help us to understand the mechanisms of plants to adapt to AR stress. PMID:24595051

T helper 1 immunity requires complement-driven NLRP3 inflammasome activity in CD4+ T cells

PubMed Central

Spolski, Rosanne; Robertson, Avril A. B.; Klos, Andreas; Rheinheimer, Claudia; Dutow, Pavel; Woodruff, Trent M.; Yu, Zu Xi; O'Neill, Luke A.; Coll, Rebecca C.; Sher, Alan; Leonard, Warren J.; Köhl, Jörg; Monk, Pete; Cooper, Matthew A.; Arno, Matthew; Afzali, Behdad; Lachmann, Helen J.; Cope, Andrew P.; Mayer-Barber, Katrin D.; Kemper, Claudia

2016-01-01

The NLRP3 inflammasome controls interleukin-1β maturation in antigen-presenting cells, but a direct role for NLRP3 in human adaptive immune cells has not been described. We found that the NLRP3 inflammasome assembles in human CD4+ T cells and initiates caspase-1–dependent interleukin-1β secretion, thereby promoting interferon-γ production and T helper 1 (TH1) differentiation in an autocrine fashion. NLRP3 assembly requires intracellular C5 activation and stimulation of C5a receptor 1 (C5aR1), which is negatively regulated by surface-expressed C5aR2. Aberrant NLRP3 activity in T cells affects inflammatory responses in human autoinflammatory disease and in mouse models of inflammation and infection. Our results demonstrate that NLRP3 inflammasome activity is not confined to “innate immune cells” but is an integral component of normal adaptive TH1 responses. PMID:27313051

T helper 1 immunity requires complement-driven NLRP3 inflammasome activity in CD4⁺ T cells.

PubMed

Arbore, Giuseppina; West, Erin E; Spolski, Rosanne; Robertson, Avril A B; Klos, Andreas; Rheinheimer, Claudia; Dutow, Pavel; Woodruff, Trent M; Yu, Zu Xi; O'Neill, Luke A; Coll, Rebecca C; Sher, Alan; Leonard, Warren J; Köhl, Jörg; Monk, Pete; Cooper, Matthew A; Arno, Matthew; Afzali, Behdad; Lachmann, Helen J; Cope, Andrew P; Mayer-Barber, Katrin D; Kemper, Claudia

2016-06-17

The NLRP3 inflammasome controls interleukin-1β maturation in antigen-presenting cells, but a direct role for NLRP3 in human adaptive immune cells has not been described. We found that the NLRP3 inflammasome assembles in human CD4(+) T cells and initiates caspase-1-dependent interleukin-1β secretion, thereby promoting interferon-γ production and T helper 1 (T(H)1) differentiation in an autocrine fashion. NLRP3 assembly requires intracellular C5 activation and stimulation of C5a receptor 1 (C5aR1), which is negatively regulated by surface-expressed C5aR2. Aberrant NLRP3 activity in T cells affects inflammatory responses in human autoinflammatory disease and in mouse models of inflammation and infection. Our results demonstrate that NLRP3 inflammasome activity is not confined to "innate immune cells" but is an integral component of normal adaptive T(H)1 responses. Copyright © 2016, American Association for the Advancement of Science.

Genomics of immune response to typhoid and cholera vaccines

PubMed Central

Majumder, Partha P.

2015-01-01

Considerable variation in antibody response (AR) was observed among recipients of an injectable typhoid vaccine and an oral cholera vaccine. We sought to find whether polymorphisms in genes of the immune system, both innate and adaptive, were associated with the observed variation in response. For both vaccines, we were able to discover and validate several polymorphisms that were significantly associated with immune response. For the typhoid vaccines, these polymorphisms were on genes that belonged to pathways of polysaccharide recognition, signal transduction, inhibition of T-cell proliferation, pro-inflammatory signalling and eventual production of antimicrobial peptides. For the cholera vaccine, the pathways included epithelial barrier integrity, intestinal homeostasis and leucocyte recruitment. Even though traditional wisdom indicates that both vaccines should act as T-cell-independent antigens, our findings reveal that the vaccines induce AR using different pathways. PMID:25964454

Space shuttle atmospheric revitalization subsystem/active thermal control subsystem computer program (users manual)

NASA Technical Reports Server (NTRS)

1973-01-01

A shuttle (ARS) atmosphere revitalization subsystem active thermal control subsystem (ATCS) performance routine was developed. This computer program is adapted from the Shuttle EC/LSS Design Computer Program. The program was upgraded in three noteworthy areas: (1) The functional ARS/ATCS schematic has been revised to accurately synthesize the shuttle baseline system definition. (2) The program logic has been improved to provide a more accurate prediction of the integrated ARS/ATCS system performance. Additionally, the logic has been expanded to model all components and thermal loads in the ARS/ATCS system. (3) The program is designed to be used on the NASA JSC crew system division's programmable calculator system. As written the new computer routine has an average running time of five minutes. The use of desk top type calculation equipment, and the rapid response of the program provides the NASA with an analytical tool for trade studies to refine the system definition, and for test support of the RSECS or integrated Shuttle ARS/ATCS test programs.

Applied Genomics in Cattle – Identification of the SLICK locus in tropically adapted cattle

USDA-ARS?s Scientific Manuscript database

Over the past 3 years, ARS scientists have been working to identify the underlying genetic variants responsible for a heat tolerance phenotype in cattle associated with the SLICK locus typically found in Senepol cattle. This presentation reviews the general field of applied genomics in cattle, and ...

Validation of the Arabic version of the score for allergic rhinitis tool.

PubMed

Alharethy, Sami; Wedami, Mawaheb Al; Syouri, Falah; Alqabbani, Almaha A; Baqays, Abdulsalam; Mesallam, Tamer; Aldrees, Turki

2017-01-01

Allergic rhinitis (AR) is a common inflammation of the nasal mucosa in response to allergen exposure. We translated and validated the Score for Allergic Rhinitis (SFAR) into an Arabic version so that the disease can be studied in an Arabic population. SFAR is a non-invasive self-administered tool that evaluates eight items related to AR. This study aimed to translate and culturally adapt the SFAR questionnaire into Arabic, and assess the validity, consistency, and reliability of the translated version in an Arabic-speaking population of patients with suspected AR. Cross-sectional. Tertiary care hospital in Riyadh. The Arabic version of the SFAR was administered to patients with suspected AR and control participants. Comparison of the AR and control groups to determine the test-retest reliability and internal consistency of the instrument. The AR (n=173) and control (n=75) groups had significantly different Arabic SFAR scores (P < .0001). The instrument provided satisfactory internal consistency (Cronbach's alpha value of 0.7). The test-retest reliability was excellent for the total Arabic SFAR score (r =0.836, P < .0001). These findings demonstrate that the Arabic version of the SFAR is a valid tool that can be used to screen Arabic speakers with suspected AR. The absence of objective allergy testing.

“Protective Bystander Effects Simulated with the State-Vector Model”—HeLa x Skin Exposure to 137Cs Not Protective Bystander Response But Mammogram and Diagnostic X-Rays Are

PubMed Central

Leonard, Bobby E.

2008-01-01

The recent Dose Response journal article “Protective Bystander Effects Simulated with the State-Vector Model” (Schollnberger and Eckl 2007) identified the suppressive (below natural occurring, zero primer dose, spontaneous level) dose response for HeLa x skin exposure to 137Cs gamma rays (Redpath et al 2001) as a protective Bystander Effect (BE) behavior. I had previously analyzed the Redpath et al (2001) data with a Microdose Model and conclusively showed that the suppressive response was from Adaptive Response (AR) radio-protection (Leonard 2005, 2007a). The significance of my microdose analysis has been that low LET radiation induced single (i.e. only one) charged particle traversals through a cell can initiate a Poisson distributed activation of AR radio-protection. The purpose of this correspondence is to clarify the distinctions relative to the BE and the AR behaviors for the Redpath groups 137Cs data, show conversely however that the Redpath group data for mammography (Ko et al 2004) and diagnostic (Redpath et al 2003) X-rays do conclusively reflect protective bystander behavior and also herein emphasize the need for radio-biologist to apply microdosimetry in planning and analyzing their experiments for BE and AR. Whether we are adamantly pro-LNT, adamantly anti-LNT or, like most of us, just simple scientists searching for the truth in radio-biology, it is important that we accurately identify our results, especially when related to the LNT hypothesis controversy. PMID:18846260

Effect of eccentricity and light level on the timing of light adaptation mechanisms.

PubMed

Barrionuevo, Pablo A; Matesanz, Beatriz M; Gloriani, Alejandro H; Arranz, Isabel; Issolio, Luis; Mar, Santiago; Aparicio, Juan A

2018-04-01

We explored the complexity of the light adaptation process, assessing adaptation recovery (Ar) at different eccentricities and light levels. Luminance thresholds were obtained with transient background fields at mesopic and photopic light levels for temporal retinal eccentricities (0°-15°) with test/background stimulus size of 0.5°/1° using a staircase procedure in a two-channel Maxwellian view optical system. Ar was obtained in comparison with steady data [Vis. Res.125, 12 (2016)VISRAM0042-698910.1016/j.visres.2016.04.008]. Light level proportionally affects Ar only at fovea. Photopic extrafoveal thresholds were one log unit higher for transient conditions. Adaptation was equally fast at low light levels for different retinal locations with variations mainly affected by noise. These results evidence different timing in the mechanisms of adaptation involved.

Development, validation and psychometric properties of the Arabic version of the Orofacial Esthetic Scale: OES-Ar.

PubMed

Alhajj, Mohammed Nasser; Amran, Abdullah Ghalib; Halboub, Esam; Al-Basmi, Abdulghani Ali; Al-Ghabri, Fawaz Abdullah

2017-07-01

This study aimed at developing the Arabic version of the Orofacial Esthetic Scale (OES-Ar) and to investigate its psychometric properties among Arabic-speaking population with and without esthetic impairments. Translation and cross-cultural adaptation was done according to the standard guidelines. Internal consistency was assessed on 230 participants. For test-retest reliability, 50 subjects with natural teeth were recalled within a period of 2 weeks. Validity of the OES-Ar was tested by construct, convergent, and discriminant validity tests. Responsiveness to esthetic changes was assessed in 60 patients. The results showed excellent internal consistency with Cronbach's alpha value of 0.92 and inter-item correlation average value of 0.60. The ICC values ranged from 0.87 to 0.96 which indicated excellent agreement. Construct validity of the OES-Ar was confirmed to be one-factor structure (one-dimensional). For convergent validity, a significant correlation was found between OES summary score and overall impression of the orofacial esthetic as well as between OES summary score and the summary score of the three questions of the OHIP-49Ar related to esthetic. The discriminant validity test revealed significant differences between different study groups (P<0.001). Responsiveness to treatment was confirmed by significant differences between pre- and post-treatment OES total summary score (P<0.001). The OES-Ar has excellent psychometric properties making it valuable instrument to assess orofacial esthetics in Arabic-speaking patients. Copyright © 2016 Japan Prosthodontic Society. Published by Elsevier Ltd. All rights reserved.

Augmented reality for personalized nanomedicines.

PubMed

Lee, Yugyung; Lee, Chi H

As our understanding of onset and progress of diseases at the genetic and molecular level rapidly progresses, the potential of advanced technologies, such as 3D-printing, Socially-Assistive Robots (SARs) or augmented reality (AR), that are applied to personalized nanomedicines (PNMs) to alleviate pathological conditions, has become more prominent. Among advanced technologies, AR in particular has the greatest potential to address those challenges and facilitate the translation of PNMs into formidable clinical application of personalized therapy. As AR is about to adapt additional new methods, such as speech, voice recognition, eye tracing and motion tracking, to enable interaction with host response or biological systems in 3-D space, a combination of multiple approaches to accommodate varying environmental conditions, such as public noise and atmosphere brightness, will be explored to improve its therapeutic outcomes in clinical applications. For instance, AR glasses still being developed by Facebook or Microsoft will serve as new platform that can provide people with the health information they are interested in or various measures through which they can interact with medical services. This review has addressed the current progress and impact of AR on PNMs and its application to the biomedical field. Special emphasis is placed on the application of AR based PNMs to the treatment strategies against senior care, drug addiction and medication adherence. Published by Elsevier Inc.

FOG Random Drift Signal Denoising Based on the Improved AR Model and Modified Sage-Husa Adaptive Kalman Filter.

PubMed

Sun, Jin; Xu, Xiaosu; Liu, Yiting; Zhang, Tao; Li, Yao

2016-07-12

In order to reduce the influence of fiber optic gyroscope (FOG) random drift error on inertial navigation systems, an improved auto regressive (AR) model is put forward in this paper. First, based on real-time observations at each restart of the gyroscope, the model of FOG random drift can be established online. In the improved AR model, the FOG measured signal is employed instead of the zero mean signals. Then, the modified Sage-Husa adaptive Kalman filter (SHAKF) is introduced, which can directly carry out real-time filtering on the FOG signals. Finally, static and dynamic experiments are done to verify the effectiveness. The filtering results are analyzed with Allan variance. The analysis results show that the improved AR model has high fitting accuracy and strong adaptability, and the minimum fitting accuracy of single noise is 93.2%. Based on the improved AR(3) model, the denoising method of SHAKF is more effective than traditional methods, and its effect is better than 30%. The random drift error of FOG is reduced effectively, and the precision of the FOG is improved.

Altered Exosomal RNA Profiles in Bronchoalveolar Lavage from Lung Transplants with Acute Rejection.

PubMed

Gregson, Aric L; Hoji, Aki; Injean, Patil; Poynter, Steven T; Briones, Claudia; Palchevskiy, Vyacheslav; Weigt, S Sam; Shino, Michael Y; Derhovanessian, Ariss; Sayah, David; Saggar, Rajan; Ross, David; Ardehali, Abbas; Lynch, Joseph P; Belperio, John A

2015-12-15

The mechanism by which acute allograft rejection leads to chronic rejection remains poorly understood despite its common occurrence. Exosomes, membrane vesicles released from cells within the lung allograft, contain a diverse array of biomolecules that closely reflect the biologic state of the cell and tissue from which they are released. Exosome transcriptomes may provide a better understanding of the rejection process. Furthermore, biomarkers originating from this transcriptome could provide timely and sensitive detection of acute cellular rejection (AR), reducing the incidence of severe AR and chronic lung allograft dysfunction and improving outcomes. To provide an in-depth analysis of the bronchoalveolar lavage fluid exosomal shuttle RNA population after lung transplantation and evaluate for differential expression between acute AR and quiescence. Serial bronchoalveolar lavage specimens were ultracentrifuged to obtain the exosomal pellet for RNA extraction, on which RNA-Seq was performed. AR demonstrates an intense inflammatory environment, skewed toward both innate and adaptive immune responses. Novel, potential upstream regulators identified offer potential therapeutic targets. Our findings validate bronchoalveolar lavage fluid exosomal shuttle RNA as a source for understanding the pathophysiology of AR and for biomarker discovery in lung transplantation.

Altered Exosomal RNA Profiles in Bronchoalveolar Lavage from Lung Transplants with Acute Rejection

PubMed Central

Hoji, Aki; Injean, Patil; Poynter, Steven T.; Briones, Claudia; Palchevskiy, Vyacheslav; Sam Weigt, S.; Shino, Michael Y.; Derhovanessian, Ariss; Saggar, Rajan; Ross, David; Ardehali, Abbas; Lynch, Joseph P.; Belperio, John A.

2015-01-01

Rationale: The mechanism by which acute allograft rejection leads to chronic rejection remains poorly understood despite its common occurrence. Exosomes, membrane vesicles released from cells within the lung allograft, contain a diverse array of biomolecules that closely reflect the biologic state of the cell and tissue from which they are released. Exosome transcriptomes may provide a better understanding of the rejection process. Furthermore, biomarkers originating from this transcriptome could provide timely and sensitive detection of acute cellular rejection (AR), reducing the incidence of severe AR and chronic lung allograft dysfunction and improving outcomes. Objectives: To provide an in-depth analysis of the bronchoalveolar lavage fluid exosomal shuttle RNA population after lung transplantation and evaluate for differential expression between acute AR and quiescence. Methods: Serial bronchoalveolar lavage specimens were ultracentrifuged to obtain the exosomal pellet for RNA extraction, on which RNA-Seq was performed. Measurements and Main Results: AR demonstrates an intense inflammatory environment, skewed toward both innate and adaptive immune responses. Novel, potential upstream regulators identified offer potential therapeutic targets. Conclusions: Our findings validate bronchoalveolar lavage fluid exosomal shuttle RNA as a source for understanding the pathophysiology of AR and for biomarker discovery in lung transplantation. PMID:26308930

Protracted Oxidative Alterations in the Mechanism of Hematopoietic Acute Radiation Syndrome

PubMed Central

Gorbunov, Nikolai V.; Sharma, Pushpa

2015-01-01

The biological effects of high-dose total body ionizing irradiation [(thereafter, irradiation (IR)] are attributed to primary oxidative breakage of biomolecule targets, mitotic, apoptotic and necrotic cell death in the dose-limiting tissues, clastogenic and epigenetic effects, and cascades of functional and reactive responses leading to radiation sickness defined as the acute radiation syndrome (ARS). The range of remaining and protracted injuries at any given radiation dose as well as the dynamics of post-IR alterations is tissue-specific. Therefore, functional integrity of the homeostatic tissue barriers may decline gradually within weeks in the post-IR period culminating with sepsis and failure of organs and systems. Multiple organ failure (MOF) leading to moribundity is a common sequela of the hemotapoietic form of ARS (hARS). Onset of MOF in hARS can be presented as “two-hit phenomenon” where the “first hit” is the underlying consequences of the IR-induced radiolysis in cells and biofluids, non-septic inflammation, metabolic up-regulation of pro-oxidative metabolic reactions, suppression of the radiosensitive hematopoietic and lymphoid tissues and the damage to gut mucosa and vascular endothelium. While the “second hit” derives from bacterial translocation and spread of the bacterial pathogens and inflammagens through the vascular system leading to septic inflammatory, metabolic responses and a cascade of redox pro-oxidative and adaptive reactions. This sequence of events can create a ground for development of prolonged metabolic, inflammatory, oxidative, nitrative, and carbonyl, electrophilic stress in crucial tissues and thus exacerbate the hARS outcomes. With this perspective, the redox mechanisms, which can mediate the IR-induced protracted oxidative post-translational modification of proteins, oxidation of lipids and carbohydrates and their countermeasures in hARS are subjects of the current review. Potential role of ubiquitous, radioresistant mesenchymal stromal cells in the protracted responses to IR and IR-related septicemia is also discussed. PMID:26785342

Protracted Oxidative Alterations in the Mechanism of Hematopoietic Acute Radiation Syndrome.

PubMed

Gorbunov, Nikolai V; Sharma, Pushpa

2015-02-27

The biological effects of high-dose total body ionizing irradiation [(thereafter, irradiation (IR)] are attributed to primary oxidative breakage of biomolecule targets, mitotic, apoptotic and necrotic cell death in the dose-limiting tissues, clastogenic and epigenetic effects, and cascades of functional and reactive responses leading to radiation sickness defined as the acute radiation syndrome (ARS). The range of remaining and protracted injuries at any given radiation dose as well as the dynamics of post-IR alterations is tissue-specific. Therefore, functional integrity of the homeostatic tissue barriers may decline gradually within weeks in the post-IR period culminating with sepsis and failure of organs and systems. Multiple organ failure (MOF) leading to moribundity is a common sequela of the hemotapoietic form of ARS (hARS). Onset of MOF in hARS can be presented as "two-hit phenomenon" where the "first hit" is the underlying consequences of the IR-induced radiolysis in cells and biofluids, non-septic inflammation, metabolic up-regulation of pro-oxidative metabolic reactions, suppression of the radiosensitive hematopoietic and lymphoid tissues and the damage to gut mucosa and vascular endothelium. While the "second hit" derives from bacterial translocation and spread of the bacterial pathogens and inflammagens through the vascular system leading to septic inflammatory, metabolic responses and a cascade of redox pro-oxidative and adaptive reactions. This sequence of events can create a ground for development of prolonged metabolic, inflammatory, oxidative, nitrative, and carbonyl, electrophilic stress in crucial tissues and thus exacerbate the hARS outcomes. With this perspective, the redox mechanisms, which can mediate the IR-induced protracted oxidative post-translational modification of proteins, oxidation of lipids and carbohydrates and their countermeasures in hARS are subjects of the current review. Potential role of ubiquitous, radioresistant mesenchymal stromal cells in the protracted responses to IR and IR-related septicemia is also discussed.

Unleashing Expert Judgment in the IPCC's Fifth Assessment Report

NASA Astrophysics Data System (ADS)

Freeman, P. T.; Mach, K. J.; Mastrandrea, M.; Field, C. B.

2016-12-01

IPCC assessments are critical vehicles for evaluating and synthesizing existing knowledge about climate change, its impacts, and potential options for adaptation and mitigation. In these assessments, rigorous expert judgment is essential for characterizing current scientific understanding including persistent and complex uncertainties related to climate change. Over its history the IPCC has iteratively developed frameworks for evaluating and communicating what is known and what is not known about climate change science. In this presentation, we explore advances and challenges in approaches to evaluating and communicating expert judgment in the Intergovernmental Panel on Climate Change's Fifth Assessment Report (IPCC AR5). We present an analysis of the frequency of the use of calibrated degree-of-certainty terms in the policymaker summaries from the IPCC's AR5 and Fourth Assessment Report (AR4). We find that revised guidance for IPCC author teams in the AR5 improved the development of balanced judgments on scientific evidence across disciplines. Overall, degree-of-certainty terms are more abundant in the AR5 policymaker summaries compared to those of the AR4, demonstrating an increased commitment to extensively and transparently characterizing expert judgments underpinning report conclusions. This analysis also shows that while working groups still favor different degree-of-certainty scales in the AR5, authors employed a wider array of degree-of-certainty scales to communicate expert judgment supporting report findings compared to the policymaker summaries of the AR4. Finally, our analysis reveals greater inclusion of lower-certainty findings in the AR5 as compared to the AR4, critical for communicating a fuller range of possible climate change impacts and response options. Building on our findings we propose a simpler, more transparent, and more rigorous framework for developing and communicating expert judgments in future climate and environmental assessments.

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

Intelligent Augmented Reality Training for Motherboard Assembly

ERIC Educational Resources Information Center

Westerfield, Giles; Mitrovic, Antonija; Billinghurst, Mark

2015-01-01

We investigate the combination of Augmented Reality (AR) with Intelligent Tutoring Systems (ITS) to assist with training for manual assembly tasks. Our approach combines AR graphics with adaptive guidance from the ITS to provide a more effective learning experience. We have developed a modular software framework for intelligent AR training…

5-HT2a receptor in mPFC influences context-guided reconsolidation of object memory in perirhinal cortex.

PubMed

Morici, Juan Facundo; Miranda, Magdalena; Gallo, Francisco Tomás; Zanoni, Belén; Bekinschtein, Pedro; Weisstaub, Noelia V

2018-05-02

Context-dependent memories may guide adaptive behavior relaying in previous experience while updating stored information through reconsolidation. Retrieval can be triggered by partial and shared cues. When the cue is presented, the most relevant memory should be updated. In a contextual version of the object recognition task, we examined the effect of medial PFC (mPFC) serotonin 2a receptor (5-HT2aR) blockade during retrieval in reconsolidation of competing objects memories. We found that mPFC 5-HT2aR controls retrieval and reconsolidation of object memories in the perirhinal cortex (PRH), but not in the dorsal hippocampus in rats. Also, reconsolidation of objects memories in PRH required a functional interaction between the ventral hippocampus and the mPFC. Our results indicate that in the presence of conflicting information at retrieval, mPFC 5-HT2aR may facilitate top-down context-guided control over PRH to control the behavioral response and object memory reconsolidation. © 2018, Morici et al.

5-HT2a receptor in mPFC influences context-guided reconsolidation of object memory in perirhinal cortex

PubMed Central

Morici, Juan Facundo; Miranda, Magdalena; Gallo, Francisco Tomás; Zanoni, Belén; Bekinschtein, Pedro

2018-01-01

Context-dependent memories may guide adaptive behavior relaying in previous experience while updating stored information through reconsolidation. Retrieval can be triggered by partial and shared cues. When the cue is presented, the most relevant memory should be updated. In a contextual version of the object recognition task, we examined the effect of medial PFC (mPFC) serotonin 2a receptor (5-HT2aR) blockade during retrieval in reconsolidation of competing objects memories. We found that mPFC 5-HT2aR controls retrieval and reconsolidation of object memories in the perirhinal cortex (PRH), but not in the dorsal hippocampus in rats. Also, reconsolidation of objects memories in PRH required a functional interaction between the ventral hippocampus and the mPFC. Our results indicate that in the presence of conflicting information at retrieval, mPFC 5-HT2aR may facilitate top-down context-guided control over PRH to control the behavioral response and object memory reconsolidation. PMID:29717980

Brazilian Portuguese version of the Anger Rumination Scale (ARS-Brazil).

PubMed

Sperotto, Daniela; Manfro, Arthur Gus; Axelrud, Luiza Kvitko; Manfro, Pedro Henrique; Salum, Giovanni Abrahão; DeSousa, Diogo Araújo

2018-03-01

Objective To describe the cross-cultural adaptation of the Anger Rumination Scale (ARS) for use in Brazil. Methods The cross-cultural adaptation followed a four-step process, based on specialized literature: 1) investigation of conceptual and item equivalence; 2) translation and back-translation; 3) pretest; and 4) investigation of operational equivalence. Results A final Brazilian version of the instrument (ARS-Brazil) was defined and is presented. Pretest results revealed that the instrument was generally well understood by adults as well as indicated a few modifications that were included in the final version presented here. Conclusion The Brazilian Portuguese version of the ARS seems to be very similar to the original ARS in terms of conceptual and item equivalence, semantics, and operational equivalence, suggesting that future cross-cultural studies may benefit from this early version. As a result, a new instrument is now available for the assessment of rumination symptoms of anger and irritability for adults in community, clinical, and research settings.

Managing the Risks of Extreme Events and Disasters in a Changing Climate: Lessons for Adaptation to Climate Change (Invited)

NASA Astrophysics Data System (ADS)

Mastrandrea, M.; Field, C. B.; Mach, K. J.; Barros, V.

2013-12-01

The IPCC Special Report on Managing the Risks of Extreme Events and Disasters to Advance Climate Change Adaptation, published in 2012, integrates expertise in climate science, disaster risk reduction, and adaptation to inform discussions on how to reduce and manage the risks of extreme events and disasters in a changing climate. Impacts and the risks of disasters are determined by the interaction of the physical characteristics of weather and climate events with the vulnerability of exposed human society and ecosystems. The Special Report evaluates the factors that make people and infrastructure vulnerable to extreme events, trends in disaster losses, recent and future changes in the relationship between climate change and extremes, and experience with a wide range of options used by institutions, organizations, and communities to reduce exposure and vulnerability, and improve resilience, to climate extremes. Actions ranging from incremental improvements in governance and technology to more transformational changes are assessed. The Special Report provides a knowledge base that is also relevant to the broader context of managing the risks of climate change through mitigation, adaptation, and other responses, assessed in the IPCC's Fifth Assessment Report (AR5), to be completed in 2014. These themes include managing risks through an iterative process involving learning about risks and the effectiveness of responses, employing a portfolio of actions tailored to local circumstances but with links from local to global scales, and considering additional benefits of actions such as improving livelihoods and well-being. The Working Group II contribution to the AR5 also examines the ways that extreme events and their impacts contribute to understanding of vulnerabilities and adaptation deficits in the context of climate change, the extent to which impacts of climate change are experienced through changes in the frequency and severity of extremes as opposed to mean changes, and the emergence of risks that are place-based vs. systemic.

Immunology.

PubMed

Toskala, Elina

2014-09-01

Knowledge of our immune system functions is critical for understanding allergic airway disease development as well as for selection of appropriate diagnostic and therapeutic options for patients with respiratory allergies. This review explains the current understanding of the basic immunology of the upper airways and the pathophysiology of allergic responses, including the mechanisms behind allergic rhinitis. The immune system can be divided to 2 main defense systems that function differently-innate immunity and adaptive immunity. Innate immunity includes several defensive mechanisms such as anatomic or physical barriers, physiological barriers, phagocytosis, and inflammation. The adaptive immune response is activated in an antigen-specific way to provide for the elimination of antigen and induce lasting protection. Hypersensitivity reactions occur when an exaggerated adaptive immune response is activated. Allergic rhinitis is an example of a type I, immunoglobulin E, mediated hypersensitivity reaction. Today we have several immunomodulatory treatment options for patients with allergic airway diseases, such as subcutaneous and sublingual immunotherapy. An understanding of the basics of our immune system and its method of functions is key for using these therapies appropriately. © 2014 ARS-AAOA, LLC.

Reciprocal feedback regulation of PI3K and androgen receptor signaling in PTEN-deficient prostate cancer

PubMed Central

Carver, Brett S; Chapinski, Caren; Wongvipat, John; Hieronymus, Haley; Chen, Yu; Chandarlapaty, Sarat; Arora, Vivek K; Le, Carl; Koutcher, Jason; Scher, Howard; Scardino, Peter T; Rosen, Neal; Sawyers, Charles L

2011-01-01

Summary Prostate cancer is characterized by its dependence on androgen receptor and frequent activation of PI3K signaling. We find that AR transcriptional output is decreased in human and murine tumors with PTEN deletion and that PI3K pathway inhibition activates AR signaling by relieving feedback inhibition of HER kinases. Similarly, AR inhibition activates AKT signaling by reducing levels of the AKT phosphatase PHLPP. Thus, these two oncogenic pathways cross-regulate each other by reciprocal feedback. Inhibition of one activates the other, thereby maintaining tumor cell survival. However, combined pharmacologic inhibition of PI3K and AR signaling caused near complete prostate cancer regressions in a Pten-deficient murine prostate cancer model and in human prostate cancer xenografts, indicating that both pathways coordinately support survival. Significance The two most frequently activated signaling pathways in prostate cancer are driven by AR and PI3K. Inhibitors of the PI3K pathway are in early clinical trials and AR inhibitors confer clinical responses in most patients. However, these inhibitors rarely induce tumor regression in preclinical models. Here we show that these pathways regulate each other by reciprocal negative feedback, such that inhibition of one activates the other. Therefore, tumor cells can adapt and survive when either single pathway is inhibited pharmacologically. Our demonstration of profound tumor regressions with combined pathway inhibition in preclinical prostate tumor models provides rationale for combination therapy in patients. PMID:21575859

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.

Cross-Cultural Adaptation and Validation of the Back Beliefs Questionnaire to the Arabic Language.

PubMed

Alamrani, Samia; Alsobayel, Hana; Alnahdi, Ali H; Moloney, Niamh; Mackey, Martin

2016-06-01

Translation, cross-cultural adaptation, and psychometric testing. To translate the Back Beliefs Questionnaire (BBQ) into Arabic and investigate its psychometric properties in an Arabic-speaking sample of individuals with low back pain (LBP). Back pain beliefs are associated with pain chronicity and disability in people with LBP. The BBQ is a recognized and frequently used tool for measuring these beliefs. To date the BBQ has not been translated into Arabic. The English version of the BBQ was translated and culturally adapted into Arabic (BBQ-Ar) according to published guidelines. The BBQ-Ar was then tested in a sample of 115 Arabic-speaking individuals with LBP. Reliability was evaluated through internal consistency (Cronbach α) and test-retest reliability (intraclass correlation coefficient), the latter in a subgroup of 25. Construct validity was assessed using exploratory factor analysis and by examining the correlation between the BBQ-Ar, the Oswestry Disability Index and a Numerical Pain Rating Scale. Internal consistency of the BBQ-Ar was good (Cronbach α = 0.77). Test-retest reliability was good (intraclass correlation coefficient [2,1] = 0.88). Exploratory factor analysis revealed a three-factor structure, explaining 46% of total variance, with the first factor alone explaining 24%. Eight of the nine scoring items were loaded on the first factor thus forming a unidimensional scale. A significant negative correlation was found between Oswestry Disability Index and BBQ-Ar scores (r = -0.307; P < 0.01), whereas no significant correlation was found between BBQ-Ar and Pain Rating Scale scores. No floor or celling effects were observed. The BBQ-Ar is a valid and reliable tool that can be used to assess back pain beliefs in Arabic-speaking individuals. N/A.

Ventricular action potential adaptation to regular exercise: role of β-adrenergic and KATP channel function.

PubMed

Wang, Xinrui; Fitts, Robert H

2017-08-01

Regular exercise training is known to affect the action potential duration (APD) and improve heart function, but involvement of β-adrenergic receptor (β-AR) subtypes and/or the ATP-sensitive K + (K ATP ) channel is unknown. To address this, female and male Sprague-Dawley rats were randomly assigned to voluntary wheel-running or control groups; they were anesthetized after 6-8 wk of training, and myocytes were isolated. Exercise training significantly increased APD of apex and base myocytes at 1 Hz and decreased APD at 10 Hz. Ca 2+ transient durations reflected the changes in APD, while Ca 2+ transient amplitudes were unaffected by wheel running. The nonselective β-AR agonist isoproterenol shortened the myocyte APD, an effect reduced by wheel running. The isoproterenol-induced shortening of APD was largely reversed by the selective β 1 -AR blocker atenolol, but not the β 2 -AR blocker ICI 118,551, providing evidence that wheel running reduced the sensitivity of the β 1 -AR. At 10 Hz, the K ATP channel inhibitor glibenclamide prolonged the myocyte APD more in exercise-trained than control rats, implicating a role for this channel in the exercise-induced APD shortening at 10 Hz. A novel finding of this work was the dual importance of altered β 1 -AR responsiveness and K ATP channel function in the training-induced regulation of APD. Of physiological importance to the beating heart, the reduced response to adrenergic agonists would enhance cardiac contractility at resting rates, where sympathetic drive is low, by prolonging APD and Ca 2+ influx; during exercise, an increase in K ATP channel activity would shorten APD and, thus, protect the heart against Ca 2+ overload or inadequate filling. NEW & NOTEWORTHY Our data demonstrated that regular exercise prolonged the action potential and Ca 2+ transient durations in myocytes isolated from apex and base regions at 1-Hz and shortened both at 10-Hz stimulation. Novel findings were that wheel running shifted the β-adrenergic receptor agonist dose-response curve rightward compared with controls by reducing β 1 -adrenergic receptor responsiveness and that, at the high activation rate, myocytes from trained animals showed higher K ATP channel function. Copyright © 2017 the American Physiological Society.

α7 Nicotinic Agonist AR-R17779 Protects Mice against 2,4,6-Trinitrobenzene Sulfonic Acid-Induced Colitis in a Spleen-Dependent Way.

PubMed

Grandi, Andrea; Zini, Irene; Flammini, Lisa; Cantoni, Anna M; Vivo, Valentina; Ballabeni, Vigilio; Barocelli, Elisabetta; Bertoni, Simona

2017-01-01

The existence of a cholinergic anti-inflammatory pathway negatively modulating the inflammatory and immune responses in various clinical conditions and experimental models has long been postulated. In particular, the protective involvement of the vagus nerve and of nicotinic Ach receptors (nAChRs) has been proposed in intestinal inflammation and repeatedly investigated in DSS- and TNBS-induced colitis. However, the role of α 7 nAChRs stimulation is still controversial and the potential contribution of α 4 β 2 nAChRs has never been explored in this experimental condition. Our aims were therefore to pharmacologically investigate the role played by both α 7 and α 4 β 2 nAChRs in the modulation of the local and systemic inflammatory responses activated in TNBS-induced colitis in mice and to assess the involvement of the spleen in nicotinic responses. To this end, TNBS-exposed mice were sub-acutely treated with various subcutaneous doses of highly selective agonists (AR-R17779 and TC-2403) and antagonists (methyllycaconitine and dihydro-β-erythroidine) of α 7 and α 4 β 2 nAChRs, respectively, or with sulfasalazine 50 mg/kg per os and clinical and inflammatory responses were evaluated by means of biochemical, histological and flow cytometry assays. α 4 β 2 ligands evoked weak and contradictory effects, while α 7 nAChR agonist AR-R17779 emerged as the most beneficial treatment, able to attenuate several local markers of colitis severity and to revert the rise in splenic T-cells and in colonic inflammatory cytokines levels induced by haptenization. After splenectomy, AR-R17779 lost its protective effects, demonstrating for the first time that, in TNBS-model of experimental colitis, the anti-inflammatory effect of exogenous α 7 nAChR stimulation is strictly spleen-dependent. Our findings showed that the selective α 7 nAChRs agonist AR-R17779 exerted beneficial effects in a model of intestinal inflammation characterized by activation of the adaptive immune system and that the spleen is essential to mediate this cholinergic protection.

Adaptive multimodal interaction in mobile augmented reality: A conceptual framework

NASA Astrophysics Data System (ADS)

Abidin, Rimaniza Zainal; Arshad, Haslina; Shukri, Saidatul A'isyah Ahmad

2017-10-01

Recently, Augmented Reality (AR) is an emerging technology in many mobile applications. Mobile AR was defined as a medium for displaying information merged with the real world environment mapped with augmented reality surrounding in a single view. There are four main types of mobile augmented reality interfaces and one of them are multimodal interfaces. Multimodal interface processes two or more combined user input modes (such as speech, pen, touch, manual gesture, gaze, and head and body movements) in a coordinated manner with multimedia system output. In multimodal interface, many frameworks have been proposed to guide the designer to develop a multimodal applications including in augmented reality environment but there has been little work reviewing the framework of adaptive multimodal interface in mobile augmented reality. The main goal of this study is to propose a conceptual framework to illustrate the adaptive multimodal interface in mobile augmented reality. We reviewed several frameworks that have been proposed in the field of multimodal interfaces, adaptive interface and augmented reality. We analyzed the components in the previous frameworks and measure which can be applied in mobile devices. Our framework can be used as a guide for designers and developer to develop a mobile AR application with an adaptive multimodal interfaces.

The RNA-editing deaminase ADAR is involved in stress resistance of Artemia diapause embryos.

PubMed

Dai, Li; Liu, Xue-Chen; Ye, Sen; Li, Hua-Wei; Chen, Dian-Fu; Yu, Xiao-Jian; Huang, Xue-Ting; Zhang, Li; Yang, Fan; Yang, Jin-Shu; Yang, Wei-Jun

2016-11-01

The most widespread type of RNA editing, conversion of adenosine to inosine (A→I), is catalyzed by two members of the adenosine deaminase acting on RNA (ADAR) family, ADAR1 and ADAR2. These enzymes edit transcripts for neurotransmitter receptors and ion channels during adaption to changes in the physical environment. In the primitive crustacean Artemia, when maternal adults are exposed to unfavorable conditions, they release diapause embryos to withstand harsh environments. The aim of the current study was therefore to elucidate the role of ADAR of Artemia diapause embryos in resistance to stress. Here, we identified Artemia ADAR (Ar-ADAR), which harbors a putative nuclear localization sequence (NLS) and two double-stranded RNA-binding motifs (dsRBMs) in the amino-terminal region and an adenosine deaminase (AD) domain in the carboxyl-terminal region. Western blot and immunofluorescence analysis revealed that Ar-ADAR is expressed abundantly in post-diapause embryos. Artemia (n = 200, three replicates) were tested under basal and stress conditions. We found that Ar-ADAR was significantly induced in response to the stresses of salinity and heat-shock. Furthermore, in vivo knockdown of Ar-ADAR (n = 100, three replicates) by RNA interference induced formation of pseudo-diapause embryos, which lack resistance to the stresses and exhibit high levels of apoptosis. These results indicate that Ar-ADAR contributes to resistance to stress in Artemia diapause embryos.

AT1 and AT2 Receptors in the Prelimbic Cortex Modulate the Cardiovascular Response Evoked by Acute Exposure to Restraint Stress in Rats.

PubMed

Brasil, Taíz F S; Fassini, Aline; Corrêa, Fernando M

2018-01-01

The prelimbic cortex (PL) is an important structure in the neural pathway integrating stress responses. Brain angiotensin is involved in cardiovascular control and modulation of stress responses. Blockade of angiotensin receptors has been reported to reduce stress responses. Acute restraint stress (ARS) is a stress model, which evokes sustained blood pressure increase, tachycardia, and reduction in tail temperature. We therefore hypothesized that PL locally generated angiotensin and angiotensin receptors modulate stress autonomic responses. To test this hypothesis, we microinjected an angiotensin-converting enzyme (ACE) inhibitor or angiotensin antagonists into the PL, prior to ARS. Male Wistar rats were used; guide cannulas were bilaterally implanted in the PL for microinjection of vehicle or drugs. A polyethylene catheter was introduced into the femoral artery to record cardiovascular parameters. Tail temperature was measured using a thermal camera. ARS was started 10 min after PL treatment with drugs. Pretreatment with ACE inhibitor lisinopril (0.5 nmol/100 nL) reduced the pressor response, but did not affect ARS-evoked tachycardia. At a dose of 1 nmol/100 nL, it reduced both ARS pressor and tachycardic responses. Pretreatment with candesartan, AT1 receptor antagonist reduced ARS-evoked pressor response, but not tachycardia. Pretreatment with PD123177, AT2 receptor antagonist, reduced tachycardia, but did not affect ARS pressor response. No treatment affected ARS fall in tail temperature. Results suggest involvement of PL angiotensin in the mediation of ARS cardiovascular responses, with participation of both AT1 and AT2 receptors. In conclusion, results indicate that PL AT1-receptors modulate the ARS-evoked pressor response, while AT2-receptors modulate the tachycardic component of the autonomic response.

Chronic high-fat diet-induced obesity decreased survival and increased hypertrophy of rats with experimental eccentric hypertrophy from chronic aortic regurgitation.

PubMed

Dhahri, Wahiba; Drolet, Marie-Claude; Roussel, Elise; Couet, Jacques; Arsenault, Marie

2014-09-24

The composition of a diet can influence myocardial metabolism and development of left ventricular hypertrophy (LVH). The impact of a high-fat diet in chronic left ventricular volume overload (VO) causing eccentric LVH is unknown. This study examined the effects of chronic ingestion of a high-fat diet in rats with chronic VO caused by severe aortic valve regurgitation (AR) on LVH, function and on myocardial energetics and survival. Male Wistar rats were divided in four groups: Shams on control or high-fat (HF) diet (15 rats/group) and AR rats fed with the same diets (ARC (n = 56) and ARHF (n = 32)). HF diet was started one week before AR induction and the protocol was stopped 30 weeks later. As expected, AR caused significant LV dilation and hypertrophy and this was exacerbated in the ARHF group. Moreover, survival in the ARHF group was significantly decreased compared the ARC group. Although the sham animals on HF also developed significant obesity compared to those on control diet, this was not associated with heart hypertrophy. The HF diet in AR rats partially countered the expected shift in myocardial energy substrate preference usually observed in heart hypertrophy (from fatty acids towards glucose). Systolic function was decreased in AR rats but HF diet had no impact on this parameter. The response to HF diet of different fatty acid oxidation markers as well as the increase in glucose transporter-4 translocation to the plasma membrane compared to ARC was blunted in AR animals compared to those on control diet. HF diet for 30 weeks decreased survival of AR rats and worsened eccentric hypertrophy without affecting systolic function. The expected adaptation of myocardial energetics to volume-overload left ventricle hypertrophy in AR animals seemed to be impaired by the high-fat diet suggesting less metabolic flexibility.

[Changes in cellular radiosensitivity after low dose irradiation].

PubMed

Pelevina, I I; Aleshchenko, A V; Antoshchina, M M; Kudriashova, O V; Riabchenko, N I; Akleev, A V

2012-01-01

When the adaptive response (AR) was studied on human blood lymphocytes, a new dependence was discovered. This dependence defines the direction of the radiosensitivity change after a low dose of irradiation. Using micronucleus (MN) test with cytochalasin B the dependence between the cell reaction after low level irradiation and radiosensititvity (the effect after irradiation at the dose of 1 Gy) was observed. The negative correlation between the frequency of AR manifestation, sensibilization, intermediate links and radiosensitivity was discovered. This regularity is observed in the population of Moscow, Obninsk, Chelyabinsk region (irradiated and control) inhabitants, Chernobyl accident liquidators, Moscow children, in individuals with Hodgkin's lymphoma before and during treatment. The negative correlation is also noted by AR determination with two irradiation schemes: in one or two different cell cycle phases (G1-G1 or G1-G2). Similar links are observed using the chromosome methaphase analysis (the frequency of cells with chromosome aberrations). So, the results of the experiments conducted allow us to suppose that the connection between the cell radiosensitivity and a different type of reaction after low dose irradiation--from AR to the increase in radiosensitivity (sensibilization) is a general regularity. AR is induced by low level irradiation and high cell radiosensitivity, while sensibilization is induced by low radiosensitivity. Since AR and sensibilization can be induced not only by irradiation, but many different chemicals and physical agents, the described correlation can be observed in the case of different exposures. Cellular AR and sensibilization are integral indexes depending on many genetic and epigenetic factors, as well as on the initiation of a large number of events. However, the discovered mechanisms of interrelations are still difficult to explain.

Early Activation of Growth Pathways in Mitral Leaflets Exposed to Aortic Regurgitation: New Insights from an Animal Model.

PubMed

Marsit, Ons; Royer, Olivier; Drolet, Marie-Claude; Arsenault, Marie; Couet, Jacques; Morin, Stéphane; Levine, Robert A; Pibarot, Philippe; Beaudoin, Jonathan

2017-05-01

Mitral leaflet enlargement in patients with chronic aortic regurgitation (AR) has been identified as an adaptive mechanism potentially able to prevent functional mitral regurgitation (FMR) in response to left ventricular (LV) dilatation. The timing of valve enlargement is not known, and the related mechanisms are largely unexplored. AR was induced in 58 rats, and another 54 were used as sham controls. Animals were euthanized at different time points after AR creation (48 h, one week, and three months), and AR severity, FMR and LV dilatation were assessed using echocardiography. Mitral valves were harvested to document the reactivation of embryonic growth pathways. AR animals had increased LV dimensions and mitral annulus size. No animal developed FMR. No change in leaflet length or thickness was seen at 48 h; however, anterior mitral leaflets were longer and thicker in AR animals at one week and three months. Molecular changes were present early (at 48 h and at one week), with positive staining for transforming growth factor-b1 (TGF-b1), Alpha-smooth muscle actin (α-SMA) and matrix metalloproteinase-2 (MMP-2), which suggested active matrix remodeling. Increased gene expression for collagen 1, TGF-β1, α-SMA and MMP-2 was found in the mitral valve at 48 h and at one week, but after three months their expression had returned to normal. This model of AR induces active expansion and thickening of the mitral leaflets. Growth signals are expressed acutely, but not at three months, which suggests that most of this enlargement occurs at an early stage. The stimulation of valvular growth could represent a new strategy for the prevention of FMR.

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

Adaptation response surfaces from an ensemble of wheat projections under climate change in Europe

NASA Astrophysics Data System (ADS)

Ruiz-Ramos, Margarita; Ferrise, Roberto

2016-04-01

The uncertainty about climate change (CC) complicates impact adaptation and risk management evaluation at the regional level. Approaches for managing this uncertainty and for simulating and communicating climate change impacts and adaptation opportunities are required. Here we apply an ensemble of crop models for adapting rainfed winter wheat at Lleida (NE Spain), constructing adaptation response surfaces (ARS). Our methodology has been adapted from Pirttioja et al. (2015). Impact response surfaces (IRS) are plotted surfaces showing the response of an impact variable (here crop yield Y) to changes in two explanatory variables (here precipitation P and temperature T). By analyzing adaptation variables such as changes in crop yield (ΔY) when an adaptation option is simulated, these can be interpreted as the adaptation response to potential changes of P and T, i.e. ARS. To build these ARS, we explore the sensitivity of an ensemble of wheat models to changes in T and P. Baseline (1981-2010) T and P were modified using a delta change approach with changes in the seasonal patterns. Three levels of CO2 (representing future conditions until 2050) and two actual soil profiles are considered. Crop models were calibrated with field data from Abeledo et al. (2008) and Cartelle et al. (2006). Most promising adaptation options to be analyzed by the ARS approach are identified in a pilot stage with the models DSSAT4.5 and SiriusQuality v.2, subsequently simulating the selected adaptation combinations by the whole ensemble of 11 crop models. The adaptation options identified from pilot stage were: a cultivar with no vernalisation requirements, shortening or extending a 10 % the crop cycle of the standard cultivar, sowing 15 days earlier and 30 days later than the standard date, supplementary irrigation with 40 mm at flowering and full irrigation. These options and those of the standard cultivar and management resulted in 54 combinations and 450.000 runs per crop model. Our preliminary ARSs show some adaptation options allow recover up to ca. 2000 kg/ha. Compared to the historical yields recorded at Lleida province (2550 kg/ha in 1981-2010) our results indicate that adaptation is feasible and may help to reduce detrimental effects of CC. Our analysis evaluates if the explored adaptations fulfill the biophysical requirements to become a practical adaptive solution. This study exemplifies how adaptation options and their impacts can be analyzed, evaluated and communicated in a context of high regional uncertainty for current and future conditions and for short to long-term perspective. This work was funded by MACSUR project within FACCE-JPI. References Abeledo, L.G., R. Savin and G.A. Slafer (2008). European Journal of Agronomy 28:541-550. Cartelle, J., A. Pedró, R. Savin, G.A. Slafer (2006) European Journal of Agronomy 25:365-371. Pirttioja, N., T. Carter, S. Fronzek, M. Bindi, H. Hoffmann, T. Palosuo, M. Ruiz-Ramos, F. Tao, M. Acutis, S. Asseng, P. Baranowski, B. Basso, P. Bodin, S. Buis, D. Cammarano, P. Deligios, M.-F. Destain, B. Dumont, R. Ewert, R. Ferrise, L. François, T. Gaiser, P. Hlavinka, I. Jacquemin, K.C. Kersebaum, C. Kollas, J. Krzyszczak, I.J. Lorite, J. Minet, M.I. Minguez, M. Montesino, M. Moriondo, C. Müller, C. Nendel, I. Öztürk, A. Perego, A. Rodríguez, A.C. Ruane, F. Ruget, M. Sanna, M.A. Semenov, C. Slawinski, P. Stratonovitch, I. Supit, K. Waha, E. Wang, L. Wu, Z. Zhao, and R.P. Rötter, 2015: A crop model ensemble analysis of temperature and precipitation effects on wheat yield across a European transect using impact response surfaces. Clim. Res., 65, 87-105, doi:10.3354/cr01322. IRS2 TEAM: Alfredo Rodríguez(1), Ignacio J. Lorite(3), Fulu Tao(4), Nina Pirttioja(5), Stefan Fronzek(5), Taru Palosuo(4), Timothy R. Carter(5), Marco Bindi(2), Jukka G Höhn(4), Kurt Christian Kersebaum(6), Miroslav Trnka(7,8), Holger Hoffmann(9), Piotr Baranowski(10), Samuel Buis(11), Davide Cammarano(12), Yi Chen(13,4), Paola Deligios(14), Petr Hlavinka(7,8), Frantisek Jurecka(7,8), Jaromir Krzyszczak(10), Marcos Lana(6), Julien Minet(15), Manuel Montesino(16), Claas Nendel(6), John Porter(16), Jaime Recio(1), Françoise Ruget(11), Alberto Sanz(1), Zacharias Steinmetz(17,18), Pierre Stratonovitch(19), Iwan Supit(20), Domenico Ventrella(21), Allard de Wit(20) and Reimund P. Rötter(4). 1 Universidad Politecnica de Madrid, ETSIAgrónomos,28040 Madrid, Spain, margarita.ruiz.ramos@upm.es 2 University of Florence, 50144 Florence, Italy 3 IFAPA Junta de Andalucia, 14004 Córdoba, Spain 4 Natural Resources Institute (LUKE), 01370 Vantaa, Finland 5 Finnish Environment Institute (SYKE), 00250 Helsinki, Finland 6 Leibniz Centre for Agricultural Landscape Research (ZALF), 15374 Müncheberg, Germany 7 Institute of Agrosystems and Bioclimatology, Mendel University in Brno, Brno 613 00, Czech Republic 8 Global Change Research Institute CAS, 603 00 Brno, Czech Republic 9 INRES, University of Bonn, 53115 Bonn, Germany 10 Institute of Agrophysics Polish Academy of Sciences, Lublin, Poland 11 INRA, UMR 1114 EMMAH, F-84914 Avignon, France 12 James Hutton Institute, Invergowrie, Dundee, DD2 5DA, Scotland 13 State Key Laboratory of Earth Surface Processes and Resource Ecology, Academy of Disaster Reduction and Emergency Management, Beijing Normal University, Beijing 100875, China 14 University of Sassari, 07100 Sassari, Italy 15 Université de Liège, 4000 Liège, Belgium 16 University of Copenhagen, 2630 Taastrup, Denmark 17 RIFCON GmbH, 69493 Hirschberg, Germany 18 Group of Environmental and Soil Chemistry, Institute for Environmental Sciences, University of Koblenz-Landau, 76829 Landau, Germany 19 Rothamsted Research, Harpenden, Herts, AL5 2JQ, UK 20 Wageningen University, 6700AA Wageningen, The Netherlands 21 Consiglio per la ricerca in agricoltura e l'analisi dell'economia agraria. CRA-SCA

On-The-Fly Data Processing with Scanamorphos: Application To ArTéMiS

NASA Astrophysics Data System (ADS)

Roussel, Hélène

2018-03-01

Scanamorphos is a suite of IDL based routines to optimally subtract low-frequency noise making maximal use of the redundancy in the data. The procedures were adapted to be applicable to ArTéMiS data.

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

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.

[The teaching and practice of ars dictaminis from the 12(th) to the 14 (th) century].

PubMed

Grévin, Benoît

2012-01-01

The medieval discipline of the ars dictaminis (or dictamen), which flourished during the 12(th)-14(th) centuries, can be considered as an adaptation of classical Latin rhetoric to the communicational needs of the medieval society. Yet, although the relation between the teaching of the ars and its practice is an important one, it has rarely been addressed because of the persistence of numerous misunderstandings about the various different levels at which the ars was taught. This article offers some suggestions to fill this gap.

Real-Time Motion Tracking for Mobile Augmented/Virtual Reality Using Adaptive Visual-Inertial Fusion

PubMed Central

Fang, Wei; Zheng, Lianyu; Deng, Huanjun; Zhang, Hongbo

2017-01-01

In mobile augmented/virtual reality (AR/VR), real-time 6-Degree of Freedom (DoF) motion tracking is essential for the registration between virtual scenes and the real world. However, due to the limited computational capacity of mobile terminals today, the latency between consecutive arriving poses would damage the user experience in mobile AR/VR. Thus, a visual-inertial based real-time motion tracking for mobile AR/VR is proposed in this paper. By means of high frequency and passive outputs from the inertial sensor, the real-time performance of arriving poses for mobile AR/VR is achieved. In addition, to alleviate the jitter phenomenon during the visual-inertial fusion, an adaptive filter framework is established to cope with different motion situations automatically, enabling the real-time 6-DoF motion tracking by balancing the jitter and latency. Besides, the robustness of the traditional visual-only based motion tracking is enhanced, giving rise to a better mobile AR/VR performance when motion blur is encountered. Finally, experiments are carried out to demonstrate the proposed method, and the results show that this work is capable of providing a smooth and robust 6-DoF motion tracking for mobile AR/VR in real-time. PMID:28475145

Real-Time Motion Tracking for Mobile Augmented/Virtual Reality Using Adaptive Visual-Inertial Fusion.

PubMed

Fang, Wei; Zheng, Lianyu; Deng, Huanjun; Zhang, Hongbo

2017-05-05

In mobile augmented/virtual reality (AR/VR), real-time 6-Degree of Freedom (DoF) motion tracking is essential for the registration between virtual scenes and the real world. However, due to the limited computational capacity of mobile terminals today, the latency between consecutive arriving poses would damage the user experience in mobile AR/VR. Thus, a visual-inertial based real-time motion tracking for mobile AR/VR is proposed in this paper. By means of high frequency and passive outputs from the inertial sensor, the real-time performance of arriving poses for mobile AR/VR is achieved. In addition, to alleviate the jitter phenomenon during the visual-inertial fusion, an adaptive filter framework is established to cope with different motion situations automatically, enabling the real-time 6-DoF motion tracking by balancing the jitter and latency. Besides, the robustness of the traditional visual-only based motion tracking is enhanced, giving rise to a better mobile AR/VR performance when motion blur is encountered. Finally, experiments are carried out to demonstrate the proposed method, and the results show that this work is capable of providing a smooth and robust 6-DoF motion tracking for mobile AR/VR in real-time.

β-Adrenoceptor-Mediated Relaxation of Carbachol-Pre-Contracted Mouse Detrusor.

PubMed

Propping, Stefan; Newe, Manja; Lorenz, Kristina; Wirth, Manfred P; Ravens, Ursula

2015-01-01

To study the β-adrenoceptor subtypes involved in the relaxation responses to (-)-isoprenaline in carbachol-pre-contracted (CCh) mouse detrusor muscle with intact and denuded mucosa. Isolated muscle strips from the urinary bladder of male C57BL6 mice or β2-adrenoceptor knockout mice were pre-contracted with CCh, 1 µM and relaxed with increasing concentrations of the β-adrenoceptor (β-AR) agonist (-)-isoprenaline and forskolin. For estimating the β-AR subtypes involved, subtype-selective receptor blockers were used, that is, CGP 20712A (β1-ARs), ICI 118,551 (β2-ARs), and L748,337 (β3-ARs). Unlike in KCl-pre-contracted muscle, the mucosa did not affect the sensitivity of the relaxation response to (-)-isoprenaline in CCh-pre-contracted murine detrusor strips. Increasing concentrations of (-)-isoprenaline produced a biphasic concentration-relaxation response without any difference both during the presence and absence of mucosa. The relaxation fraction produced by low (-)-isoprenaline concentrations was mediated by β2-AR as evidenced by a shift of the concentration-response curve to higher concentrations with ICI 118,551, but not with CGP 20712A and L748,337, and by the absence of this fraction in β2-AR-KO mice. The relaxation response with low sensitivity to (-)-isoprenaline was not affected by any of the β-AR subtype-selective blockers and was the only response detected in detrusor strips from β2-AR-KO mice. In CCh-pre-contracted mouse detrusor, β2-ARs are responsible for the relaxation component with high sensitivity to (-)-isoprenaline as indicated by the conversion of a biphasic into a monophasic CRC with ICI 118,551 or by its absence in β2-AR KO mice. The mucosa does not impair relaxation under these conditions. © 2015 S. Karger AG, Basel.

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

Adaptive Nulling in Hybrid Reflector Antennas

DTIC Science & Technology

1992-09-01

correction of reflector distortion and vernier beamsteering, MEEE Trans. Antennas Propagat, 36:1351-1358. 4 Cherrette , A.R., et al (1989) Compensation of...Propagat, 36:1351-1358. 4. Cherrette , A.R., et al (1989) Compensation of reflector antenna surface distortion using an array feed,IEEE Trans. Antennas

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.

Combined Interactions with I1-, I2-Imidazoline Binding Sites and α2-Adrenoceptors To Manage Opioid Addiction

PubMed Central

2016-01-01

Tolerance and dependence associated with chronic opioid exposure result from molecular, cellular, and neural network adaptations. Such adaptations concern opioid and nonopioid systems, including α2-adrenoceptors (α2-ARs) and I1- and I2-imidazoline binding sites (IBS). Agmatine, one of the hypothesized endogenous ligands of IBS, targeting several systems including α2-ARs and IBS, proved to be able to regulate opioid-induced analgesia and to attenuate the development of tolerance and dependence. Interested in the complex pharmacological profile of agmatine and considering the nature of its targets, we evaluated two series of imidazolines, rationally designed to simultaneously interact with I1-/I2-IBS or I1-/I2-IBS/α2-ARs. The compounds showing the highest affinities for I1-/I2-IBS or I1-/I2-IBS/α2-ARs have been selected for their in vivo evaluation on opiate withdrawal syndrome. Interestingly, 9, displaying I1-/I2-IBS/α2-ARs interaction profile, appears more effective in reducing expression and acquisition of morphine dependence and, therefore, might be considered a promising tool in managing opioid addiction. PMID:27774136

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

Bypass Mechanisms of the Androgen Receptor Pathway in Therapy-Resistant Prostate Cancer Cell Models

PubMed Central

Marques, Rute B.; Dits, Natasja F.; Erkens-Schulze, Sigrun; van Weerden, Wytske M.; Jenster, Guido

2010-01-01

Background Prostate cancer is initially dependent on androgens for survival and growth, making hormonal therapy the cornerstone treatment for late-stage tumors. However, despite initial remission, the cancer will inevitably recur. The present study was designed to investigate how androgen-dependent prostate cancer cells eventually survive and resume growth under androgen-deprived and antiandrogen supplemented conditions. As model system, we used the androgen-responsive PC346C cell line and its therapy-resistant sublines: PC346DCC, PC346Flu1 and PC346Flu2. Methodology/Principal Findings Microarray technology was used to analyze differences in gene expression between the androgen-responsive and therapy-resistant PC346 cell lines. Microarray analysis revealed 487 transcripts differentially-expressed between the androgen-responsive and the therapy-resistant cell lines. Most of these genes were common to all three therapy-resistant sublines and only a minority (∼5%) was androgen-regulated. Pathway analysis revealed enrichment in functions involving cellular movement, cell growth and cell death, as well as association with cancer and reproductive system disease. PC346DCC expressed residual levels of androgen receptor (AR) and showed significant down-regulation of androgen-regulated genes (p-value = 10−7). Up-regulation of VAV3 and TWIST1 oncogenes and repression of the DKK3 tumor-suppressor was observed in PC346DCC, suggesting a potential AR bypass mechanism. Subsequent validation of these three genes in patient samples confirmed that expression was deregulated during prostate cancer progression. Conclusions/Significance Therapy-resistant growth may result from adaptations in the AR pathway, but androgen-independence may also be achieved by alternative survival mechanisms. Here we identified TWIST1, VAV3 and DKK3 as potential players in the bypassing of the AR pathway, making them good candidates as biomarkers and novel therapeutical targets. PMID:20976069

Global Floods and Water Availability Driven by Atmospheric Rivers

NASA Astrophysics Data System (ADS)

Paltan, Homero; Waliser, Duane; Lim, Wee Ho; Guan, Bin; Yamazaki, Dai; Pant, Raghav; Dadson, Simon

2017-10-01

While emerging regional evidence shows that atmospheric rivers (ARs) can exert strong impacts on local water availability and flooding, their role in shaping global hydrological extremes has not yet been investigated. Here we quantify the relative contribution of ARs variability to both flood hazard and water availability. We find that globally, precipitation from ARs contributes 22% of total global runoff, with a number of regions reaching 50% or more. In areas where their influence is strongest, ARs may increase the occurrence of floods by 80%, while absence of ARs may increase the occurrence of hydrological droughts events by up to 90%. We also find that 300 million people are exposed to additional floods and droughts due the occurrence of ARs. ARs provide a source of hydroclimatic variability whose beneficial or damaging effects depend on the capacity of water resources managers to predict and adapt to them.

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.

Monitoring of Dual CRISPR/Cas9-Mediated Steroidogenic Acute Regulatory Protein Gene Deletion and Cholesterol Accumulation Using High-Resolution Fluorescence In Situ Hybridization in a Single Cell

PubMed Central

Lee, Jinwoo; Jefcoate, Colin

2017-01-01

Recent advances in fluorescence microscopy, coupled with CRISPR/Cas9 gene editing technology, provide opportunities for understanding gene regulation at the single-cell level. The application of direct imaging shown here provides an in situ side-by-side comparison of CRISPR/Cas9-edited cells and adjacent unedited cells. We apply this methodology to the steroidogenic acute regulatory protein (StAR) gene in Y-1 adrenal cells and MA-10 testis cells. StAR is a gatekeeper protein that controls the access of cholesterol from the cytoplasm to the inner mitochondria. The loss of this mitochondrial cholesterol transfer mediator rapidly increases lipid droplets in cells, as seen in StAR−/− mice. Here, we describe a dual CRISPR/Cas9 strategy marked by GFP/mCherry expression that deletes StAR activity within 12 h. We used single-molecule fluorescence in situ hybridization (sm-FISH) imaging to directly monitor the time course of gene editing in single cells. We achieved StAR gene deletion at high efficiency dual gRNA targeting to the proximal promoter and exon 2. Seventy percent of transfected cells showed a slow DNA deletion as measured by PCR, and loss of Br-cAMP stimulated transcription. This DNA deletion was seen by sm-FISH in both loci of individual cells relative to non-target Cyp11a1 and StAR exon 7. sm-FISH also distinguishes two effects on stimulated StAR expression without this deletion. Br-cAMP stimulation of primary and spliced StAR RNA at the gene loci were removed within 4 h in this dual CRISPR/Cas9 strategy before any effect on cytoplasmic mRNA and protein occurred. StAR mRNA disappeared between 12 and 24 h in parallel with this deletion, while cholesterol ester droplets increased fourfold. These alternative changes match distinct StAR expression processes. This dual gRNA and sm-FISH approach to CRISPR/Cas9 editing facilitates rapid testing of editing strategies and immediate assessment of single-cell adaptation responses without the perturbation of clonal expansion procedures. PMID:29118738

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.

Getting the Most out of Audience Response Systems: Predicting Student Reactions

ERIC Educational Resources Information Center

Trew, Jennifer L.; Nelsen, Jacqueline L.

2012-01-01

Audience response systems (ARS) are effective tools for improving learning outcomes and student engagement in large undergraduate classes. However, if students do not accept ARS and do not find them to be useful, ARS may be less effective. Predicting and improving student perceptions of ARS may help to ensure positive outcomes. The present study…

Regulation of β1- and β3-adrenergic agonist-stimulated lipolytic response in hyperthyroid and hypothyroid rat white adipocytes

PubMed Central

Germack, Renée; Starzec, Anna; Perret, Gérard Y

2000-01-01

This study examined the effects of thyroid status on the lipolytic responses of rat white adipocytes to β-adrenoceptor (β-AR) stimulation. The β1- and β3-AR mRNAs and proteins were measured by Northern and saturation analyses, respectively. Glycerol production and adenyl cyclase (AC) activity induced by various non-selective and selective β1/β3-AR agonists and drugs which act distal to the receptor in the signalling cascade were measured in cells from untreated, tri-iodothyronine (T3)-treated and thyroidectomized rats. The β3-AR density was enhanced (72%) by T3-treatment and reduced (50%) by introduction of a hypothyroid state while β1-AR number remained unaffected. The β1- and β3-AR density was correlated with the specific mRNA level in all thyroid status. The lipolytic responses to isoprenaline, noradrenaline (β1/β3/β3-AR agonists) and BRL 37344 (β3-AR agonist) were potentiated by 48, 58 and 48%, respectively in hyperthyroidism and reduced by about 80% in hypothyroidism. T3-treatment increased the maximal lipolytic response to the partial β3-AR (CGP 12177) and β1-AR (xamoterol) agonists by 234 and 260%, respectively, increasing their efficacy (intrinsic activity: 0.95 versus 0.43 and 1.02 versus 0.42). The maximal AC response to these agonists was increased by 84 and 58%, respectively, without changing their efficacy. In the hypothyroid state, the maximal lipolytic and AC responses were decreased with CGP (0.17±0.03 versus 0.41±0.08 μmol glycerol/106 adipocytes; 0.048±0.005 versus 0.114±0.006 pmol cyclic AMP min−1 mg−1) but not changed with xamoterol. The changes in lipolytic responses to postreceptor-acting agents (forskolin, enprofylline and dibutenyl cyclic AMP, (Bu)2cAMP) suggest the modifications on receptor coupling and phosphodiesterase levels in both thyroid states. Thyroid status affects lipolysis by modifying β3-AR density and postreceptor events without changes in the β1-AR functionality. PMID:10711342

Androgen biosynthesis in castration-resistant prostate cancer

PubMed Central

Penning, Trevor M

2014-01-01

Prostate cancer is the second leading cause of death in adult males in the USA. Recent advances have revealed that the fatal form of this cancer, known as castration-resistant prostate cancer (CRPC), remains hormonally driven despite castrate levels of circulating androgens. CRPC arises as the tumor undergoes adaptation to low levels of androgens by either synthesizing its own androgens (intratumoral androgens) or altering the androgen receptor (AR). This article reviews the major routes to testosterone and dihydrotestosterone synthesis in CRPC cells and examines the enzyme targets and progress in the development of isoform-specific inhibitors that could block intratumoral androgen biosynthesis. Because redundancy exists in these pathways, it is likely that inhibition of a single pathway will lead to upregulation of another so that drug resistance would be anticipated. Drugs that target multiple pathways or bifunctional agents that block intratumoral androgen biosynthesis and antagonize the AR offer the most promise. Optimal use of enzyme inhibitors or AR antagonists to ensure maximal benefits to CRPC patients will also require application of precision molecular medicine to determine whether a tumor in a particular patient will be responsive to these treatments either alone or in combination. PMID:24829267

Using audience response technology in hospital education programs.

PubMed

McRae, Marion E; Elgie-Watson, Jeanne

2010-07-01

An audience response system (ARS) is an interactive teaching tool that permits an instructor to poll an audience, either anonymously or in a tracked manner, in response to questions. The instructor can then display the responses to the audience. An ARS can be used in hospital-based education programs to assess group learning. The instructor receives immediate feedback that allows review of concepts that were not grasped by the majority of students. This article reviews systems currently on the market and offers tips for choosing an ARS for hospital-based use. Survey data of nurses attending in-service education sessions show that participants overwhelmingly favor the use of an ARS and the nonthreatening learning environment that these systems create. Instructor survey data show positive responses regarding the benefits of ARS use in hospital-based education programs.

Physiological responses of root-less epiphytic plants to acid rain.

PubMed

Kováčik, Jozef; Klejdus, Bořivoj; Bačkor, Martin; Stork, František; Hedbavny, Josef

2011-03-01

Selected physiological responses of Tillandsia albida (Bromeliaceae) and two lichens (Hypogymnia physodes and Xanthoria parietina) exposed to simulated acid rain (AR) over 3 months were studied. Pigments were depressed in all species being affected the most in Tillandsia. Amounts of hydrogen peroxide and superoxide were elevated and soluble proteins decreased only in AR-exposed Hypogymnia. Free amino acids were slightly affected among species and only glutamate sharply decreased in AR-exposed Xanthoria. Slight increase in soluble phenols but decrease in flavonoids in almost all species suggests that the latter are not essential for tolerance to AR. Almost all phenolic acids in Tillandsia leaves decreased in response to AR and activities of selected enzymes (phenylalanine ammonia-lyase, polyphenol oxidase, ascorbate- and guaiacol-peroxidase) were enhanced by AR. In lichens, considerable increase in metabolites (physodalic acid, atranorin and parietin) in response to AR was found but amount of ergosterol was unchanged. Macronutrients (K, Ca, Mg) decreased more pronouncedly in comparison with micronutrients in all species. Xanthoria showed higher tolerance in comparison with Hypogymnia, suggesting that could be useful for long-term biomonitoring.

Identifying artificial selection signals in the chicken genome.

PubMed

Ma, Yunlong; Gu, Lantao; Yang, Liubin; Sun, Chenghao; Xie, Shengsong; Fang, Chengchi; Gong, Yangzhang; Li, Shijun

2018-01-01

Identifying the signals of artificial selection can contribute to further shaping economically important traits. Here, a chicken 600k SNP-array was employed to detect the signals of artificial selection using 331 individuals from 9 breeds, including Jingfen (JF), Jinghong (JH), Araucanas (AR), White Leghorn (WL), Pekin-Bantam (PB), Shamo (SH), Gallus-Gallus-Spadiceus (GA), Rheinlander (RH) and Vorwerkhuhn (VO). Per the population genetic structure, 9 breeds were combined into 5 breed-pools, and a 'two-step' strategy was used to reveal the signals of artificial selection. GA, which has little artificial selection, was defined as the reference population, and a total of 204, 155, 305 and 323 potential artificial selection signals were identified in AR_VO, PB, RH_WL and JH_JF, respectively. We also found signals derived from standing and de-novo genetic variations have contributed to adaptive evolution during artificial selection. Further enrichment analysis suggests that the genomic regions of artificial selection signals harbour genes, including THSR, PTHLH and PMCH, responsible for economic traits, such as fertility, growth and immunization. Overall, this study found a series of genes that contribute to the improvement of chicken breeds and revealed the genetic mechanisms of adaptive evolution, which can be used as fundamental information in future chicken functional genomics study.

Modulation of Androgen Receptor Signaling in Hormonal Therapy-Resistant Prostate Cancer Cell Lines

PubMed Central

Marques, Rute B.; Dits, Natasja F.; Erkens-Schulze, Sigrun; van IJcken, Wilfred F. J.; van Weerden, Wytske M.; Jenster, Guido

2011-01-01

Background Prostate epithelial cells depend on androgens for survival and function. In (early) prostate cancer (PCa) androgens also regulate tumor growth, which is exploited by hormonal therapies in metastatic disease. The aim of the present study was to characterize the androgen receptor (AR) response in hormonal therapy-resistant PC346 cells and identify potential disease markers. Methodology/Principal Findings Human 19K oligoarrays were used to establish the androgen-regulated expression profile of androgen-responsive PC346C cells and its derivative therapy-resistant sublines: PC346DCC (vestigial AR levels), PC346Flu1 (AR overexpression) and PC346Flu2 (T877A AR mutation). In total, 107 transcripts were differentially-expressed in PC346C and derivatives after R1881 or hydroxyflutamide stimulations. The AR-regulated expression profiles reflected the AR modifications of respective therapy-resistant sublines: AR overexpression resulted in stronger and broader transcriptional response to R1881 stimulation, AR down-regulation correlated with deficient response of AR-target genes and the T877A mutation resulted in transcriptional response to both R1881 and hydroxyflutamide. This AR-target signature was linked to multiple publicly available cell line and tumor derived PCa databases, revealing that distinct functional clusters were differentially modulated during PCa progression. Differentiation and secretory functions were up-regulated in primary PCa but repressed in metastasis, whereas proliferation, cytoskeletal remodeling and adhesion were overexpressed in metastasis. Finally, the androgen-regulated genes ENDOD1, MCCC2 and ACSL3 were selected as potential disease markers for RT-PCR quantification in a distinct set of human prostate specimens. ENDOD1 and ACSL3 showed down-regulation in high-grade and metastatic PCa, while MCCC2 was overexpressed in low-grade PCa. Conclusions/Significance AR modifications altered the transcriptional response to (anti)androgens in therapy-resistant cells. Furthermore, selective down-regulation of genes involved in differentiation and up-regulation of genes promoting proliferation and invasion suggest a disturbed balance between the growth and differentiation functions of the AR pathway during PCa progression. These findings may have implications in the current treatment and development of novel therapeutical approaches for metastatic PCa. PMID:21829708

Androgen receptor stimulates bone sialoprotein (BSP) gene transcription via cAMP response element and activator protein 1/glucocorticoid response elements.

PubMed

Takai, Hideki; Nakayama, Youhei; Kim, Dong-Soon; Arai, Masato; Araki, Shouta; Mezawa, Masaru; Nakajima, Yu; Kato, Naoko; Masunaga, Hiroshi; Ogata, Yorimasa

2007-09-01

Bone sialoprotein (BSP) is an early marker of osteoblast differentiation. Androgens are steroid hormones that are essential for skeletal development. The androgen receptor (AR) is a transcription factor and a member of the steroid receptor superfamily that plays an important role in male sexual differentiation and prostate cell proliferation. To determine the molecular mechanism involved in the stimulation of bone formation, we have analyzed the effects of androgens and AR effects on BSP gene transcription. AR protein levels were increased after AR overexpression in ROS17/2.8 cells. BSP mRNA levels were increased by AR overexpression. However, the endogenous and overexpressed BSP mRNA levels were not changed by DHT (10(-8) M, 24 h). Whereas luciferase (LUC) activities in all constructs, including a short construct (nts -116 to +60), were increased by AR overexpression, the basal and LUC activities enhanced by AR overexpression were not induced by DHT (10(-8)M, 24 h). The effect of AR overexpression was abrogated by 2 bp mutations in either the cAMP response element (CRE) or activator protein 1 (AP1)/glucocorticoid response element (GRE). Gel shift analyses showed that AR overexpression increased binding to the CRE and AP1/GRE elements. Notably, the CRE-protein complexes were supershifted by phospho-CREB antibody, and CREB, c-Fos, c-Jun, and AR antibodies disrupted the complexes formation. The AP1/GRE-protein complexes were supershifted by c-Fos antibody and c-Jun, and AR antibodies disrupted the complexes formation. These studies demonstrate that AR stimulates BSP gene transcription by targeting the CRE and AP1/GRE elements in the promoter of the rat BSP gene.

Langerhans cells beta 2-adrenoceptors: role in migration, cytokine production, Th priming and contact hypersensitivity.

PubMed

Maestroni, Georges J M; Mazzola, Paola

2003-11-01

We showed that norepinephrine (NE) hampers IL-12 and stimulates IL-10 production via adrenoceptors (ARs) in bone marrow-derived dendritic cells (BMDC) influencing their Th priming ability. Others have shown that Langerhans cells (LC) express mRNA for beta1-, beta2- and alpha1(A)-(ARs) and that catecholamines may inhibit the antigen-presenting capability via beta2-ARs. Here, we show that also BMDC express mRNA for beta1-, beta2-, alpha2(A)- and alpha2(C)-ARs. Inhibition of IL-12 is mediated by both beta2- and alpha2(A)-ARs, while stimulation of IL-10 by beta2-ARs only. In addition, LC migration, the contact hypersensitivity response (CHS) and production of IFN-gamma and IL-2 in draining lymph node cells is increased in mice treated topically with the beta2-AR antagonist ICI 118,551 during FITC sensitization. Activation of beta2-ARs in BMDC before adoptive transfer could reduce both migration and CHS response to FITC. Finally, preincubation of BMDC with LPS in presence of the specific beta2-AR agonist salbutamol impaired their chemotactic response to CCL19 and CCL21 and this effect was neutralized by anti-IL-10 mAb. We suggest that the physiological activation of beta2-ARs in DC (LC) results in stimulation of IL-10 which in turn restrains DC (LC) migration influencing antigen presentation and the consequent CHS response.

A modified impulse-response representation of the global near-surface air temperature and atmospheric concentration response to carbon dioxide emissions

NASA Astrophysics Data System (ADS)

Millar, Richard J.; Nicholls, Zebedee R.; Friedlingstein, Pierre; Allen, Myles R.

2017-06-01

Projections of the response to anthropogenic emission scenarios, evaluation of some greenhouse gas metrics, and estimates of the social cost of carbon often require a simple model that links emissions of carbon dioxide (CO2) to atmospheric concentrations and global temperature changes. An essential requirement of such a model is to reproduce typical global surface temperature and atmospheric CO2 responses displayed by more complex Earth system models (ESMs) under a range of emission scenarios, as well as an ability to sample the range of ESM response in a transparent, accessible and reproducible form. Here we adapt the simple model of the Intergovernmental Panel on Climate Change 5th Assessment Report (IPCC AR5) to explicitly represent the state dependence of the CO2 airborne fraction. Our adapted model (FAIR) reproduces the range of behaviour shown in full and intermediate complexity ESMs under several idealised carbon pulse and exponential concentration increase experiments. We find that the inclusion of a linear increase in 100-year integrated airborne fraction with cumulative carbon uptake and global temperature change substantially improves the representation of the response of the climate system to CO2 on a range of timescales and under a range of experimental designs.

Directing driver attention with augmented reality cues

PubMed Central

Rusch, Michelle L.; Schall, Mark C.; Gavin, Patrick; Lee, John D.; Dawson, Jeffrey D.; Vecera, Shaun; Rizzo, Matthew

2013-01-01

This simulator study evaluated the effects of augmented reality (AR) cues designed to direct the attention of experienced drivers to roadside hazards. Twenty-seven healthy middle-aged licensed drivers with a range of attention capacity participated in a 54 mile (1.5 hour) drive in an interactive fixed-base driving simulator. Each participant received AR cues to potential roadside hazards in six simulated straight (9 mile long) rural roadway segments. Drivers were evaluated on response time for detecting a potentially hazardous event, detection accuracy for target (hazard) and non-target objects, and headway with respect to the hazards. Results showed no negative outcomes associated with interference. AR cues did not impair perception of non-target objects, including for drivers with lower attentional capacity. Results showed near significant response time benefits for AR cued hazards. AR cueing increased response rate for detecting pedestrians and warning signs but not vehicles. AR system false alarms and misses did not impair driver responses to potential hazards. PMID:24436635

Human Lung Cancer Risks from Radon – Part III - Evidence of Influence of Combined Bystander and Adaptive Response Effects on Radon Case-Control Studies - A Microdose Analysis

PubMed Central

Leonard, Bobby E.; Thompson, Richard E.; Beecher, Georgia C.

2012-01-01

Since the publication of the BEIR VI (1999) report on health risks from radon, a significant amount of new data has been published showing various mechanisms that may affect the ultimate assessment of radon as a carcinogen, in particular the potentially deleterious Bystander Effect (BE) and the potentially beneficial Adaptive Response radio-protection (AR). The case-control radon lung cancer risk data of the pooled 13 European countries radon study (Darby et al 2005, 2006) and the 8 North American pooled study (Krewski et al 2005, 2006) have been evaluated. The large variation in the odds ratios of lung cancer from radon risk is reconciled, based on the large variation in geological and ecological conditions and variation in the degree of adaptive response radio-protection against the bystander effect induced lung damage. The analysis clearly shows Bystander Effect radon lung cancer induction and Adaptive Response reduction in lung cancer in some geographical regions. It is estimated that for radon levels up to about 400 Bq m−3 there is about a 30% probability that no human lung cancer risk from radon will be experienced and a 20% probability that the risk is below the zero-radon, endogenic spontaneous or perhaps even genetically inheritable lung cancer risk rate. The BEIR VI (1999) and EPA (2003) estimates of human lung cancer deaths from radon are most likely significantly excessive. The assumption of linearity of risk, by the Linear No-Threshold Model, with increasing radon exposure is invalid. PMID:22942874

Enemy at the gates: Rapid defensive trait diversification in an adaptive radiation of lizards.

PubMed

Broeckhoven, Chris; Diedericks, Genevieve; Hui, Cang; Makhubo, Buyisile G; Mouton, P le Fras N

2016-11-01

Adaptive radiation (AR), the product of rapid diversification of an ancestral species into novel adaptive zones, has become pivotal in our understanding of biodiversity. Although it has widely been accepted that predators may drive the process of AR by creating ecological opportunity (e.g., enemy-free space), the role of predators as selective agents in defensive trait diversification remains controversial. Using phylogenetic comparative methods, we provide evidence for an "early burst" in the diversification of antipredator phenotypes in Cordylinae, a relatively small AR of morphologically diverse southern African lizards. The evolution of body armor appears to have been initially rapid, but slowed down over time, consistent with the ecological niche-filling model. We suggest that the observed "early burst" pattern could be attributed to shifts in vulnerability to different types of predators (i.e., aerial versus terrestrial) associated with thermal habitat partitioning. These results provide empirical evidence supporting the hypothesis that predators or the interaction therewith might be key components of ecological opportunity, although the way in which predators influence morphological diversification requires further study. © 2016 The Author(s). Evolution © 2016 The Society for the Study of Evolution.

Determine the Dynamic Response to Androgen-Blockade Therapy in Circulating Tumor Cells of CRPC Patients by Transcription-Based Reporter Vectors

DTIC Science & Technology

2016-08-01

green fluorescent reporter gene. Specific Aim 2: To evaluate the functional capability of Ad-mediated CTC detection and the response to AR...6 Specific Aim 3: To evaluate the therapeutic responses to AR antagonists in CTCs of CRPC patients before, during and after AR blockade...A., Mali, A., Khirade, M. & Bapat, S. A tumor deconstruction platform identifies definitive end points in the evaluation of drug responses. Oncogene

Hydrological time series modeling: A comparison between adaptive neuro-fuzzy, neural network and autoregressive techniques

NASA Astrophysics Data System (ADS)

Lohani, A. K.; Kumar, Rakesh; Singh, R. D.

2012-06-01

SummaryTime series modeling is necessary for the planning and management of reservoirs. More recently, the soft computing techniques have been used in hydrological modeling and forecasting. In this study, the potential of artificial neural networks and neuro-fuzzy system in monthly reservoir inflow forecasting are examined by developing and comparing monthly reservoir inflow prediction models, based on autoregressive (AR), artificial neural networks (ANNs) and adaptive neural-based fuzzy inference system (ANFIS). To take care the effect of monthly periodicity in the flow data, cyclic terms are also included in the ANN and ANFIS models. Working with time series flow data of the Sutlej River at Bhakra Dam, India, several ANN and adaptive neuro-fuzzy models are trained with different input vectors. To evaluate the performance of the selected ANN and adaptive neural fuzzy inference system (ANFIS) models, comparison is made with the autoregressive (AR) models. The ANFIS model trained with the input data vector including previous inflows and cyclic terms of monthly periodicity has shown a significant improvement in the forecast accuracy in comparison with the ANFIS models trained with the input vectors considering only previous inflows. In all cases ANFIS gives more accurate forecast than the AR and ANN models. The proposed ANFIS model coupled with the cyclic terms is shown to provide better representation of the monthly inflow forecasting for planning and operation of reservoir.

Confinement of β1- and β2-adrenergic receptors in the plasma membrane of cardiomyocyte-like H9c2 cells is mediated by selective interactions with PDZ domain and A-kinase anchoring proteins but not caveolae

PubMed Central

Valentine, Cathleen D.; Haggie, Peter M.

2011-01-01

The sympathetic nervous system regulates cardiac output by activating adrenergic receptors (ARs) in cardiac myocytes. The predominant cardiac ARs, β1- and β2AR, are structurally similar but mediate distinct signaling responses. Scaffold protein–mediated compartmentalization of ARs into discrete, multiprotein complexes has been proposed to dictate differential signaling responses. To test the hypothesis that βARs integrate into complexes in live cells, we measured receptor diffusion and interactions by single-particle tracking. Unstimulated β1- and β2AR were highly confined in the membrane of H9c2 cardiomyocyte-like cells, indicating that receptors are tethered and presumably integrated into protein complexes. Selective disruption of interactions with postsynaptic density protein 95/disks large/zonula occludens-1 (PDZ)–domain proteins and A-kinase anchoring proteins (AKAPs) increased receptor diffusion, indicating that these scaffold proteins participate in receptor confinement. In contrast, modulation of interactions between the putative scaffold caveolae and β2AR did not alter receptor dynamics, suggesting that these membrane domains are not involved in β2AR confinement. For both β1- and β2AR, the receptor carboxy-terminus was uniquely responsible for scaffold interactions. Our data formally demonstrate that distinct and stable protein complexes containing β1- or β2AR are formed in the plasma membrane of cardiomyocyte-like cells and that selective PDZ and AKAP interactions are responsible for the integration of receptors into complexes. PMID:21680711

Confinement of β(1)- and β(2)-adrenergic receptors in the plasma membrane of cardiomyocyte-like H9c2 cells is mediated by selective interactions with PDZ domain and A-kinase anchoring proteins but not caveolae.

PubMed

Valentine, Cathleen D; Haggie, Peter M

2011-08-15

The sympathetic nervous system regulates cardiac output by activating adrenergic receptors (ARs) in cardiac myocytes. The predominant cardiac ARs, β(1)- and β(2)AR, are structurally similar but mediate distinct signaling responses. Scaffold protein-mediated compartmentalization of ARs into discrete, multiprotein complexes has been proposed to dictate differential signaling responses. To test the hypothesis that βARs integrate into complexes in live cells, we measured receptor diffusion and interactions by single-particle tracking. Unstimulated β(1)- and β(2)AR were highly confined in the membrane of H9c2 cardiomyocyte-like cells, indicating that receptors are tethered and presumably integrated into protein complexes. Selective disruption of interactions with postsynaptic density protein 95/disks large/zonula occludens-1 (PDZ)-domain proteins and A-kinase anchoring proteins (AKAPs) increased receptor diffusion, indicating that these scaffold proteins participate in receptor confinement. In contrast, modulation of interactions between the putative scaffold caveolae and β(2)AR did not alter receptor dynamics, suggesting that these membrane domains are not involved in β(2)AR confinement. For both β(1)- and β(2)AR, the receptor carboxy-terminus was uniquely responsible for scaffold interactions. Our data formally demonstrate that distinct and stable protein complexes containing β(1)- or β(2)AR are formed in the plasma membrane of cardiomyocyte-like cells and that selective PDZ and AKAP interactions are responsible for the integration of receptors into complexes.

Enhanced tubuloglomerular feedback in mice with vascular overexpression of A1 adenosine receptors

PubMed Central

Oppermann, Mona; Qin, Yan; Lai, En Yin; Eisner, Christoph; Li, Lingli; Huang, Yuning; Mizel, Diane; Fryc, Justyna; Wilcox, Christopher S.; Briggs, Josephine; Schnermann, Jurgen

2009-01-01

Adenosine 1 receptors (A1AR) in the kidney are expressed in the vasculature and the tubular system. Pharmacological inhibition or global genetic deletion of A1AR causes marked reductions or abolishment of tubuloglomerular feedback (TGF) responses. To assess the function of vascular A1AR in TGF, we generated transgenic mouse lines in which A1AR expression in smooth muscle was augmented by placing A1AR under the control of a 5.38-kb fragment of the rat smooth muscle α-actin promoter and first intron (12). Two founder lines with highest expression in the kidney [353 ± 42 and 575 ± 43% compared with the wild type (WT)] were used in the experiments. Enhanced expression of A1AR at the expected site in these lines was confirmed by augmented constrictor responses of isolated afferent arterioles to administration of the A1AR agonist N6-cyclohexyladenosine. Maximum TGF responses (0–30 nl/min flow step) were increased from 8.4 ± 0.9 mmHg in WT (n = 21) to 14.2 ± 0.7 mmHg in A1AR-transgene (tg) 4 (n = 22; P < 0.0001), and to 12.6 ± 1.2 mmHg in A1AR-tg7 (n = 12; P < 0.02). Stepwise changes in perfusion flow caused greater numerical TGF responses in A1AR-tg than WT in all flow ranges with differences reaching levels of significance in the intermediate flow ranges of 7.5–10 and 10–15 nl/min. Proximal-distal single-nephron glomerular filtration rate (SNGFR) differences (free-flow micropuncture) were also increased in A1AR-tg, averaging 6.25 ± 1.5 nl/min compared with 2.6 ± 0.51 nl/min in WT (P = 0.034). Basal plasma renin concentrations as well as the suppression of renin secretion after volume expansion were similar in A1AR-tg and WT mice, suggesting lack of transgene expression in juxtaglomerular cells. These data indicate that A1AR expression in vascular smooth muscle cells is a critical component for TGF signaling and that changes in renal vascular A1AR expression may determine the magnitude of TGF responses. PMID:19741017

An iteratively reweighted least-squares approach to adaptive robust adjustment of parameters in linear regression models with autoregressive and t-distributed deviations

NASA Astrophysics Data System (ADS)

Kargoll, Boris; Omidalizarandi, Mohammad; Loth, Ina; Paffenholz, Jens-André; Alkhatib, Hamza

2018-03-01

In this paper, we investigate a linear regression time series model of possibly outlier-afflicted observations and autocorrelated random deviations. This colored noise is represented by a covariance-stationary autoregressive (AR) process, in which the independent error components follow a scaled (Student's) t-distribution. This error model allows for the stochastic modeling of multiple outliers and for an adaptive robust maximum likelihood (ML) estimation of the unknown regression and AR coefficients, the scale parameter, and the degree of freedom of the t-distribution. This approach is meant to be an extension of known estimators, which tend to focus only on the regression model, or on the AR error model, or on normally distributed errors. For the purpose of ML estimation, we derive an expectation conditional maximization either algorithm, which leads to an easy-to-implement version of iteratively reweighted least squares. The estimation performance of the algorithm is evaluated via Monte Carlo simulations for a Fourier as well as a spline model in connection with AR colored noise models of different orders and with three different sampling distributions generating the white noise components. We apply the algorithm to a vibration dataset recorded by a high-accuracy, single-axis accelerometer, focusing on the evaluation of the estimated AR colored noise model.

Coral Calcification Across a Natural Gradient in Ocean Acidification

NASA Astrophysics Data System (ADS)

Cohen, A. L.; Brainard, R. E.; Young, C.; Shamberger, K. E.; McCorkle, D. C.; Feely, R. A.; Mcleod, E.; Cantin, N.; Rose, K.; Lohmann, G. P.

2011-12-01

Much of our understanding of the impact of ocean acidification on coral calcification comes from laboratory manipulation experiments in which corals are reared under a range of seawater pH and aragonite saturation states (μar) equivalent to those projected for the next hundred years. In general, experiments show a consistently negative impact of acidification on coral calcification, leading to predictions of mass coral reef extinctions by dissolution as natural rates of carbonate erosion exceed the rates at which corals and other reef calcifiers can replace it. The tropical oceans provide a natural laboratory within which to test hypotheses about the longer term impact and adaptive potential of corals to acidification of the reef environment. Here we report results of a study in which 3-D CT scan and imaging techniques were used to quantify annual rates of calcification by conspecifics at 12 reefs sites spanning a natural gradient in ocean acidification. In situ μar calculated from alkalinity and DIC measurements of reef seawater ranged from less than 2.7 on an eastern Pacific Reef to greater than 4.0 in the central Red Sea. No correlation between μar and calcification was observed across this range. Corals living on low μar reefs appear to be calcifying as fast, sometimes faster than conspecifics living on high μar reefs. We used total lipid and tissue thickness to index the energetic status of colonies collected at each of our study sites. Our results support the hypothesis that energetics plays a key role in the coral calcification response to ocean acidification. Indeed, the true impact of acidification on coral reefs will likely be felt as temperatures rise and the ocean becomes more stratified, depleting coral energetic reserves through bleaching and reduced nutrient delivery to oceanic reefs.

Relationship between serum response factor and androgen receptor in prostate cancer.

PubMed

Prencipe, Maria; O'Neill, Amanda; O'Hurley, Gillian; Nguyen, Lan K; Fabre, Aurelie; Bjartell, Anders; Gallagher, William M; Morrissey, Colm; Kay, Elaine W; Watson, R William

2015-11-01

Serum response factor (SRF) is an important transcription factor in castrate-resistant prostate cancer (CRPC). Since CRPC is associated with androgen receptor (AR) hypersensitivity, we investigated the relationship between SRF and AR. Transcriptional activity was assessed by luciferase assay. Cell proliferation was measured by MTT and flow cytometry. Protein expression in patients was assessed by immunohistochemistry. To investigate AR involvement in SRF response to androgen, AR expression was down-regulated using siRNA. This resulted in the abrogation of SRF induction post-DHT. Moreover, DHT stimulation failed to induce SRF transcriptional activity in AR-negative PC346 DCC cells, which was only restored following AR over-expression. Next, SRF expression was down-regulated by siRNA, resulting in AR increased transcriptional activity in castrate-resistant LNCaP Abl cells but not in the parental LNCaP. This negative feedback loop in the resistant cells was confirmed by immunohistochemistry which showed a negative correlation between AR and SRF expression in CRPC bone metastases and a positive correlation in androgen-naïve prostatectomies. Cell proliferation was next assessed following SRF inhibition, demonstrating that SRF inhibition is more effective than AR inhibition in castrate-resistant cells. Our data support SRF as a promising therapeutic target in combination with current treatments. © 2015 Wiley Periodicals, Inc.

5-HT1A Receptors on Mature Dentate Gyrus Granule Cells are Critical for the Antidepressant Response

PubMed Central

Samuels, Benjamin Adam; Anacker, Christoph; Hu, Alice; Levinstein, Marjorie R.; Pickenhagen, Anouchka; Tsetsenis, Theodore; Madroñal, Noelia; Donaldson, Zoe R.; Drew, Liam John; Dranovsky, Alex; Gross, Cornelius T.; Tanaka, Kenji F.; Hen, René

2015-01-01

Selective serotonin reuptake inhibitors (SSRIs) are widely used antidepressants, but the mechanisms by which they influence behavior are only partially resolved. Adult hippocampal neurogenesis is necessary for some of the responses to SSRIs, but it is unknown whether the mature dentate gyrus granule cells (mature DG GCs) also contribute. We deleted Serotonin 1A receptor (5HT1AR; a receptor required for the SSRI response) specifically from DG GCs and found that the effects of the SSRI fluoxetine on behavior and the Hypothalamic-Pituitary-Adrenal (HPA) axis were abolished. By contrast, mice lacking 5HT1ARs only in young adult born granule cells (abGCs) showed normal fluoxetine responses. Importantly, 5HT1AR deficient mice engineered to express functional 5HT1ARs only in DG GCs responded to fluoxetine, indicating that 5HT1ARs in DG GCs are sufficient to mediate an antidepressant response. Taken together, these data indicate that both mature DG GCs and young abGCs must be engaged for an antidepressant response. PMID:26389840

Atypical antibody responses in dengue vaccine recipients.

PubMed

Kanesa-Thasan, N; Sun, W; Ludwig, G V; Rossi, C; Putnak, J R; Mangiafico, J A; Innis, B L; Edelman, R

2003-12-01

Eight of 69 (12%) healthy adult volunteers vaccinated with monovalent live-attenuated dengue virus (DENV) vaccine candidates had atypical antibody responses, with depressed IgM:IgG antibody ratios and induction of high-titer hemagglutination-inhibiting and neutralizing (NT) antibodies to all four DENV serotypes. These features suggested flavivirus exposure prior to DENV vaccination, yet no volunteer had a history of previous flavivirus infection, flavivirus vaccination, or antibody to flaviviruses evident before DENV vaccination. Moreover, production of antibody to DENV by atypical responders (AR) was not accelerated compared with antibody responses in the 61 flavivirus-naive responders (NR). Further evaluation revealed no differences in sex, age, race, DENV vaccine candidate received, or clinical signs and symptoms following vaccination between AR and NR. However, viremia was delayed at the onset in AR compared with NR. A comparative panel of all AR and five randomly selected NR found flavivirus cross-reactive antibody after vaccination only in AR. Unexpectedly, six of eight AR had NT antibodies to yellow fever virus (YFV) > 1:10 before vaccination while NR had none (P = 0.04). The AR also universally demonstrated YFV NT antibody titers > or = 1:160 after DENV vaccination, whereas four of five NR failed to seroconvert (P = 0.02). Yellow fever virus priming broadens the antibody response to monovalent DENV vaccination. The effect of flavivirus priming on the clinical and immunologic response to tetravalent DENV vaccine remains to be determined.

Action Research and Response to Intervention: Bridging the Discourse Divide

ERIC Educational Resources Information Center

Little, Mary E.

2012-01-01

The purpose of this article is to define and clarify the process of instructional problem-solving using assessment data within action research (AR) and Response to Intervention (RtI). Similarities between AR and RtI are defined and compared. Lastly, specific resources and examples of the instructional problem-solving process of AR within…

Aggravation of airway inflammation and hyper-responsiveness following nasal challenge with Dermatophagoides pteronyssinus in perennial allergic rhinitis without symptoms of asthma.

PubMed

Wang, W; Xian, M; Xie, Y; Zheng, J; Li, J

2016-03-01

House dust mites are the most prevalent allergen causing sensitizations in patients with rhinitis and asthma in China. We aimed to investigate the changes in both upper and lower airway inflammation and responsiveness following Dermatophagoides pteronyssinus (Der-p) nasal provocation test (NPT) in rhinitis patients. Study subjects included 15 nonasthmatic Der-p-sensitized rhinitis (AR) patients with airway hyper-responsiveness (AHR) (AR+AHR+), 15 AR patients without AHR (AR+AHR-), 15 healthy controls (HCs) with Der-p sensitization (HC+DP+), and 15 HC without Der-p sensitization (HC+DP-). All subjects underwent Der-p NPT. Visual analogue scale (VAS) scores of nasal symptoms, nasal lavage and nasal airway resistance (NAR) measurement, sputum induction, and forced expiratory volume in 1 second (FEV1 ) were performed. Airway responsiveness to histamine bronchoprovocation (PD20 -FEV1 ) and exhaled nitric oxide (FeNO) was determined. NAR increased significantly in all subjects with the greatest effect seen in AR+AHR+ individuals. VAS increased in all subjects at 30 min and returned to baseline at 6 h, with significantly higher levels in AR+AHR+ and AR+AHR- subjects (P < 0.05). Eosinophils in nasal lavage fluid and sputum increased significantly after NPT in AR+AHR+ and AR+AHR- subjects (P < 0.001). FEV1 % and PD20 -FEV1 decreased and FeNO increased significantly after NPT only in AR+AHR+ subjects (P < 0.05). Nasal lavage eosinophil count was positively correlated with sputum eosinophil count and the level of FeNO and negatively correlated with FEV1 and PD20 . House dust mite nasal provocation test induces and aggravates both upper and lower airway inflammation and hyper-responsiveness in patients with persistent allergic rhinitis without asthmatic symptoms. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Antigen specific suppression of humoral immunity by anergic Ars/A1 B cells1

PubMed Central

Aviszus, Katja; MacLeod, Megan K.L.; Kirchenbaum, Greg A.; Detanico, Thiago O.; Heiser, Ryan A.; St. Clair, James B.; Guo, Wenzhong; Wysocki, Lawrence J.

2012-01-01

Autoreactive anergic B lymphocytes are considered to be dangerous because of their potential for activation and recruitment into autoimmune responses. Yet they persist for days and constitute ~5% of the B cell pool. We assessed their functional potential in the Ars/A1 transgene model, where anergic B cells express a dual-reactive antigen receptor that binds, in addition to a self-antigen, the hapten p-azophenylarsonate (Ars). When Ars/A1 B cells were transferred into adoptive recipients that were immunized with foreign proteins covalently conjugated with Ars, endogenous IgG immune responses to both were selectively and severely diminished, and the development of T helper cells was impaired. Approximately 95% inhibition of the anti-Ars response was attained with ~4000 transferred Ars/A1 B cells through redundant mechanisms, one of which depended upon their expression of MHC II but not upon secretion of IL-10 or IgM. This antigen-specific suppressive activity implicates the autoreactive anergic B cell as an enforcer of immunological tolerance to self-antigens. PMID:23008448

Antigen-specific suppression of humoral immunity by anergic Ars/A1 B cells.

PubMed

Aviszus, Katja; Macleod, Megan K L; Kirchenbaum, Greg A; Detanico, Thiago O; Heiser, Ryan A; St Clair, James B; Guo, Wenzhong; Wysocki, Lawrence J

2012-11-01

Autoreactive anergic B lymphocytes are considered to be dangerous because of their potential for activation and recruitment into autoimmune responses. However, they persist for days and constitute ∼5% of the B cell pool. We assessed their functional potential in the Ars/A1 transgene model, where anergic B cells express a dual-reactive Ag receptor that binds, in addition to a self-Ag, the hapten p-azophenylarsonate (Ars). When Ars/A1 B cells were transferred into adoptive recipients that were immunized with foreign proteins covalently conjugated with Ars, endogenous IgG immune responses to both were selectively and severely diminished, and the development of T helper cells was impaired. Approximately 95% inhibition of the anti-Ars response was attained with ∼4000 transferred Ars/A1 B cells through redundant mechanisms, one of which depended on their expression of MHC class II but not upon secretion of IL-10 or IgM. This Ag-specific suppressive activity implicates the autoreactive anergic B cell as an enforcer of immunological tolerance to self-Ags.

Using an audience response system (ARS) in a face-to-face and distance education CPT/HCPCS coding course.

PubMed

Harris, Susie T; Zeng, Xiaoming

2010-01-01

We report the use of an audience response system (ARS) in an undergraduate health information management course. The ARS converts a standard PowerPoint presentation into an interactive learning system that engages students in active participation, and it allows instructors to display questions, surveys, opinion polls, and games. We used the ARS in a 2008 course, Health Services Coding, for lecture and test reviews. The class consisted of 15 students; nine were on-campus students and six were distance education students. All of the responding students agreed that the ARS software facilitated learning and made lectures and reviews more interesting and interactive, and they preferred taking a class using an ARS.

The Chromobacterium violaceum ArsR Arsenite Repressor Exerts Tighter Control on Its Cognate Promoter Than the Escherichia coli System

PubMed Central

Arruda, Letícia M.; Monteiro, Lummy M. O.; Silva-Rocha, Rafael

2016-01-01

Environmental bacteria are endowed with several regulatory systems that have potential applications in biotechnology. In this report, we characterize the arsenic biosensing features of the ars response system from Chromobacterium violaceum in the heterologous host Escherichia coli. We show that the native Pars/arsR system of C. violaceum outperforms the chromosomal ars copy of E. coli when exposed to micromolar concentrations of arsenite. To understand the molecular basis of this phenomenon, we analyzed the interaction between ArsR regulators and their promoter target sites as well as induction of the system at saturating concentrations of the regulators. In vivo titration experiments indicate that ArsR from C. violaceum has stronger binding affinity for its target promoter than the regulator from E. coli does. Additionally, arsenite induction experiments at saturating regulator concentration demonstrates that although the Pars/arsR system from E. coli displays a gradual response to increasing concentration of the inducer, the system from C. violaceum has a steeper response with a stronger promoter induction after a given arsenite threshold. Taken together, these data demonstrate the characterization of a novel arsenic response element from an environmental bacterium with potentially enhanced performance that could be further explored for the construction of an arsenic biosensor. PMID:27917165

The Chromobacterium violaceum ArsR Arsenite Repressor Exerts Tighter Control on Its Cognate Promoter Than the Escherichia coli System.

PubMed

Arruda, Letícia M; Monteiro, Lummy M O; Silva-Rocha, Rafael

2016-01-01

Environmental bacteria are endowed with several regulatory systems that have potential applications in biotechnology. In this report, we characterize the arsenic biosensing features of the ars response system from Chromobacterium violaceum in the heterologous host Escherichia coli . We show that the native Pars/arsR system of C. violaceum outperforms the chromosomal ars copy of E. coli when exposed to micromolar concentrations of arsenite. To understand the molecular basis of this phenomenon, we analyzed the interaction between ArsR regulators and their promoter target sites as well as induction of the system at saturating concentrations of the regulators. In vivo titration experiments indicate that ArsR from C. violaceum has stronger binding affinity for its target promoter than the regulator from E. coli does. Additionally, arsenite induction experiments at saturating regulator concentration demonstrates that although the Pars/arsR system from E. coli displays a gradual response to increasing concentration of the inducer, the system from C. violaceum has a steeper response with a stronger promoter induction after a given arsenite threshold. Taken together, these data demonstrate the characterization of a novel arsenic response element from an environmental bacterium with potentially enhanced performance that could be further explored for the construction of an arsenic biosensor.

ArF halftone PSM cleaning process optimization for next-generation lithography

NASA Astrophysics Data System (ADS)

Son, Yong-Seok; Jeong, Seong-Ho; Kim, Jeong-Bae; Kim, Hong-Seok

2000-07-01

ArF lithography which is expected for the next generation optical lithography is adapted for 0.13 micrometers design-rule and beyond. ArF half-tone phase shift mask (HT PSM) will be applied as 1st generation of ArF lithography. Also ArF PSM cleaning demands by means of tighter controls related to phase angle, transmittance and contamination on the masks. Phase angle on ArF HT PSM should be controlled within at least +/- 3 degree and transmittance controlled within at least +/- 3 percent after cleaning process and pelliclization. In the cleaning process of HT PSM, requires not only the remove the particle on mask, but also control to half-tone material for metamorphosis. Contamination defects on the Qz of half tone type PSM is not easy to remove on the photomask surface. New technology and methods of cleaning will be developed in near future, but we try to get out for limit contamination on the mask, without variation of phase angle and transmittance after cleaning process.

Repeatability of Sugarcane Selection on Sand and Organic Soils

USDA-ARS?s Scientific Manuscript database

The Canal Point (CP) Sugarcane Cultivar Development Program (a cooperative program between the USDA-ARS, the University of Florida and the Florida Sugarcane League) has been more successful at breeding for cultivars adapted to organic soils (muck) than for those adapted to sand soils. Currently, onl...

The tomato mutant ars1 (altered response to salt stress 1) identifies an R1-type MYB transcription factor involved in stomatal closure under salt acclimation.

PubMed

Campos, Juan F; Cara, Beatriz; Pérez-Martín, Fernando; Pineda, Benito; Egea, Isabel; Flores, Francisco B; Fernandez-Garcia, Nieves; Capel, Juan; Moreno, Vicente; Angosto, Trinidad; Lozano, Rafael; Bolarin, Maria C

2016-06-01

A screening under salt stress conditions of a T-DNA mutant collection of tomato (Solanum lycopersicum L.) led to the identification of the altered response to salt stress 1 (ars1) mutant, which showed a salt-sensitive phenotype. Genetic analysis of the ars1 mutation revealed that a single T-DNA insertion in the ARS1 gene was responsible of the mutant phenotype. ARS1 coded for an R1-MYB type transcription factor and its expression was induced by salinity in leaves. The mutant reduced fruit yield under salt acclimation while in the absence of stress the disruption of ARS1 did not affect this agronomic trait. The stomatal behaviour of ars1 mutant leaves induced higher Na(+) accumulation via the transpiration stream, as the decreases of stomatal conductance and transpiration rate induced by salt stress were markedly lower in the mutant plants. Moreover, the mutation affected stomatal closure in a response mediated by abscisic acid (ABA). The characterization of tomato transgenic lines silencing and overexpressing ARS1 corroborates the role of the gene in regulating the water loss via transpiration under salinity. Together, our results show that ARS1 tomato gene contributes to reduce transpirational water loss under salt stress. Finally, this gene could be interesting for tomato molecular breeding, because its manipulation could lead to improved stress tolerance without yield penalty under optimal culture conditions. © 2015 Society for Experimental Biology, Association of Applied Biologists and John Wiley & Sons Ltd.

Haemolytic activities and adjuvant effect of Anemone raddeana saponins (ARS) on the immune responses to ovalbumin in mice.

PubMed

Sun, Yongxu; Li, Mingquan; Liu, Jicheng

2008-08-01

In this study, saponins (ARS) extracted from the rhizoma of Anemone raddeana were evaluated for their haemolytic activities and its potential ability as adjuvant on the cellular and humoral immune responses of ICR mice against ovalbumin. The haemolytic activity of ARS was determined using 0.5% rabbit red blood cell. ARS showed a slight haemolytic effect, with its haemolytic percents being 16.50 and 3.56% at the concentrations of 500 and 250 microg/ml, respectively. ICR mice were immunized subcutaneously with OVA 100 microg alone or with OVA 100 mug dissolved in saline containing Alum (200 microg), QuilA (10 and 20 microg) or ARS (50, 100 or 200 microg) on Days 1 and 15. Two weeks later (Day 28), concanavalin A (Con A)-, lipopolysaccharide (LPS)- and OVA-stimulated splenocyte proliferation and OVA-specific antibodies in serum were measured. ARS significantly enhanced the Con A-, LPS-, and OVA-induced splenocyte proliferation in the OVA-immunized mice especially at a dose of 100 microg (P<0.01 or P<0.05). The OVA-specific IgG, IgG1 and IgG2b antibody levels in serum were also significantly enhanced by ARS compared with OVA control group (P<0.01 or P<0.05). Moreover, no significant differences (P>0.05) were observed between enhancing effect of ARS and QuilA on the OVA-specific IgG2b antibody responses to OVA in mice. The results suggest that ARS showed a slight haemolytic effect and enhanced significantly a specific antibody and cellular response against OVA in mice.

One-Carbon Metabolism in Prostate Cancer: The Role of Androgen Signaling

PubMed Central

Corbin, Joshua M.; Ruiz-Echevarría, Maria J.

2016-01-01

Cancer cell metabolism differs significantly from the metabolism of non-transformed cells. This altered metabolic reprogramming mediates changes in the uptake and use of nutrients that permit high rates of proliferation, growth, and survival. The androgen receptor (AR) plays an essential role in the establishment and progression of prostate cancer (PCa), and in the metabolic adaptation that takes place during this progression. In its role as a transcription factor, the AR directly affects the expression of several effectors and regulators of essential catabolic and biosynthetic pathways. Indirectly, as a modulator of the one-carbon metabolism, the AR can affect epigenetic processes, DNA metabolism, and redox balance, all of which are important factors in tumorigenesis. In this review, we focus on the role of AR-signaling on one-carbon metabolism in tumorigenesis. Clinical implications of one-carbon metabolism and AR-targeted therapies for PCa are discussed in this context. PMID:27472325

The effect of using an audience response system on learning, motivation and information retention in the orthodontic teaching of undergraduate dental students: a cross-over trial.

PubMed

Dhaliwal, Harmeet Kaur; Allen, Mark; Kang, Jing; Bates, Claire; Hodge, Trevor

2015-06-01

New methods of teaching and learning are constantly being sought in the adult learning environment. Audience Response Systems (ARS) have been used in many different learning environments, especially in the field of medical education. The objective of this investigation was to ascertain the effect of ARS use in undergraduate teaching in a UK dental school. A cross-over clustered randomized educational trial. Leeds Dental Institute. Year 4 undergraduate dental students in orthodontics. Students at Leeds Dental Institute were taught two different topics within the curriculum to test the use of ARS in a cross-over trial. A questionnaire was delivered to the test (ARS) and control (non-ARS) groups. The response rate to the questionnaires was 89·5% (test group) and 82·9% (control group). The ARS enabled students to perform better as shown by knowledge retention (P = 0·013). Students found the seminar more interesting (P = 0·013), easier to concentrate (P = 0·025) and easier to participate in (P = 0·020) when ARS was used. When ARS was used, students were more able to answer questions (P<0·0001), were more likely to prepare for the seminar (P<0·0001) and significantly preferred using ARS (P<0·0001). ARS was found to significantly improve student concentration and participation in small group seminar teaching and significantly improved knowledge retention. ARS may be useful in facilitating orthodontic teaching in the future.

Survey Response Styles, Acculturation, and Culture Among a Sample of Mexican American Adults.

PubMed

Davis, Rachel E; Resnicow, Ken; Couper, Mick P

2011-10-01

A number of studies have investigated use of extreme (ERS) and acquiescent (ARS) response styles across cultural groups. However, due to within-group heterogeneity, it is important to also examine use of response styles, acculturation, and endorsement of cultural variables at the individual level. This study explores relationships between acculturation, six Mexican cultural factors, ERS, and ARS among a sample of 288 Mexican American telephone survey respondents. Three aspects of acculturation were assessed: Spanish use, the importance of preserving Mexican culture, and interaction with Mexican Americans versus Anglos. These variables were hypothesized to positively associate with ERS and ARS. Participants with higher Spanish use did utilize more ERS and ARS; however, value for preserving Mexican culture and interaction with Mexican Americans were not associated with response style use. In analyses of cultural factors, endorsement of familismo and simpatia were related to more frequent ERS and ARS, machismo was associated with lower ERS among men, and la mujer was related to higher ERS among women. Caballerismo was marginally associated with utilization of ERS among men. No association was found between la mujer abnegada and ERS among women. Relationships between male gender roles and ARS were nonsignificant. Relationships between female gender roles and ARS were mixed but trended in the positive direction. Overall, these findings suggest that Mexican American respondents vary in their use of response styles by acculturation and cultural factors. This usage may be specifically influenced by participants' valuing of and engagement with constructs directly associated with social behavior.

Use of an audience response system (ARS) in a dual-campus classroom environment.

PubMed

Medina, Melissa S; Medina, Patrick J; Wanzer, Donald S; Wilson, Jane E; Er, Nelson; Britton, Mark L

2008-04-15

To implement an audience response system in a dual-campus classroom that aggregated data during graded (attendance and quizzes) and non-graded classroom activities (formative quizzes, case discussions, examination reviews, and team activities) and explore its strengths, weaknesses, and impact on active learning. After extensive research, an appropriate audience response system was selected and implemented in a dual-classroom setting for a third-year required PharmD course. Students were assigned a clicker and training and policies regarding clicker use were reviewed. Activities involving clicker use were carefully planned to simultaneously engage students in both classrooms in real time. Focus groups were conducted with students to gather outcomes data. Students and faculty members felt that the immediate feedback the automated response system (ARS) provided was most beneficial during non-graded activities. Student anxiety increased with use of ARS during graded activities due to fears regarding technology failure, user error, and academic integrity. ARS is a viable tool for increasing active learning in a doctor of pharmacy (PharmD) program, especially when used for non-graded class activities. Faculty members should proceed cautiously with using ARS for graded classroom activities and develop detailed and documented policies for ARS use.

Lecture-Free High School Biology Using an Audience Response System

ERIC Educational Resources Information Center

Barnes, Larry J.

2008-01-01

Audience Response Systems (ARS) represent a powerful new tool for increasing student engagement. ARS technology (known variously as electronic voting systems, personal response systems, interactive student response systems, and classroom performance systems) includes one hand-held remote per student, a receiver (infrared or radio frequency,…

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.

Exclusion of aldose reductase as a mediator of ERG deficits in a mouse model of diabetic eye disease.

PubMed

Samuels, Ivy S; Lee, Chieh-Allen; Petrash, J Mark; Peachey, Neal S; Kern, Timothy S

2012-11-01

Streptozotocin (STZ)-induced diabetes is associated with reductions in the electrical response of the outer retina and retinal pigment epithelium (RPE) to light. Aldose reductase (AR) is the first enzyme required in the polyol-mediated metabolism of glucose, and AR inhibitors have been shown to improve diabetes-induced electroretinogram (ERG) defects. Here, we used control and AR -/- mice to determine if genetic inactivation of this enzyme likewise inhibits retinal electrophysiological defects observed in a mouse model of type 1 diabetes. STZ was used to induce hyperglycemia and type 1 diabetes. Diabetic and age-matched nondiabetic controls of each genotype were maintained for 22 weeks, after which ERGs were used to measure the light-evoked components of the RPE (dc-ERG) and the neural retina (a-wave, b-wave). In comparison to their nondiabetic controls, wildtype (WT) and AR -/- diabetic mice displayed significant decreases in the c-wave, fast oscillation, and off response components of the dc-ERG but not in the light peak response. Nondiabetic AR -/- mice displayed larger ERG component amplitudes than did nondiabetic WT mice; however, the amplitude of dc-ERG components in diabetic AR -/- animals were similar to WT diabetics. ERG a-wave amplitudes were not reduced in either diabetic group, but b-wave amplitudes were lower in WT and AR -/-diabetic mice. These findings demonstrate that the light-induced responses of the RPE and outer retina are disrupted in diabetic mice, but these defects are not due to photoreceptor dysfunction, nor are they ameliorated by deletion of AR. This latter finding suggests that benefits observed in other studies utilizing pharmacological inhibitors of AR might have been secondary to off-target effects of the drugs.

The Yeast Anaerobic Response Element AR1b Regulates Aerobic Antifungal Drug-dependent Sterol Gene Expression*

PubMed Central

Gallo-Ebert, Christina; Donigan, Melissa; Liu, Hsing-Yin; Pascual, Florencia; Manners, Melissa; Pandya, Devanshi; Swanson, Robert; Gallagher, Denise; Chen, WeiWei; Carman, George M.; Nickels, Joseph T.

2013-01-01

Saccharomyces cerevisiae ergosterol biosynthesis, like cholesterol biosynthesis in mammals, is regulated at the transcriptional level by a sterol feedback mechanism. Yeast studies defined a 7-bp consensus sterol-response element (SRE) common to genes involved in sterol biosynthesis and two transcription factors, Upc2 and Ecm22, which direct transcription of sterol biosynthetic genes. The 7-bp consensus SRE is identical to the anaerobic response element, AR1c. Data indicate that Upc2 and Ecm22 function through binding to this SRE site. We now show that it is two novel anaerobic AR1b elements in the UPC2 promoter that direct global ERG gene expression in response to a block in de novo ergosterol biosynthesis, brought about by antifungal drug treatment. The AR1b elements are absolutely required for auto-induction of UPC2 gene expression and protein and require Upc2 and Ecm22 for function. We further demonstrate the direct binding of recombinant expressed S. cerevisiae ScUpc2 and pathogenic Candida albicans CaUpc2 and Candida glabrata CgUpc2 to AR1b and SRE/AR1c elements. Recombinant endogenous promoter studies show that the UPC2 anaerobic AR1b elements act in trans to regulate ergosterol gene expression. Our results indicate that Upc2 must occupy UPC2 AR1b elements in order for ERG gene expression induction to take place. Thus, the two UPC2-AR1b elements drive expression of all ERG genes necessary for maintaining normal antifungal susceptibility, as wild type cells lacking these elements have increased susceptibility to azole antifungal drugs. Therefore, targeting these specific sites for antifungal therapy represents a novel approach to treat systemic fungal infections. PMID:24163365

Alpha1-adrenergic receptor blockade in the VTA modulates fear memories and stress responses.

PubMed

Solecki, Wojciech B; Szklarczyk, Klaudia; Klasa, Adam; Pradel, Kamil; Dobrzański, Grzegorz; Przewłocki, Ryszard

2017-08-01

Activity of the ventral tegmental area (VTA) and its terminals has been implicated in the Pavlovian associative learning of both stressful and rewarding stimuli. However, the role of the VTA noradrenergic signaling in fear responses remains unclear. We aimed to examine how alpha 1 -adrenergic receptor (α 1 -AR) signaling in the VTA affects conditioned fear. The role of α 1 -AR was assessed using the micro-infusions into the VTA of the selective antagonists (0.1-1µg/0.5µl prazosin and 1µg/0.5µl terazosin) in acquisition and expression of fear memory. In addition, we performed control experiments with α 1 -AR blockade in the mammillary bodies (MB) - a brain region with α 1 -AR expression adjacent to the VTA. Intra-VTA but not intra-MB α 1 -AR blockade prevented formation and retrieval of fear memories. Importantly, local administration of α 1 -AR antagonists did not influence footshock sensitivity, locomotion or anxiety-like behaviors. Similarly, α 1 -AR blockade in the VTA had no effects on negative affect measured as number of 22kHz ultrasonic vocalizations during fear conditioning training. We propose that noradrenergic signaling in the VTA via α 1 -AR regulates formation and retrieval of fear memories but not other behavioral responses to stressful environmental stimuli. It enhances the encoding of environmental stimuli by the VTA to form and retrieve conditioned fear memories and to predict future behavioral outcomes. Our results provide novel insight into the role of the VTA α 1 -AR signaling in the regulation of stress responsiveness and fear memory. Copyright © 2017 Elsevier B.V. and ECNP. All rights reserved.

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.

High-precision 40Ar/39Ar geochronology and the advent of North America’s Late Cretaceous terrestrial fauna

PubMed Central

Cifelli, Richard L.; Kirkland, James I.; Weil, Anne; Deino, Alan L.; Kowallis, Bart J.

1997-01-01

A densely sampled, diverse new fauna from the uppermost Cedar Mountain Formation, Utah, indicates that the basic pattern of faunal composition for the Late Cretaceous of North America was already established by the Albian-Cenomanian boundary. Multiple, concordant 40Ar/39Ar determinations from a volcanic ash associated with the fauna have an average age of 98.39 ± 0.07 million years. The fauna of the Cedar Mountain Formation records the first global appearance of hadrosaurid dinosaurs, advanced lizard (e.g., Helodermatidae), and mammal (e.g., Marsupialia) groups, and the first North American appearance of other taxa such as tyrannosaurids, pachycephalosaurs, and snakes. Although the origin of many groups is unclear, combined biostratigraphic and phylogenetic evidence suggests an Old World, specifically Asian, origin for some of the taxa, an hypothesis that is consistent with existing evidence from tectonics and marine invertebrates. Large-bodied herbivores are mainly represented by low-level browsers, ornithopod dinosaurs, whose radiations have been hypothesized to be related to the initial diversification of angiosperm plants. Diversity at the largest body sizes (>106 g) is low, in contrast to both preceding and succeeding faunas; sauropods, which underwent demise in the Northern hemisphere coincident with the radiation of angiosperms, apparently went temporarily unreplaced by other megaherbivores. Morphologic and taxonomic diversity among small, omnivorous mammals, multituberculates, is also low. A later apparent increase in diversity occurred during the Campanian, coincident with the appearance of major fruit types among angiosperms, suggesting the possibility of adaptive response to new resources. PMID:9326579

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

Climatological Impact of Atmospheric River Based on NARCCAP and DRI-RCM Datasets

NASA Astrophysics Data System (ADS)

Mejia, J. F.; Perryman, N. M.

2012-12-01

This study evaluates spatial responses of extreme precipitation environments, typically associated with Atmospheric River events, using Regional Climate Model (RCM) output from NARCCAP dataset (50km grid size) and the Desert Research Institute-RCM simulations (36 and 12 km grid size). For this study, a pattern-detection algorithm was developed to characterize Atmospheric Rivers (ARs)-like features from climate models. Topological analysis of the enhanced elongated moisture flux (500-300hPa; daily means) cores is used to objectively characterize such AR features in two distinct groups: (i) zonal, north Pacific ARs, and (ii) subtropical ARs, also known as "Pineapple Express" events. We computed the climatological responses of the different RCMs upon these two AR groups, from which intricate differences among RCMs stand out. This study presents these climatological responses from historical and scenario driven simulations, as well as implications for precipitation extreme-value analyses.

Augmentation of the noradrenergic system in alpha-2 adrenergic receptor deficient mice: anatomical changes associated with enhanced fear memory.

PubMed

Davies, M Frances; Tsui, Janet Y; Flannery, Judy A; Li, Xiangqi; DeLorey, Timothy M; Hoffman, Brian B

2003-10-03

We have investigated sensitivity to the conditioned fear procedure of mice is influenced by the genetic deletion of alpha2A adrenoceptors (ARs). We observed a heightened freezing response in the discrete cue memory test in alpha2A AR knockout (alpha2A AR KO) mice and in D79N mice, a transgenic mouse strain with functionally impaired alpha2A ARs. No significant differences in contextual memory were observed between control and alpha2A AR KO or D79N mice suggesting a minimal role for the noradrenergic system in contextual memory. We speculated that the increased freezing response of the alpha2A AR KO and D79N mice in the discrete cue setting was due to increased release of norepinephrine evoked by the unconditioned footshock stimulus. In alpha2A AR KO mice we measured a doubling in the number of noradrenergic neurons in the locus coeruleus (LC) and a large increase in the cell volume of tyrosine hydroxylase positive neurons, likely due to selective preservation of large, multipolar neurons in the subcoeruleus. Hyperplasia of the noradrenergic neurons in the nucleus tractus solitarius, A5 and A7, was also observed. Alpha2A AR KO mice exhibit greater c-Fos expression in the LC compared to wild type mice suggesting that the LC neurons in the alpha2A AR KO mice were spontaneously more active. This study suggests that alpha2A ARs are involved in the development of the central noradrenergic system and raises the possibility that alterations in alpha2A AR expression may contribute to variations in fear and stress responses.

Blockade of adenosine A2A receptor enhances CD8+ T cells response and decreases regulatory T cells in head and neck squamous cell carcinoma.

PubMed

Ma, Si-Rui; Deng, Wei-Wei; Liu, Jian-Feng; Mao, Liang; Yu, Guang-Tao; Bu, Lin-Lin; Kulkarni, Ashok B; Zhang, Wen-Feng; Sun, Zhi-Jun

2017-06-07

Cancer immunotherapy offers a promising approach in cancer treatment. The adenosine A2A receptor (A2AR) could protect cancerous tissues from immune clearance via inhibiting T cells response. To date, the role of A2AR in head and neck squamous cell carcinoma (HNSCC) has not been investigated. Here, we sought to explore the expression and immunotherapeutic value of A2AR blockade in HNSCC. The expression of A2AR was evaluated by immunostaining in 43 normal mucosae, 48 dysplasia and 165 primary HNSCC tissues. The immunotherapeutic value of A2AR blockade was assessed in vivo in genetically defined immunocompetent HNSCC mouse model. Immunostaining of HNSCC tissue samples revealed that increased expression of A2AR on tumor infiltrating immune cells correlated with advanced pathological grade, larger tumor size and positive lymph node status. Elevated A2AR expression was also detected in recurrent HNSCC and HNSCC tissues with induction chemotherapy. The expression of A2AR was found to be significantly correlated with HIF-1α, CD73, CD8 and Foxp3. Furthermore, the increased population of CD4 + Foxp3 + regulatory T cells (Tregs), which partially expressed A2AR, was observed in an immunocompetent mouse model that spontaneously develops HNSCC. Pharmacological blockade of A2AR by SCH58261 delayed the tumor growth in the HNSCC mouse model. Meanwhile, A2AR blockade significantly reduced the population of CD4 + Foxp3 + Tregs and enhanced the anti-tumor response of CD8 + T cells. These results offer a preclinical proof for the administration of A2AR inhibitor on prophylactic experimental therapy of HNSCC and suggest that A2AR blockade can be a potential novel strategy for HNSCC immunotherapy.

Synergistic Activation of Steroidogenic Acute Regulatory Protein Expression and Steroid Biosynthesis by Retinoids: Involvement of cAMP/PKA Signaling

PubMed Central

Manna, Pulak R.; Slominski, Andrzej T.; King, Steven R.; Stetson, Cloyce L.

2014-01-01

Both retinoic acid receptors (RARs) and retinoid X receptors (RXRs) mediate the action of retinoids that play important roles in reproductive development and function, as well as steroidogenesis. Regulation of steroid biosynthesis is principally mediated by the steroidogenic acute regulatory protein (StAR); however, the modes of action of retinoids in the regulation of steroidogenesis remain obscure. In this study we demonstrate that all-trans retinoic acid (atRA) enhances StAR expression, but not its phosphorylation (P-StAR), and progesterone production in MA-10 mouse Leydig cells. Activation of the protein kinase A (PKA) cascade, by dibutyrl-cAMP or type I/II PKA analogs, markedly increased retinoid-responsive StAR, P-StAR, and steroid levels. Targeted silencing of endogenous RARα and RXRα, with small interfering RNAs, resulted in decreases in 9-cis RA-stimulated StAR and progesterone levels. Truncation of and mutational alterations in the 5′-flanking region of the StAR gene demonstrated the importance of the −254/−1-bp region in retinoid responsiveness. An oligonucleotide probe encompassing an RXR/liver X receptor recognition motif, located within the −254/−1-bp region, specifically bound MA-10 nuclear proteins and in vitro transcribed/translated RXRα and RARα in EMSAs. Transcription of the StAR gene in response to atRA and dibutyrl-cAMP was influenced by several factors, its up-regulation being dependent on phosphorylation of cAMP response-element binding protein (CREB). Chromatin immunoprecipitation studies revealed the association of phosphorylation of CREB, CREB binding protein, RXRα, and RARα to the StAR promoter. Further studies elucidated that hormone-sensitive lipase plays an important role in atRA-mediated regulation of the steroidogenic response that involves liver X receptor signaling. These findings delineate the molecular events by which retinoids influence cAMP/PKA signaling and provide additional and novel insight into the regulation of StAR expression and steroidogenesis in mouse Leydig cells. PMID:24265455

The steroidogenic response and corpus luteum expression of the steroidogenic acute regulatory protein after human chorionic gonadotropin administration at different times in the human luteal phase.

PubMed

Kohen, Paulina; Castro, Olga; Palomino, Alberto; Muñoz, Alex; Christenson, Lane K; Sierralta, Walter; Carvallo, Pilar; Strauss, Jerome F; Devoto, Luigi

2003-07-01

This study was designed 1) to assess corpus luteum (CL) steroidogenesis in response to exogenous human chorionic gonadotropin (hCG) at different times during the luteal phase, 2) to examine the effect of hCG on steroidogenic acute regulatory protein (StAR) expression within the CL, 3) to correlate StAR expression and luteal steroidogenic responses to hCG, and 4) to determine whether endogenous LH regulates ovarian steroidogenesis in the early luteal phase. Blood was collected before and after hCG treatment for steroid and hCGbeta determinations. CL were obtained at the time of surgery to assess StAR gene and protein expression. During the early luteal phase various women received the GnRH antagonist for 24-48 h; some of them also received hCG 24 h after the GnRH antagonist. A slight steroidogenic response to hCG was observed in early luteal phase; 17alpha-hydroxyprogesterone, but not progesterone (P4), levels were significantly increased 8 h post-hCG, indicating a differential response by the granulosa and theca-lutein cells. The 1.6- and 4.4-kb StAR transcripts and the 37-kDa preprotein and 30-kDa mature StAR protein did not change post-hCG administration in early luteal phase CL. In contrast, the StAR 4.4- and 1.6-kb transcripts diminished significantly (P < 0.05) after the antagonist treatment. Immunohistochemical staining for StAR protein was weak, particularly in granulosa-lutein cells. Treatment with hCG restored StAR mRNA and protein and plasma P4 levels within 24 h in antagonist-treated women. hCG stimulated the highest plasma concentrations of P4 and estradiol in the midluteal phase, indicating its greatest steroidogenic capacity. Midluteal tissue StAR gene and protein expression increased by 1.6- and 1.4-fold after 24 h of hCG treatment, respectively. Administration of hCG resulted in the greatest increment in plasma P4 (4-fold) and 17alpha-hydroxyprogesterone (3-fold) levels over baseline in the late luteal phase. This was associated with an increase in StAR mRNA (3.5-fold) and protein (1.8-fold). Collectively, these data indicate that 1) the hCG-stimulated steroidogenic response is dependent on the age of the CL; 2) the early luteal phase CL is relatively insensitive to exogenous hCG in the presence of normal pituitary gonadotropin support, but becomes responsive when the latter is withdrawn; 3) the hCG-stimulated steroidogenic response in the mid- and late luteal phase is correlated with increased StAR mRNA and protein abundance; and 4) there are differential responses of small and large luteal cells to hCG stimulation that depend upon the age of the CL.

Role of an audience response system in didactic attendance and assessment.

PubMed

Stoneking, Lisa R; Grall, Kristi H; Min, Alice; Dreifuss, Bradley; Spear Ellinwood, Karen C

2014-06-01

The Residency Review Committee for Emergency Medicine mandates conference participation, but tracking attendance is difficult and fraught with errors. Feedback on didactic sessions, if not collected in real time, is challenging to obtain. We assessed whether an audience response system (ARS) would (1) encourage residents to arrive on time for lectures, and (2) increase anonymous real-time audience feedback. The ARS (Poll Everywhere) provided date/time-stamped responses to polls from residents, including a question to verify attendance and questions to gather immediate, anonymous postconference evaluations. Fisher exact test was used to calculate proportions. The proportion of residents who completed evaluations prior to the institution of the ARS was 8.75, and it was 59.42 after (P < .001). The proportion of faculty who completed evaluations prior to using the ARS was 6.12, and it was 85.71 after (P < .001). The proportion of residents who reported they had attended the conference session was 55 for the 3 weeks prior to initiating the ARS, decreasing to 46.67 for the 3 weeks during which the ARS was used to take attendance (P  =  .46). The proportion of faculty who reported attending the conference was 5.56 for the 3 weeks prior to ARS initiation, decreasing to 4.44 for the 3 weeks while using the ARS (P  =  .81). Audience response systems are an effective way to verify attendance and tardiness, eliminating the subjective effect of attendance takers' leniency and increasing completion of evaluations for didactic sessions.

Survey Response Styles, Acculturation, and Culture Among a Sample of Mexican American Adults

PubMed Central

Davis, Rachel E.; Resnicow, Ken; Couper, Mick P.

2011-01-01

A number of studies have investigated use of extreme (ERS) and acquiescent (ARS) response styles across cultural groups. However, due to within-group heterogeneity, it is important to also examine use of response styles, acculturation, and endorsement of cultural variables at the individual level. This study explores relationships between acculturation, six Mexican cultural factors, ERS, and ARS among a sample of 288 Mexican American telephone survey respondents. Three aspects of acculturation were assessed: Spanish use, the importance of preserving Mexican culture, and interaction with Mexican Americans versus Anglos. These variables were hypothesized to positively associate with ERS and ARS. Participants with higher Spanish use did utilize more ERS and ARS; however, value for preserving Mexican culture and interaction with Mexican Americans were not associated with response style use. In analyses of cultural factors, endorsement of familismo and simpatia were related to more frequent ERS and ARS, machismo was associated with lower ERS among men, and la mujer was related to higher ERS among women. Caballerismo was marginally associated with utilization of ERS among men. No association was found between la mujer abnegada and ERS among women. Relationships between male gender roles and ARS were nonsignificant. Relationships between female gender roles and ARS were mixed but trended in the positive direction. Overall, these findings suggest that Mexican American respondents vary in their use of response styles by acculturation and cultural factors. This usage may be specifically influenced by participants' valuing of and engagement with constructs directly associated with social behavior. PMID:21927503

Breast-feeding, aeroallergen sensitization, and environmental exposures during infancy are determinants of childhood allergic rhinitis.

PubMed

Codispoti, Christopher D; Levin, Linda; LeMasters, Grace K; Ryan, Patrick; Reponen, Tiina; Villareal, Manuel; Burkle, Jeff; Stanforth, Sherry; Lockey, James E; Khurana Hershey, Gurjit K; Bernstein, David I

2010-05-01

Infant predictors of early childhood allergic rhinitis (AR) are poorly understood. We sought to identify environmental exposures and host factors during infancy that predict AR at age 3 years. High-risk children from greater Cincinnati were followed annually from ages 1 to 3 years. AR was defined as sneezing, runny, or blocked nose in the prior 12 months and a positive skin prick test (SPT) response to 1 or more aeroallergens. Environmental and standardized medical questionnaires determined exposures and clinical outcomes. Primary activity area dust samples were analyzed for house dust endotoxin (HDE) and (1-3)-beta-D-glucan. Fine particulate matter sampled at 27 monitoring stations was used to estimate personal elemental carbon attributable to traffic exposure by using a land-use regression model. Of 361 children in this analysis, 116 had AR, and 245 were nonatopic and nonsymptomatic. Prolonged breast-feeding in African American children (adjusted odds ratio [aOR], 0.8; 95% CI, 0.6-0.9) and multiple children in the home during infancy was protective against AR (aOR, 0.4; 95% CI, 0.2-0.8). Food SPT response positivity and tree SPT response positivity in infancy increased the risk of AR at age 3 years (aOR of 4.4 [95% CI, 2.1-9.2] and aOR of 6.8 [95% CI, 2.5-18.7], respectively). HDE exposure was associated with AR; the effect was dependent on exposure level. Elemental carbon attributable to traffic and environmental tobacco smoke exposure showed no effect on AR. Prolonged breast-feeding in African American subjects and multiple children in the home during infancy reduced the risk of AR at age 3 years. SPT response positivity to food and tree allergens enhanced risk. The HDE effect on AR was related to exposure. Copyright 2010 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

The ethics of animal research: a survey of pediatric health care workers.

PubMed

Joffe, Ari R; Bara, Meredith; Anton, Natalie; Nobis, Nathan

2014-12-30

Pediatric health care workers (HCW) often perform, promote, and advocate use of public funds for animal research (AR). We aim to determine whether HCW consider common arguments (and counterarguments) in support (or not) of AR convincing. 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, support for AR, and common arguments (with their counterarguments) to justify the moral permissibility (or not) of AR. Responses are reported using standard tabulations. Responses of pediatricians and nurses/RTs were compared using Chi-square, with P < .05 considered significant. Response rate was 53/115(46%) (pediatricians), and 73/120(61%) (nurses/RTs). Pediatricians and nurses/RTs are supportive of AR. Most considered 'benefits arguments' sufficient to justify AR; however, most acknowledged that counterarguments suggesting alternative research methods may be available, or that it is unclear why the same 'benefits arguments' do not apply to using humans in research, significantly weakened 'benefits arguments'. Almost all were not convinced of the moral permissibility of AR by 'characteristics of non-human-animals arguments', including that non-human-animals may not be sentient, or are simply property. Most were not convinced of the moral permissibility of AR by 'human exceptionalism' arguments, including that humans have more advanced mental abilities, are of a special 'kind', can enter into social contracts, or face a 'lifeboat situation'. Counterarguments explained much of this, including that not all humans have these more advanced abilities [the argument from species overlap], and that the notion of 'kind' is arbitrary [e.g., why are we not of the kind 'sentient animal' or 'subject-of-a-life']. Pediatrician and nurse/RT responses were similar. Most respondents were not convinced of the moral permissibility of AR when given common arguments and counterarguments from the literature. HCW should seriously consider arguments on both sides of the AR debate.

Adherence to AHA Guidelines When Adapted for Augmented Reality Glasses for Assisted Pediatric Cardiopulmonary Resuscitation: A Randomized Controlled Trial

PubMed Central

Gervaix, Alain; Haddad, Kevin; Lacroix, Laurence; Schrurs, Philippe; Sahin, Ayhan; Lovis, Christian; Manzano, Sergio

2017-01-01

Background The American Heart Association (AHA) guidelines for cardiopulmonary resuscitation (CPR) are nowadays recognized as the world’s most authoritative resuscitation guidelines. Adherence to these guidelines optimizes the management of critically ill patients and increases their chances of survival after cardiac arrest. Despite their availability, suboptimal quality of CPR is still common. Currently, the median hospital survival rate after pediatric in-hospital cardiac arrest is 36%, whereas it falls below 10% for out-of-hospital cardiac arrest. Among emerging information technologies and devices able to support caregivers during resuscitation and increase adherence to AHA guidelines, augmented reality (AR) glasses have not yet been assessed. In order to assess their potential, we adapted AHA Pediatric Advanced Life Support (PALS) guidelines for AR glasses. Objective The study aimed to determine whether adapting AHA guidelines for AR glasses increased adherence by reducing deviation and time to initiation of critical life-saving maneuvers during pediatric CPR when compared with the use of PALS pocket reference cards. Methods We conducted a randomized controlled trial with two parallel groups of voluntary pediatric residents, comparing AR glasses to PALS pocket reference cards during a simulation-based pediatric cardiac arrest scenario—pulseless ventricular tachycardia (pVT). The primary outcome was the elapsed time in seconds in each allocation group, from onset of pVT to the first defibrillation attempt. Secondary outcomes were time elapsed to (1) initiation of chest compression, (2) subsequent defibrillation attempts, and (3) administration of drugs, as well as the time intervals between defibrillation attempts and drug doses, shock doses, and number of shocks. All these outcomes were assessed for deviation from AHA guidelines. Results Twenty residents were randomized into 2 groups. Time to first defibrillation attempt (mean: 146 s) and adherence to AHA guidelines in terms of time to other critical resuscitation endpoints and drug dose delivery were not improved using AR glasses. However, errors and deviations were significantly reduced in terms of defibrillation doses when compared with the use of the PALS pocket reference cards. In a total of 40 defibrillation attempts, residents not wearing AR glasses used wrong doses in 65% (26/40) of cases, including 21 shock overdoses >100 J, for a cumulative defibrillation dose of 18.7 Joules per kg. These errors were reduced by 53% (21/40, P<.001) and cumulative defibrillation dose by 37% (5.14/14, P=.001) with AR glasses. Conclusions AR glasses did not decrease time to first defibrillation attempt and other critical resuscitation endpoints when compared with PALS pocket cards. However, they improved adherence and performance among residents in terms of administering the defibrillation doses set by AHA. PMID:28554878

Use of an Audience Response System (ARS) in a Dual-Campus Classroom Environment

PubMed Central

Medina, Patrick J; Wanzer, Donald S; Wilson, Jane E; Er, Nelson; Britton, Mark L

2008-01-01

Objectives To implement an audience response system in a dual-campus classroom that aggregated data during graded (attendance and quizzes) and non-graded classroom activities (formative quizzes, case discussions, examination reviews, and team activities) and explore its strengths, weaknesses, and impact on active learning. Design After extensive research, an appropriate audience response system was selected and implemented in a dual-classroom setting for a third-year required PharmD course. Students were assigned a clicker and training and policies regarding clicker use were reviewed. Activities involving clicker use were carefully planned to simultaneously engage students in both classrooms in real time. Focus groups were conducted with students to gather outcomes data. Assessment Students and faculty members felt that the immediate feedback the automated response system (ARS) provided was most beneficial during non-graded activities. Student anxiety increased with use of ARS during graded activities due to fears regarding technology failure, user error, and academic integrity. Summary ARS is a viable tool for increasing active learning in a doctor of pharmacy (PharmD) program, especially when used for non-graded class activities. Faculty members should proceed cautiously with using ARS for graded classroom activities and develop detailed and documented policies for ARS use. PMID:18483604

A comparison of vestibular evoked myogenic potential (VEMP) between definite Meniere's disease patients and normal healthy adults.

PubMed

Jariengprasert, Chanchai; Tiensuwan, Montip; Euasirirattanapaisan, Khongpol

2013-12-01

To compare the results of VEMP between unilateral definite Meniere's disease patients and normal healthy adults. Thirty-two patients with unilateral definite Meniere's disease patients and 32 age-matched normal healthy adults (control) underwent VEMP tests with short tone burst of 500 Hz at 90 dBnHL. Student-t test was used for comparison of means of all parameters between two groups. Absent VEMP response was found in 14 MD patients and abnormal asymmetry ratio (AR) was found in five MD patients. Normal responses were found in all subjects of the control group. The mean P1 and N1 latencies, VEMP amplitude between unilateral MD, and control were not significantly different between two groups. However the difference between the mean AR of both groups showed statistically significant (p-value < 0.05). The upper limit of normal AR was calculated to be of 35.15%. The absence of VEMP response and AR of VEMP were more dominant than other parameters such as P1 and N1 latencies or VEMP amplitude in the detection of saccular dysfunction in MD. The results suggested that AR should be used as a tool in interpretation of VEMP response for the diagnostic batteries in MD. The upper limit of normal AR of < or = 35% should be recommended.

Expression of arsenic resistance genes in the obligate anaerobe Bacteroides vulgatus ATCC 8482, a gut microbiome bacterium

PubMed Central

Li, Jiaojiao; Mandal, Goutam; Rosen, Barry P.

2016-01-01

The response of the obligate anaerobe Bacteroides vulgatus ATCC 8482, a common human gut microbiota, to arsenic was determined. B. vulgatus ATCC 8482 is highly resistant to pentavalent As(V) and methylarsenate (MAs(V)). It is somewhat more sensitive to trivalent inorganic As(III) but 100-fold more sensitive to methylarsenite (MAs(III)) than to As(III). B. vulgatus ATCC 8482 has eight continuous genes in its genome that we demonstrate form an arsenical-inducible transcriptional unit. The first gene of this ars operon, arsR, encodes a putative ArsR As(III)-responsive transcriptional repressor. The next three genes encode proteins of unknown function. The remaining genes, arsDABC, have well-characterized roles in detoxification of inorganic arsenic, but there are no known genes for MAs(III) resistance. Expression of each gene after exposure to trivalent and pentavalent inorganic and methylarsenicals was analyzed. MAs(III) was the most effective inducer. The arsD gene was the most highly expressed of the ars operon genes. These results demonstrate that this anaerobic microbiome bacterium has arsenic-responsive genes that confer resistance to inorganic arsenic and may be responsible for the organism's ability to maintain its prevalence in the gut following dietary exposure to inorganic arsenic. PMID:27040269

The Use of an Audience Response System in an Elementary School–Based Health Education Program

PubMed Central

DeSorbo, Alexandra L.; Noble, James M.; Shaffer, Michele; Gerin, William; Williams, Olajide A.

2016-01-01

Background The audience response system (ARS) allows students to respond and interact anonymously with teachers via small handheld wireless keypads. Despite increasing popularity in classroom settings, the application of these devices to health education programming has not been studied. We assessed feasibility, engagement, and learning among children using an ARS compared with traditional pencil–paper formats, (ARS) for a stroke health education program. Method We compared outcome data generated via an ARS-based intervention to pencil–paper controls, including test scores and missing data rates among 265 schoolchildren 9 to 11 years old participating in stroke education. Among 119 children, we evaluated the feasibility of ARS use and explored student motivation with a 10-item questionnaire. We assessed facilitator experience with both methods. Results ARS use is feasible. Students reported having more fun (p < .001), increased attention (p < .001), participation (p < .001), and perceived learning outcomes (p < .001) compared with pencil–paper controls. Test scores showed highly positive improvement for both ARS and paper without additional benefits of ARS on learning. There was no difference in missing data rates (p < .001). Educators preferred the ARS. Conclusion The use of an ARS among children is feasible and improves student and facilitator engagement without additional benefits on stroke learning. PMID:23086554

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 Central

Takahashi, Shigehiro; Suzuki, Iwao; Ojima, Takuto; Minaki, Daichi

2018-01-01

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. PMID:29361775

Peripheral α2-β1 adrenergic interactions mediate the ghrelin response to brain urocortin 1 in rats

PubMed Central

Yakabi, Koji; Harada, Yumi; Takayama, Kiyoshige; Ro, Shoki; Ochiai, Mitsuko; lizuka, Seiichi; Hattori, Tomohisa; Wang, Lixin; Taché, Yvette

2018-01-01

Summary The autonomic nervous system (ANS) conveys neuronal input from the brain to the stomach. We investigated mechanisms through which urocortin 1 (UCN1) injected intracerebroventricularly (ICV, 300 pmol/rat) inhibits circulating ghrelin in rats. This was achieved by assessing (1) the induction of c-fos gene expression as a marker of neuronal activation in specific hypothalamic and caudal brainstem regulating ANS; (2) the influence of vagotomy and pharmacological blockade of central and peripheral α- and β-adrenergic receptor (AR) on ICV UCN1 -induced reduction of plasma ghrelin levels (determined by ELISA); and (3) the relevance of this pathway in the feeding response to a fast in rats. UCN1 increased c-fos mRNA expression in key brain sites influencing sympathetic activity namely the hypothalamic paraventricular and ventromedial nuclei, locus coeruleus, nucleus of the solitary tract, and rostral ventrolateral medulla, by 16-, 29-, 6-, 37-, and 13-fold, respectively. In contrast, the dorsal motor nucleus of the vagus had little c-fos mRNA expression and ICV UCN1 induced a similar reduction in acylated ghrelin in the sham-operated (31%) and vagotomized (41%) rats. An intraperitoneal (IP) injection of either a non-selective α- or selective α2-AR antagonist reduced, while a selective α2-AR agonist enhanced ICV UCN1-induced suppression of plasma acylated ghrelin levels. In addition, IP injection of a non-selective β- or selective β1-AR agonist blocked, and selective β1-AR antagonist augmented, the ghrelin response to ICV UCN1. The IP injections of a selective α1- or non-selective β or β2-AR antagonists, or any of the pretreatments given ICV had no effect. ICV UCN1 reduced the 2-h food intake in response to a fast by 80%, and this effect was partially prevented by a selective α2-AR antagonist. These data suggest that ICV UCN1 reduces plasma ghrelin mainly through the brain sympathetic component of the ANS and peripheral AR specifically α2-AR activation and inactivation of β1-AR. The α2-AR pathway contributes to the associated reduction in food intake. PMID:25265283

Clinical Features and Management of Acquired Resistance to PD-1 Axis Inhibitors in 26 Patients With Advanced Non-Small Cell Lung Cancer.

PubMed

Gettinger, Scott N; Wurtz, Anna; Goldberg, Sarah B; Rimm, David; Schalper, Kurt; Kaech, Susan; Kavathas, Paula; Chiang, Anne; Lilenbaum, Rogerio; Zelterman, Daniel; Politi, Katerina; Herbst, Roy S

2018-06-01

With expanding indications for programmed death 1 (PD-1) axis inhibitors in non-small cell lung cancer (NSCLC), acquired resistance (AR) to these therapies is increasingly being encountered. We sought to characterize clinical patterns of AR to PD-1 axis inhibitors in patients with advanced NSCLC, and evaluate subsequent outcome and management strategies for such patients. Patients with NSCLC who developed AR to PD-1 axis inhibitor therapy initiated between December 2009 and February 2016 at one institution were identified and examined by clinical and radiographic features. AR was defined as progressive disease after initial response by either Response Evaluation Criteria in Solid Tumors v1.1 or immune-related response criteria. Twenty-six patients with AR to PD-1 axis inhibitor therapy were identified and evaluated. Median time to AR was 313 days; the 2-year survival rate from AR was 70% (95% confidence interval: 0.53-0.92). Twenty patients (77%) experienced AR in lymph nodes (LNs), including 11 patients with LN-only progression. Twenty-three (88%) patients had recurrence limited to one (54%) or two (35%) sites of disease. Fourteen patients (54%) continued PD-1 axis inhibitor therapy beyond progression. Three patients were re-challenged with the same PD-1 axis inhibitor after holiday from and progression off therapy, 2 again responded. Fifteen patients (58%) received local therapy to site(s) of AR, 11 continued respective PD-1 axis inhibitor after local therapy. The 2-year survival rate from AR among these 15 patients was 92% (95% confidence interval: 0.77-1). Acquired resistance to PD-1 axis inhibitors is often limited to one or two sites when local therapy and continuation of PD-1 axis inhibitor therapy can result in prolonged benefit. LN metastases appear to be particularly susceptible sites to AR. When progression of disease following response occurs after holiday from PD-1 axis inhibitor, re-challenge can again lead to tumor regression. Copyright © 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

Androgen Triggers the Pro-Migratory CXCL12/CXCR4 Axis in AR-Positive Breast Cancer Cell Lines: Underlying Mechanism and Possible Implications for the Use of Aromatase Inhibitors in Breast Cancer.

PubMed

Azariadis, Kalliopi; Kiagiadaki, Fotini; Pelekanou, Vasiliki; Bempi, Vasiliki; Alexakis, Kostas; Kampa, Marilena; Tsapis, Andreas; Castanas, Elias; Notas, George

2017-01-01

Reports regarding the role of androgen in breast cancer (BC) are conflicting. Some studies suggest that androgen could lead to undesirable responses in the presence of certain BC tumor characteristics. We have shown that androgen induces C-X-C motif chemokine 12 (CXCL12) in BC cell lines. Our aim was to identify the mechanisms regulating the phenotypic effects of androgen-induced CXCL12 on Androgen Receptor (AR) positive BC cell lines. We analyzed the expression of CXCL12 and its receptors with qPCR and ELISA and the role of Nuclear Receptor Coactivator 1 (NCOA1) in this effect. AR effects on the CXCL12 promoter was studied via Chromatin-immunoprecipitation. We also analyzed publically available data from The Cancer Genome Atlas to verify AR-CXCL12 interactions and to identify the effect or Aromatase Inhibitors (AI) therapy on CXCL12 expression and disease progression in AR positive cases. CXCL12 induction occurs only in AR-positive BC cell lines, possibly via an Androgen Response Element, upstream of the CXCL12 promoter. The steroid receptor co-regulator NCOA1 is critical for this effect. Androgen only induced the motility of p53-mutant BC cells T47D cells via upregulation of CXCR4 expression while they had no effect on wild-type p53 MCF-7 cells. Loss of CXCR4 expression and depletion of CXCL12 abolished the effect of androgen in T47D cells while inhibition of p53 expression in MCF-7 cells made them responsive to androgen and increased their motility in the presence to androgen. Patients with estrogen receptor positive (ER+)/AR+ BC treated with AIs were at increased risk of disease progression compared to ER+/AR+ non-AI treated and ER+/AR- AI treated cases. AIs may lead to unfavorable responses in some ER/AR positive BC cases, especially in patients with AR+, p53 mutant tumors. © 2017 The Author(s). Published by S. Karger AG, Basel.

RiArsB and RiMT-11: Two novel genes induced by arsenate in arbuscular mycorrhiza.

PubMed

Maldonado-Mendoza, Ignacio E; Harrison, Maria J

Plants associated with arbuscular mycorrhizal fungi (AMF) increase their tolerance to arsenic-polluted soils. This study aims to investigate the genes involved in the AMF molecular response to arsenic pollution. Genes encoding proteins involved in arsenic metabolism were identified and their expression assessed by PCR or RT-qPCR. The As-inducible gene GiArsA (R. irregularis ABC ATPase component of the ArsAB arsenite efflux pump) and two new genes, an arsenate/arsenite permease component of ArsAB (RiArsB) and a methyltransferase type 11 (RiMT-11) were induced when arsenate was added to two-compartment in vitro monoxenic cultures of R. irregularis-transformed carrot roots. RiArsB and RiMT-11 expression in extraradical hyphae in response to arsenate displayed maximum induction 4-6 h after addition of 350 μM arsenate. Their expression was also detected in colonized root tissues grown in pots, or in the root-fungus compartment of two-compartment in vitro systems. We used a Medicago truncatula double mutant (mtpt4/mtpt8) to demonstrate that RiMT-11 and RiArsB transcripts accumulate in response to the addition of arsenate but not in response to phosphate. These results suggest that these genes respond to arsenate addition regardless of non-functional Pi symbiotic transport, and that RiMT-11 may be involved in arsenate detoxification by methylation in AMF-colonized tissues. Copyright © 2017 British Mycological Society. All rights reserved.

Evolution of copper arsenate resistance for enhanced enargite bioleaching using the extreme thermoacidophile Metallosphaera sedula.

PubMed

Ai, Chenbing; McCarthy, Samuel; Liang, Yuting; Rudrappa, Deepak; Qiu, Guanzhou; Blum, Paul

2017-12-01

Adaptive laboratory evolution (ALE) was employed to isolate arsenate and copper cross-resistant strains, from the copper-resistant M. sedula CuR1. The evolved strains, M. sedula ARS50-1 and M. sedula ARS50-2, contained 12 and 13 additional mutations, respectively, relative to M. sedula CuR1. Bioleaching capacity of a defined consortium (consisting of a naturally occurring strain and a genetically engineered copper sensitive strain) was increased by introduction of M. sedula ARS50-2, with 5.31 and 26.29% more copper recovered from enargite at a pulp density (PD) of 1 and 3% (w/v), respectively. M. sedula ARS50-2 arose as the predominant species and modulated the proportions of the other two strains after it had been introduced. Collectively, the higher Cu 2+ resistance trait of M. sedula ARS50-2 resulted in a modulated microbial community structure, and consolidating enargite bioleaching especially at elevated PD.

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.

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.

Enhancing 'Whole-of-Government' Response to Biological Events in Korea: Able Response 2014.

PubMed

Tak, Sangwoo; Jareb, Anton; Choi, Suon; Sikes, Marvin; Choi, Yeon Hwa; Boo, Hyeong-Wook

2018-01-01

Since 2011, the Republic of Korea (ROK) and United States (U.S.) have been collaborating to conduct inter- and intra-governmental exercises to jointly respond to biological events in Korea. These exercises highlight U.S. interest in increasing its global biosurveillance capability and the ROK's interest in improving cooperation among ministries to respond to crises. With Able Response (AR) exercises, the ROK and U.S. have improved coordination among US and ROK government and defense agencies responding to potential bio-threats and identified additional areas on which to apply refinements in policies and practices. In 2014, the AR exercise employed a Biosurveillance Portal (BSP) to facilitate more effective communication among participating agencies and countries including Australia. In the present paper, we seek to provide a comprehensive assessment of the AR 2014 (AR14) exercise and make recommendations for future improvements. Incorporating a more realistic response in future scenarios by integrating a tactical response episode in the exercise is recommended.

Enhancing ‘Whole-of-Government’ Response to Biological Events in Korea: Able Response 2014

PubMed Central

Tak, Sangwoo; Jareb, Anton; Choi, Suon; Sikes, Marvin; Choi, Yeon Hwa; Boo, Hyeong-wook

2018-01-01

Since 2011, the Republic of Korea (ROK) and United States (U.S.) have been collaborating to conduct inter- and intra-governmental exercises to jointly respond to biological events in Korea. These exercises highlight U.S. interest in increasing its global biosurveillance capability and the ROK’s interest in improving cooperation among ministries to respond to crises. With Able Response (AR) exercises, the ROK and U.S. have improved coordination among US and ROK government and defense agencies responding to potential bio-threats and identified additional areas on which to apply refinements in policies and practices. In 2014, the AR exercise employed a Biosurveillance Portal (BSP) to facilitate more effective communication among participating agencies and countries including Australia. In the present paper, we seek to provide a comprehensive assessment of the AR 2014 (AR14) exercise and make recommendations for future improvements. Incorporating a more realistic response in future scenarios by integrating a tactical response episode in the exercise is recommended. PMID:29503803

Escitalopram plasma levels and antidepressant response.

PubMed

Florio, Vincenzo; Porcelli, Stefano; Saria, Alois; Serretti, Alessandro; Conca, Andreas

2017-09-01

Major Depression Disorder (MDD) has a highly variable treatment response due to the large inter-individual variation in the pharmacokinetics and pharmacodynamics of drug treatments. In detail the correlation between plasma level and efficacy has been much debated. Among first-line drugs for MDD, one of the most used is escitalopram. In the present study we investigated the association between serum concentration of escitalopram (SCE) and antidepressant response (AR). 70 MDD patients treated with escitalopram monotherapy were recruited and followed for three months. Hamilton Depression Rating Scale - 21 (HAMD-21) was administrated at baseline, month 1, and month 3 to assess AR. SCE was measured at steady state. Linear regression analysis and nonlinear least-squares regression were used to estimate association between SCE and AR. We found an association between SCE and AR both at month 1 (p<0.001) and month 3 (p=0.0003), which persists also excluding 3 patients with SCE equal to 0. Interestingly, by excluding patients with SCE < 20ng/mL, i.e. with a SCE lower than the putative therapeutic threshold, these associations disappeared. The curvilinear function AR = a + (SCE-SCE 2 ) explained a higher proportion of variance compared to the linear other models (p<0.001). Our results suggest that for escitalopram the association between SCE and AR likely follows a nearly-asymptotic function, with poor AR at sub-therapeutic SCE and stable AR response at therapeutic SCE. Thus, when a patient reaches the therapeutic SCE range, further increase of escitalopram dosage seems to be useless, although further studies are needed to confirm our findings. Copyright © 2017 Elsevier B.V. and ECNP. All rights reserved.

Vasopressin V1a receptors are present in the carotid body and contribute to the control of breathing in male Sprague-Dawley rats.

PubMed

Żera, Tymoteusz; Przybylski, Jacek; Grygorowicz, Tomasz; Kasarełło, Kaja; Podobińska, Martyna; Mirowska-Guzel, Dagmara; Cudnoch-Jędrzejewska, Agnieszka

2018-04-01

Vasopressin (AVP) maintains body homeostasis by regulating water balance, cardiovascular system and stress response. AVP inhibits breathing through central vasopressin 1a receptors (V1aRs). Chemoreceptors within carotid bodies (CBs) detect chemical and hormonal signals in the bloodstream and provide sensory input to respiratory and cardiovascular centers of the brainstem. In the study we investigated if CBs contain V1aRs and how the receptors are involved in the regulation of ventilation by AVP. We first immunostained CBs for V1aRs and tyrosine hydroxylase, a marker of chemoreceptor type I (glomus) cells. In urethane-anesthetized adult Sprague-Dawley male rats, we then measured hemodynamic and respiratory responses to systemic (intravenous) or local (carotid artery) administration of AVP prior and after systemic blockade of V1aRs. Immunostaining of CBs showed colocalization of V1aRs and tyrosine hydroxylase within glomus cells. Systemic administration of AVP increased mean arterial blood pressure (MABP) and decreased respiratory rate (RR) and minute ventilation (MV). Local administration of AVP increased MV and RR without significant changes in MABP or heart rate. Pretreatment with V1aR antagonist abolished responses to local and intravenous AVP administration. Our findings show that chemosensory cells within CBs express V1aRs and that local stimulation of the CB with AVP increases ventilation, which is contrary to systemic effects of AVP manifested by decreased ventilation. The responses are mediated by V1aRs, as blockade of the receptors prevents changes in ventilation. We hypothesize that excitatory effects of AVP within the CB provide a counterbalancing mechanism for the inhibitory effects of systemically acting AVP on the respiration. Copyright © 2018 Elsevier Inc. All rights reserved.

Role of beta-adrenergic receptor gene polymorphisms in the long-term effects of beta-blockade with carvedilol in patients with chronic heart failure.

PubMed

Metra, Marco; Covolo, Loredana; Pezzali, Natalia; Zacà, Valerio; Bugatti, Silvia; Lombardi, Carlo; Bettari, Luca; Romeo, Alessia; Gelatti, Umberto; Giubbini, Raffaele; Donato, Francesco; Dei Cas, Livio

2010-02-01

Beta-blockers are mainstay of current treatment of heart failure (HF). Beta-adrenergic receptors (AR) single nucleotide gene polymorphisms (SNPs) may influence the sensitivity and density of beta-AR. We assessed the relation between three common beta-AR SNPs and the response to carvedilol administration. We studied 183 consecutive patients with chronic HF due to ischemic or nonischemic cardiomyopathy, a LV ejection fraction (LVEF) < or = 0.35, not previously treated with beta-blockers. Each patient underwent gated-SPECT radionuclide ventriculography, cardiopulmonary exercise testing and invasive hemodynamic monitoring at baseline and after 12 months of carvedilol administration at maintenance dosages. The beta1-AR gene Arg389Gly and the beta2-AR gene Arg16Gly SNPs were not related to the response to carvedilol administration. Homozygotes for the Glu27Glu allele showed a greater increase in the LVEF, compared to the other patients (+13.0 +/- 12.2% versus +7.1 +/- 8.1% in the Gln27Gln homozygotes, and 8.3 +/- 11.4% units in the Gln27Glu heterozygotes; p = 0.022 by ANOVA). Glu27Glu homozygotes also showed a greater decline in the pulmonary wedge pressure both at rest and at peak exercise. Gln27Glu SNP was selected amongst the determinants of the LVEF response to carvedilol at multivariable analysis, in addition to the cause of cardiomyopathy, baseline systolic blood pressure and the dose of carvedilol administered. Beta1-AR Arg389Gly and beta2-AR Arg16Gly SNPs are not related to the response to carvedilol therapy. In contrast, the Gln27Glu SNP is a determinant of the LVEF response to this agent in patients with chronic HF.

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.

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

Inactivation of ID4 promotes a CRPC phenotype with constitutive AR activation through FKBP52.

PubMed

Joshi, Jugal Bharat; Patel, Divya; Morton, Derrick J; Sharma, Pankaj; Zou, Jin; Hewa Bostanthirige, Dhanushka; Gorantla, Yamini; Nagappan, Peri; Komaragiri, Shravan Kumar; Sivils, Jeffrey C; Xie, Huan; Palaniappan, Ravi; Wang, Guangdi; Cox, Marc B; Chaudhary, Jaideep

2017-04-01

Castration-resistant prostate cancer (CRPC) is the emergence of prostate cancer cells that have adapted to the androgen-depleted environment of the prostate. In recent years, targeting multiple chaperones and co-chaperones (e.g., Hsp27, FKBP52) that promote androgen receptor (AR) signaling and/or novel AR regulatory mechanisms have emerged as promising alternative treatments for CRPC. We have shown that inactivation of inhibitor of differentiation 4 (ID4), a dominant-negative helix loop helix protein, promotes de novo steroidogenesis and CRPC with a gene expression signature that resembles constitutive AR activity in castrated mice. In this study, we investigated the underlying mechanism through which loss of ID4 potentiates AR signaling. Proteomic analysis between prostate cancer cell line LNCaP (L+ns) and LNCaP lacking ID4 (L(-)ID4) revealed elevated levels of Hsp27 and FKBP52, suggesting a role for these AR-associated co-chaperones in promoting constitutively active AR signaling in L(-)ID4 cells. Interestingly, protein interaction studies demonstrated a direct interaction between ID4 and the 52-kDa FK506-binding protein (FKBP52) in vitro, but not with AR. An increase in FKBP52-dependent AR transcriptional activity was observed in L(-)ID4 cells. Moreover, pharmacological inhibition of FKBP52-AR signaling, by treatment with MJC13, attenuated the tumor growth, weight, and volume in L(-)ID4 xenografts. Together, our results demonstrate that ID4 selectively regulates AR activity through direct interaction with FKBP52, and its loss, promotes CRPC through FKBP52-mediated AR signaling. © 2016 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.

Probing Androgen Receptor Signaling in Circulating Tumor Cells in Prostate Cancer

DTIC Science & Technology

2014-07-01

androgen driven) and PSMA (androgen suppressed). Application of this CTC-based assay in a small cohort of men with prostate cancer revealed that the AR...activity in CTCs as measured by PSA and PSMA expression levels could be used to monitor the treatment of patients undergoing AR targeting therapies...transitioned the laboratory to the 3rd generation CTC iChip technology (4), and have adapted the PSA/ PSMA assay for use with this new CTC isolation

Controlled release metoprolol for aortic regurgitation: a randomised clinical trial.

PubMed

Broch, Kaspar; Urheim, Stig; Lønnebakken, Mai Tone; Stueflotten, Wenche; Massey, Richard; Fosså, Kristian; Hopp, Einar; Aakhus, Svend; Gullestad, Lars

2016-02-01

Chronic aortic regurgitation (AR) creates a volume load on the left ventricle, which induces adaptive responses. With time, excessive left ventricular (LV) dilatation may precipitate heart failure. β-adrenergic receptor antagonists (β-blockers) are beneficial in patients with heart failure, but their effect in AR is unclear. This trial was designed to evaluate the effect of controlled release metoprolol on LV remodelling in patients with AR. In this double blind trial, 75 asymptomatic patients aged 44±14 years, 89% males, fulfilling at least two echocardiographic criteria for moderate or severe chronic AR, were randomised to receive metoprolol CR/XL up-titrated to 200 mg/day, or matching placebo. The primary endpoint was LV end diastolic volume, measured by MRI after 6 months of treatment. After 6 months, the difference in the baseline-adjusted LV end diastolic volume between patients allocated to metoprolol and those allocated to placebo was 8 (95% CI -8 to 25) mL (p=0.32). The adjusted LV ejection fraction was 2.7 (95% CI 0.1 to 5.3) percentage points higher in the metoprolol group than in the placebo group (p=0.04). The exercise capacity and peak oxygen consumption did not differ between treatment arms. Serum concentrations of N-terminal pro-B-type natriuretic peptide were 138 (95% CI 71 to 205) pg/mL higher in the metoprolol group (p<0.001). There were no serious adverse events in either treatment arm. Treatment with metoprolol of adults with chronic, moderate to severe AR had no effect on LV volumes. ClinicalTrials.gov Identifier: NCT01157572-results. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

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

β2-adrenergic receptor-mediated negative regulation of group 2 innate lymphoid cell responses.

PubMed

Moriyama, Saya; Brestoff, Jonathan R; Flamar, Anne-Laure; Moeller, Jesper B; Klose, Christoph S N; Rankin, Lucille C; Yudanin, Naomi A; Monticelli, Laurel A; Putzel, Gregory Garbès; Rodewald, Hans-Reimer; Artis, David

2018-03-02

The type 2 inflammatory response is induced by various environmental and infectious stimuli. Although recent studies identified group 2 innate lymphoid cells (ILC2s) as potent sources of type 2 cytokines, the molecular pathways controlling ILC2 responses are incompletely defined. Here we demonstrate that murine ILC2s express the β 2 -adrenergic receptor (β 2 AR) and colocalize with adrenergic neurons in the intestine. β 2 AR deficiency resulted in exaggerated ILC2 responses and type 2 inflammation in intestinal and lung tissues. Conversely, β 2 AR agonist treatment was associated with impaired ILC2 responses and reduced inflammation in vivo. Mechanistically, we demonstrate that the β 2 AR pathway is a cell-intrinsic negative regulator of ILC2 responses through inhibition of cell proliferation and effector function. Collectively, these data provide the first evidence of a neuronal-derived regulatory circuit that limits ILC2-dependent type 2 inflammation. Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Osteopontin-c mediates the upregulation of androgen responsive genes in LNCaP cells through PI3K/Akt and androgen receptor signaling.

PubMed

Tilli, Tatiana Martins; Ferreira, Luciana Bueno; Gimba, Etel Rodrigues Pereira

2015-04-01

Androgen receptor (AR) signaling is a key pathway modulating prostate cancer (PCa) progression. Several steps in this pathway have been investigated in order to propose novel treatment strategies for advanced PCa. Total osteopontin (OPN) has been described as a biomarker for PCa, in addition to its role in activating the progression of this tumor. Based on the known effects of the OPNc splice variant on PCa progression, the present study investigated whether this isoform can also modulate AR signaling. In order to test this, an in vitro model was used in which LNCaP cells were cultured in the presence of conditioned medium (CM) secreted by PCa cells overexpressing OPNc (OPNc-CM). The activation of AR signaling was evaluated by measuring the expression levels of AR-responsive genes (ARGs) using quantitative polymerase chain reaction and specific oligonucleotides. The data demonstrated that all nine tested ARGs ( Fgf8 , TMPRSS2 , Greb1 , Cdk2 , Ndrg1 , Cdk1 , Pmepa1 , Psa and Ar ) are significantly upregulated in response to OPNc-CM compared with LNCaP cells cultured in CM secreted by control cells transfected with empty expression vector. The specific involvement of OPNc was demonstrated by depleting OPNc from OPNc-CM using an anti-OPNc neutralizing antibody. In addition, by using a phosphoinositide 3-kinase (PI3K)-specific inhibitor and AR antagonists, such as flutamide and bicalutamide, it was also observed that upregulation of ARGs in response to OPNc-CM involves PI3K signaling and depends on the AR. In conclusion, these data indicated that OPNc is able to activate AR signaling through the PI3K pathway and the AR. These data further corroborate our previous data, revealing the OPNc splice variant to be a key molecule that is able to modulate key signaling pathways involved in PCa progression.

Osteopontin-c mediates the upregulation of androgen responsive genes in LNCaP cells through PI3K/Akt and androgen receptor signaling

PubMed Central

TILLI, TATIANA MARTINS; FERREIRA, LUCIANA BUENO; GIMBA, ETEL RODRIGUES PEREIRA

2015-01-01

Androgen receptor (AR) signaling is a key pathway modulating prostate cancer (PCa) progression. Several steps in this pathway have been investigated in order to propose novel treatment strategies for advanced PCa. Total osteopontin (OPN) has been described as a biomarker for PCa, in addition to its role in activating the progression of this tumor. Based on the known effects of the OPNc splice variant on PCa progression, the present study investigated whether this isoform can also modulate AR signaling. In order to test this, an in vitro model was used in which LNCaP cells were cultured in the presence of conditioned medium (CM) secreted by PCa cells overexpressing OPNc (OPNc-CM). The activation of AR signaling was evaluated by measuring the expression levels of AR-responsive genes (ARGs) using quantitative polymerase chain reaction and specific oligonucleotides. The data demonstrated that all nine tested ARGs (Fgf8, TMPRSS2, Greb1, Cdk2, Ndrg1, Cdk1, Pmepa1, Psa and Ar) are significantly upregulated in response to OPNc-CM compared with LNCaP cells cultured in CM secreted by control cells transfected with empty expression vector. The specific involvement of OPNc was demonstrated by depleting OPNc from OPNc-CM using an anti-OPNc neutralizing antibody. In addition, by using a phosphoinositide 3-kinase (PI3K)-specific inhibitor and AR antagonists, such as flutamide and bicalutamide, it was also observed that upregulation of ARGs in response to OPNc-CM involves PI3K signaling and depends on the AR. In conclusion, these data indicated that OPNc is able to activate AR signaling through the PI3K pathway and the AR. These data further corroborate our previous data, revealing the OPNc splice variant to be a key molecule that is able to modulate key signaling pathways involved in PCa progression. PMID:25789054

Expression of AR-V7 in Circulating Tumour Cells Does Not Preclude Response to Next Generation Androgen Deprivation Therapy in Patients with Castration Resistant Prostate Cancer.

PubMed

Bernemann, Christof; Schnoeller, Thomas J; Luedeke, Manuel; Steinestel, Konrad; Boegemann, Martin; Schrader, Andres J; Steinestel, Julie

2017-01-01

The androgen receptor splice variant AR-V7 has recently been discussed as a predictive biomarker for nonresponse to next-generation androgen deprivation therapy (ADT) in patients with castration-resistant prostate cancer. However, we recently identified one patient showing a response from abiraterone despite expression of AR-V7 in his circulating tumour cells (CTC). Therefore, we precisely assessed the response in a cohort of 21 AR-V7 positive castration-resistant prostate cancer patients who had received therapy with abiraterone or enzalutamide. We detected a subgroup of six AR-V7 positive patients showing benefit from either abiraterone or enzalutamide. Their progression free survival was 26 d (censored) to 188 d. Four patients displayed a prostate-specific antigen decrease of >50%. When analysing prior therapies, we noticed that only one of the six patients had received next-generation ADT prior to CTC collection. As a result, we conclude that AR-V7 status in CTC cannot entirely predict nonresponse to next generation ADT and AR-V7-positive patients should not be systematically denied abiraterone or enzalutamide treatment, especially as effective alternative treatment options are still limited. A subgroup of patients can benefit from abiraterone and/or enzalutamide despite detection of AR-V7 splice variants in their circulating tumour cells. Copyright © 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Performance comparison of two androgen receptor splice variant 7 (AR-V7) detection methods.

PubMed

Bernemann, Christof; Steinestel, Julie; Humberg, Verena; Bögemann, Martin; Schrader, Andres Jan; Lennerz, Jochen K

2018-01-23

To compare the performance of two established androgen receptor splice variant 7 (AR-V7) mRNA detection systems, as paradoxical responses to next-generation androgen-deprivation therapy in AR-V7 mRNA-positive circulating tumour cells (CTC) of patients with castration-resistant prostate cancer (CRPC) could be related to false-positive classification using detection systems with different sensitivities. We compared the performance of two established mRNA-based AR-V7 detection technologies using either SYBR Green or TaqMan chemistries. We assessed in vitro performance using eight genitourinary cancer cell lines and serial dilutions in three AR-V7-positive prostate cancer cell lines, as well as in 32 blood samples from patients with CRPC. Both assays performed identically in the cell lines and serial dilutions showed identical diagnostic thresholds. Performance comparison in 32 clinical patient samples showed perfect concordance between the assays. In particular, both assays determined AR-V7 mRNA-positive CTCs in three patients with unexpected responses to next-generation anti-androgen therapy. Thus, technical differences between the assays can be excluded as the underlying reason for the unexpected responses to next-generation anti-androgen therapy in a subset of AR-V7 patients. Irrespective of the method used, patients with AR-V7 mRNA-positive CRPC should not be systematically precluded from an otherwise safe treatment option. © 2018 The Authors BJU International © 2018 BJU International Published by John Wiley & Sons Ltd.

Proteomic Analysis Reveals Differences in Tolerance to Acid Rain in Two Broad-Leaf Tree Species, Liquidambar formosana and Schima superba

PubMed Central

Wang, Chao; Liu, Ting-Wu; Chalifour, Annie; Chen, Juan; Shen, Zhi-Jun; Liu, Xiang; Wang, Wen-Hua; Zheng, Hai-Lei

2014-01-01

Acid rain (AR) is a serious environmental issue inducing harmful impacts on plant growth and development. It has been reported that Liquidambar formosana, considered as an AR-sensitive tree species, was largely injured by AR, compared with Schima superba, an AR-tolerant tree species. To clarify the different responses of these two species to AR, a comparative proteomic analysis was conducted in this study. More than 1000 protein spots were reproducibly detected on two-dimensional electrophoresis gels. Among them, 74 protein spots from L. formosana gels and 34 protein spots from S. superba gels showed significant changes in their abundances under AR stress. In both L. formosana and S. superba, the majority proteins with more than 2 fold changes were involved in photosynthesis and energy production, followed by material metabolism, stress and defense, transcription, post-translational and modification, and signal transduction. In contrast with L. formosana, no hormone response-related protein was found in S. superba. Moreover, the changes of proteins involved in photosynthesis, starch synthesis, and translation were distinctly different between L. formosana and S. superba. Protein expression analysis of three proteins (ribulose-1,5-bisphosphate carboxylase/oxygenase large subunit, ascorbate peroxidase and glutathione-S-transferase) by Western blot was well correlated with the results of proteomics. In conclusion, our study provides new insights into AR stress responses in woody plants and clarifies the differences in strategies to cope with AR between L. formosana and S. superba. PMID:25025692

Spinorial Geometry and Branes

NASA Astrophysics Data System (ADS)

Sloane, Peter

2007-09-01

We adapt the spinorial geometry method introduced in [J. Gillard, U. Gran and G. Papadopoulos, "The spinorial geometry of supersymmetric backgrounds," Class. Quant. Grav. 22 (2005) 1033 [ arXiv:hep-th/0410155

Dose-response characteristics of Clematis triterpenoid saponins and clematichinenoside AR in rheumatoid arthritis rats by liquid chromatography/mass spectrometry-based serum and urine metabolomics.

PubMed

Li, Rui; Guo, Lin-Xiu; Li, Yi; Chang, Wen-Qi; Liu, Jian-Qun; Liu, Li-Fang; Xin, Gui-Zhong

2017-03-20

Clematidis Radix et Rhizoma is a traditional Chinese medicine widely used for treating arthritic disease. Clematis triterpenoid saponins (TS) and clematichinenoside AR (C-AR) have been considered to be responsible for its antiarthritic effects. However, the underling mechanism is still unclear because of their low bioavailability. To address of this issue, metabolomics tools were performed to determine metabolic variations associated with rheumatoid arthritis (RA) and responses to Clematis TS, C-AR and positive drug (Triptolide, TP) treatments. This metabolomics investigation of RA was conducted in collagen-induced arthritis (CIA) rats. Liquid chromatography/mass spectrometry and multivariate statistical tools were used to identify the alteration of serum and urine metabolites associated with RA and responses to drug treatment. As a result, 45 potential metabolites associated with RA were identified. After treatment, a total of 24 biomarkers were regulated to normal like levels. Among these, PC(18:0/20:4), 9,11-octadecadienoic acid, arachidonic acid, 1-methyladenosine, valine, hippuric acid and pantothenic acid etc, were reversed in Clematis TS and C-AR groups. Tetrahydrocortisol was regulated to normal levels in Clematis TS and TP groups, while 3,7,12-trihydroxycholan-24-oic acid was regulated in C-AR and TP groups. Biomarkers like citric acid, p-cresol glucuronide, creatinine, cortolone were reversed in TP group. Copyright © 2016 Elsevier B.V. All rights reserved.

AR-V7 in Peripheral Whole Blood of Patients with Castration-resistant Prostate Cancer: Association with Treatment-specific Outcome Under Abiraterone and Enzalutamide.

PubMed

Seitz, Anna Katharina; Thoene, Silvia; Bietenbeck, Andreas; Nawroth, Roman; Tauber, Robert; Thalgott, Mark; Schmid, Sebastian; Secci, Ramona; Retz, Margitta; Gschwend, Jürgen E; Ruland, Jürgen; Winter, Christof; Heck, Matthias M

2017-11-01

It has been demonstrated that androgen receptor splice variant 7 (AR-V7) expression in circulating tumor cells (CTCs) predicts poor treatment response in metastatic castration-resistant prostate cancer (mCRPC) patients treated with abiraterone or enzalutamide. To develop a practical and robust liquid profiling approach for direct quantification of AR-V7 in peripheral whole blood without the need for CTC capture and to determine its potential for predicting treatment response in mCRPC patients. Whole blood samples from a prospective biorepository of 85 mCRPC patients before treatment initiation with abiraterone (n=56) or enzalutamide (n=29) were analyzed via droplet digital polymerase chain reaction. The association of AR-V7 status with prostate-specific antigen (PSA) response defined by PSA decline ≥50% and with PSA-progression-free survival (PSA-PFS), clinical PFS, and overall survival (OS) was assessed. High AR-V7 expression levels in whole blood were detectable in 18% (15/85) of patients. No patient with high AR-V7 expression achieved a PSA response, and AR-V7 status was an independent predictor of PSA response in multivariable logistic regression analysis (p=0.03). High AR-V7 expression was associated with shorter PSA-PFS (median 2.4 vs 3.7 mo; p<0.001), shorter clinical PFS (median 2.7 vs 5.5 mo; p<0.001), and shorter OS (median 4.0 vs. 13.9 mo; p<0.001). On multivariable Cox regression analysis, high AR-V7 expression remained an independent predictor of shorter PSA-PFS (hazard ratio [HR] 7.0, 95% confidence interval [CI] 2.3-20.7; p<0.001), shorter clinical PFS (HR 2.3, 95% CI 1.1-4.9; p=0.02), and shorter OS (HR 3.0, 95% CI 1.4-6.3; p=0.005). Testing of AR-V7 mRNA levels in whole blood is a simple and promising approach to predict poor treatment outcome in mCRPC patients receiving abiraterone or enzalutamide. We established a method for determining AR-V7 status in whole blood. This test predicted treatment resistance in patients with metastatic castration-resistant prostate cancer undergoing treatment with abiraterone or enzalutamide. Prospective validation is needed before application to clinical practice. Copyright © 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Effect of polymorphism of the beta(2)-adrenergic receptor on response to regular use of albuterol in asthma.

PubMed

Israel, E; Drazen, J M; Liggett, S B; Boushey, H A; Cherniack, R M; Chinchilli, V M; Cooper, D M; Fahy, J V; Fish, J E; Ford, J G; Kraft, M; Kunselman, S; Lazarus, S C; Lemanske, R F; Martin, R J; McLean, D E; Peters, S P; Silverman, E K; Sorkness, C A; Szefler, S J; Weiss, S T; Yandava, C N

2001-01-01

Regular use of inhaled beta-adrenergic agonists may have adverse effects in some asthma patients. Polymorphisms of the beta(2)-adrenergic receptor (beta(2)-AR) can affect its regulation; however, results of smaller studies of the effects of such polymorphisms on response to beta-agonist therapy have been inconsistent. We examined the possible effects of polymorphisms at codons 16 (beta(2)-AR-16) and 27 (beta(2)-AR-27) on response to albuterol by genotyping 190 asthmatics who had participated in a trial of regular versus as-needed albuterol use. During the 16-week treatment period, patients homozygous for arginine (Arg/Arg) at beta(2)-AR-16 who used albuterol regularly had a small decline in morning peak expiratory flow (AM PEF). This effect was magnified during a 4-week run-out period, when all patients returned to as-needed albuterol only. By the end of the study, Arg/Arg subjects who had used albuterol regularly had an AM PEF 30.5 +/- 12.1 liters/min lower (p = 0.012) than Arg/Arg patients who had used albuterol as needed only. Subjects homozygous for glycine at beta(2)-AR-16 showed no such decline. Evening PEF also declined in the Arg/Arg regular but not in as-need albuterol users. No significant differences between regular and as-needed treatment were associated with polymorphisms at beta(2)-AR-27. Polymorphisms of the beta(2)-AR may influence airway responses to regular inhaled beta-agonist treatment. Copyright 2001 S. Karger AG, Basel

Allergic rhinitis and inflammatory airway disease: interactions within the unified airspace.

PubMed

Marple, Bradley F

2010-01-01

Allergic rhinitis (AR), the most common chronic allergic condition in outpatient medicine, is associated with immense health care costs and socioeconomic consequences. AR's impact may be partly from interacting of respiratory conditions via allergic inflammation. This study was designed to review potential interactive mechanisms of AR and associated conditions and consider the relevance of a bidirectional "unified airway" respiratory inflammation model on diagnosis and treatment of inflammatory airway disease. MEDLINE was searched for pathophysiology and pathophysiological and epidemiologic links between AR and diseases of the sinuses, lungs, middle ear, and nasopharynx. Allergic-related inflammatory responses or neural and systemic processes fostering inflammatory changes distant from initial allergen provocation may link AR and comorbidities. Treating AR may benefit associated respiratory tract comorbidities. Besides improving AR outcomes, treatment inhibiting eosinophil recruitment and migration, normalizing cytokine profiles, and reducing asthma-associated health care use in atopic subjects would likely ameliorate other upper airway diseases such as acute rhinosinusitis, chronic rhinosinusitis (CRS) with nasal polyposis (NP), adenoidal hypertrophy, and otitis media with effusion. Epidemiological concordance of AR with several airway diseases conforms to a bidirectional "unified airway" respiratory inflammation model based on anatomic and histological upper and lower airway connections. Epidemiology and current understanding of inflammatory, humoral, and neural processes make links between AR and disorders including asthma, otitis media, NP, and CRS plausible. Combining AR with associated conditions increases disease burden; worsened associated illness may accompany worsened AR. AR pharmacotherapies include antihistamines, leukotriene antagonists, intranasal corticosteroids, and immunotherapy; treatments attenuating proinflammatory responses may also benefit associated conditions.

Nucleoporin 62 and Ca(2+)/calmodulin dependent kinase kinase 2 regulate androgen receptor activity in castrate resistant prostate cancer cells.

PubMed

Karacosta, Loukia G; Kuroski, Laura A; Hofmann, Wilma A; Azabdaftari, Gissou; Mastri, Michalis; Gocher, Angela M; Dai, Shuhang; Hoste, Allen J; Edelman, Arthur M

2016-02-15

Re-activation of the transcriptional activity of the androgen receptor (AR) is an important factor mediating progression from androgen-responsive to castrate-resistant prostate cancer (CRPC). However, the mechanisms regulating AR activity in CRPC remain incompletely understood. Ca(2+) /calmodulin-dependent kinase kinase (CaMKK) 2 was previously shown to regulate AR activity in androgen-responsive prostate cancer cells. Our objective was to further explore the basis of this regulation in CRPC cells. The abundance of CaMKK2 in nuclear fractions of androgen-responsive prostate cancer and CRPC, cells were determined by subcellular fractionation and Western blotting. CaMKK2 association with nuclear pore complexes (NPCs) and nucleoporins (Nups) including Nup62, were imaged by structured illumination and super-resolution fluorescence microscopy and co-immunoprecipitation, respectively. The abundance and subcellular localization of CaMKK2 and Nup62 in human clinical specimens of prostate cancer was visualized by immunohistochemistry. The role of Nups in the growth and viability of CRPC cells was assessed by RNA interference and cell counting. The involvement of CaMKK2 and Nup62 in regulating AR transcriptional activity was addressed by RNA interference, chromatin immunoprecipitation, androgen response element reporter assay, and Western blotting. CaMKK2 was expressed at higher levels in the nuclear fraction of CPRC C4-2 cells, than in that of androgen-responsive LNCaP cells. In C4-2 cells, CaMKK2 associated with NPCs of the nuclear envelope and physically interacted with Nup62. CaMKK2 and Nup62 demonstrated pronounced, and similar increases in both expression and perinuclear/nuclear localization in human clinical specimens of advanced prostate cancer relative to normal prostate. Knockdown of Nup62, but not of Nups, 98 or 88, reduced growth and viability of C4-2 cells. Knockdown of Nup62 produced a greater reduction of the growth and viability of C4-2 cells than of non-neoplastic RWPE-1 prostatic cells. Nup62, CaMKK2, and the AR were recruited to androgen response elements of the AR target genes, prostate specific antigen, and transmembrane protease, serine 2. Knockdown of CaMKK2 and Nup62 reduced prostate specific antigen expression and AR transcriptional activity driven by androgen response elements from the prostate-specific probasin gene promoter. Nup62 and CaMKK2 are required for optimal AR transcriptional activity and a potential mechanism for AR re-activation in CRPC. © 2015 Wiley Periodicals, Inc.

The role of androgen receptor CAG repeat polymorphism and other factors which affect the clinical response to testosterone replacement in metabolic syndrome and type 2 diabetes: TIMES2 sub-study.

PubMed

Stanworth, R D; Akhtar, S; Channer, K S; Jones, T H

2014-02-01

The TIMES2 (testosterone replacement in hypogonadal men with either metabolic syndrome or type 2 diabetes) study reported beneficial effects of testosterone replacement therapy (TRT) on insulin resistance and other variables in men with diabetes or metabolic syndrome. The androgen receptor CAG repeat polymorphism (AR CAG) is known to affect stimulated AR activity and has been linked to various clinically relevant variables. To assess the role of AR CAG in the alteration of clinical response to TRT in the TIMES2 study. Subgroup analysis from a multicentre, randomised, double-blind, placebo-controlled and parallel group study. Outpatient study recruiting from secondary and primary care. A total of 139 men with hypogonadism and type 2 diabetes or metabolic syndrome, of which 73 received testosterone during the TIMES2 study. Testosterone 2% transdermal gel vs placebo. Regression coefficient of AR CAG from linear regression models for each variable. AR CAG was independently positively associated with change in fasting insulin, triglycerides and diastolic blood pressure during TRT with a trend to association with HOMA-IR - the primary outcome variable. There was a trend to negative association between AR CAG and change in PSA. There was no association of AR CAG with change in other glycaemic variables, other lipid variables or obesity. AR CAG affected the response of some variables to TRT in the TIMES2 study, although the association with HOMA-IR did not reach significance. Various factors may have limited the power of our study to detect the significant associations between AR CAG, testosterone levels and change in variables with testosterone treatment. Analysis of similar data sets from other clinical trials is warranted.

Registration Combining Wide and Narrow Baseline Feature Tracking Techniques for Markerless AR Systems.

PubMed

Duan, Liya; Guan, Tao; Yang, Bo

2009-01-01

Augmented reality (AR) is a field of computer research which deals with the combination of real world and computer generated data. Registration is one of the most difficult problems currently limiting the usability of AR systems. In this paper, we propose a novel natural feature tracking based registration method for AR applications. The proposed method has following advantages: (1) it is simple and efficient, as no man-made markers are needed for both indoor and outdoor AR applications; moreover, it can work with arbitrary geometric shapes including planar, near planar and non planar structures which really enhance the usability of AR systems. (2) Thanks to the reduced SIFT based augmented optical flow tracker, the virtual scene can still be augmented on the specified areas even under the circumstances of occlusion and large changes in viewpoint during the entire process. (3) It is easy to use, because the adaptive classification tree based matching strategy can give us fast and accurate initialization, even when the initial camera is different from the reference image to a large degree. Experimental evaluations validate the performance of the proposed method for online pose tracking and augmentation.

Isoproterenol Acts as a Biased Agonist of the Alpha-1A-Adrenoceptor that Selectively Activates the MAPK/ERK Pathway

PubMed Central

Copik, Alicja. J.; Baldys, Aleksander; Nguyen, Khanh; Sahdeo, Sunil; Ho, Hoangdung; Kosaka, Alan; Dietrich, Paul J.; Fitch, Bill; Raymond, John R.; Ford, Anthony P. D. W.; Button, Donald; Milla, Marcos E.

2015-01-01

The α1A-AR is thought to couple predominantly to the Gαq/PLC pathway and lead to phosphoinositide hydrolysis and calcium mobilization, although certain agonists acting at this receptor have been reported to trigger activation of arachidonic acid formation and MAPK pathways. For several G protein-coupled receptors (GPCRs) agonists can manifest a bias for activation of particular effector signaling output, i.e. not all agonists of a given GPCR generate responses through utilization of the same signaling cascade(s). Previous work with Gαq coupling-defective variants of α1A-AR, as well as a combination of Ca2+ channel blockers, uncovered cross-talk between α1A-AR and β2-AR that leads to potentiation of a Gαq-independent signaling cascade in response to α1A-AR activation. We hypothesized that molecules exist that act as biased agonists to selectively activate this pathway. In this report, isoproterenol (Iso), typically viewed as β-AR-selective agonist, was examined with respect to activation of α1A-AR. α1A-AR selective antagonists were used to specifically block Iso evoked signaling in different cellular backgrounds and confirm its action at α1A-AR. Iso induced signaling at α1A-AR was further interrogated by probing steps along the Gαq /PLC, Gαs and MAPK/ERK pathways. In HEK-293/EBNA cells transiently transduced with α1A-AR, and CHO_α1A-AR stable cells, Iso evoked low potency ERK activity as well as Ca2+ mobilization that could be blocked by α1A-AR selective antagonists. The kinetics of Iso induced Ca2+ transients differed from typical Gαq- mediated Ca2+ mobilization, lacking both the fast IP3R mediated response and the sustained phase of Ca2+ re-entry. Moreover, no inositol phosphate (IP) accumulation could be detected in either cell line after stimulation with Iso, but activation was accompanied by receptor internalization. Data are presented that indicate that Iso represents a novel type of α1A-AR partial agonist with signaling bias toward MAPK/ERK signaling cascade that is likely independent of coupling to Gαq. PMID:25606852

Processing on weak electric signals by the autoregressive model

NASA Astrophysics Data System (ADS)

Ding, Jinli; Zhao, Jiayin; Wang, Lanzhou; Li, Qiao

2008-10-01

A model of the autoregressive model of weak electric signals in two plants was set up for the first time. The result of the AR model to forecast 10 values of the weak electric signals is well. It will construct a standard set of the AR model coefficient of the plant electric signal and the environmental factor, and can be used as the preferences for the intelligent autocontrol system based on the adaptive characteristic of plants to achieve the energy saving on agricultural productions.

Sex differences and the effects of ovariectomy on the β-adrenergic contractile response

PubMed Central

McIntosh, Victoria J.; Chandrasekera, P. Charukeshi

2011-01-01

The presence of sex differences in myocardial β-adrenergic responsiveness is controversial, and limited studies have addressed the mechanism underlying these differences. Studies were performed using isolated perfused hearts from male, intact female and ovariectomized female mice to investigate sex differences and the effects of ovarian hormone withdrawal on β-adrenergic receptor function. Female hearts exhibited blunted contractile responses to the β-adrenergic receptor agonist isoproterenol (ISO) compared with males but not ovariectomized females. There were no sex differences in β1-adrenergic receptor gene or protein expression. To investigate the role of adenylyl cyclase, phosphodiesterase, and the cAMP-signaling cascade in generating sex differences in the β-adrenergic contractile response, dose-response studies were performed in isolated perfused male and female hearts using forskolin, 3-isobutyl-1-methylxanthine (IBMX), and 8-(4-chlorophenylthio)adenosine 3′,5′-cyclic monophosphate (CPT-cAMP). Males showed a modestly enhanced contractile response to forskolin at 300 nM and 5 μM compared with females, but there were no sex differences in the response to IBMX or CPT-cAMP. The role of the A1 adenosine receptor (A1AR) in antagonizing the β-adrenergic contractile response was investigated using both the A1AR agonist 2-chloro-N6-cyclopentyl-adenosine and A1AR knockout (KO) mice. Intact females showed an enhanced A1AR anti-adrenergic effect compared with males and ovariectomized females. The β-adrenergic contractile response was potentiated in both male and female A1ARKO hearts, with sex differences no longer present above 1 nM ISO. The β-adrenergic contractile response is greater in male hearts than females, and minor differences in the action of adenylyl cyclase or the A1AR may contribute to these sex differences. PMID:21685268

40 CFR 300.175 - Federal agencies: additional responsibilities and assistance.

Code of Federal Regulations, 2014 CFR

2014-07-01

... substances on lands under its jurisdiction. (ii) The Agriculture Research Service (ARS) administers an... nutrition. The ARS has the capabilities to provide regulation of, and evaluation and training for, employees exposed to biological, chemical, radiological, and industrial hazards. In emergency situations, the ARS...

40 CFR 300.175 - Federal agencies: additional responsibilities and assistance.

Code of Federal Regulations, 2011 CFR

2011-07-01

... substances on lands under its jurisdiction. (ii) The Agriculture Research Service (ARS) administers an... nutrition. The ARS has the capabilities to provide regulation of, and evaluation and training for, employees exposed to biological, chemical, radiological, and industrial hazards. In emergency situations, the ARS...

40 CFR 300.175 - Federal agencies: additional responsibilities and assistance.

Code of Federal Regulations, 2013 CFR

2013-07-01

... substances on lands under its jurisdiction. (ii) The Agriculture Research Service (ARS) administers an... nutrition. The ARS has the capabilities to provide regulation of, and evaluation and training for, employees exposed to biological, chemical, radiological, and industrial hazards. In emergency situations, the ARS...

78 FR 11134 - Submission for OMB Review; Comment Request

Federal Register 2010, 2011, 2012, 2013, 2014

2013-02-15

... Information: The Agricultural Research Service (ARS) will collect identifying information on the applicant... peer review of Agricultural Research Service (ARS) research plans in response to Congressional mandate... 103d). The ARS peer-review panels are scientists who review current scientific research projects. Need...

40 CFR 300.175 - Federal agencies: additional responsibilities and assistance.

Code of Federal Regulations, 2012 CFR

2012-07-01

... substances on lands under its jurisdiction. (ii) The Agriculture Research Service (ARS) administers an... nutrition. The ARS has the capabilities to provide regulation of, and evaluation and training for, employees exposed to biological, chemical, radiological, and industrial hazards. In emergency situations, the ARS...

40 CFR 300.175 - Federal agencies: additional responsibilities and assistance.

Code of Federal Regulations, 2010 CFR

2010-07-01

... substances on lands under its jurisdiction. (ii) The Agriculture Research Service (ARS) administers an... nutrition. The ARS has the capabilities to provide regulation of, and evaluation and training for, employees exposed to biological, chemical, radiological, and industrial hazards. In emergency situations, the ARS...

Concurrent Use of an Audience Response System at a Multi-Campus College of Pharmacy

PubMed Central

Alkhateeb, Fadi M.; Singh-Franco, Devada

2012-01-01

Objective. To assess the impact of an audience response system (ARS) on student engagement at a multi-campus college of pharmacy. Methods. An online questionnaire was designed and administered to measure the impact of an ARS on student engagement, distance education, projected use, and satisfaction among pharmacy students for a course delivered across 3 sites via synchronous video transmission. Results. Students reported that use of the ARS made it easier to participate (85.3%) and helped them to focus (75.7%) in classes when the lecturer was physically at a different site. They also valued that the ARS allowed them to respond anonymously (93.2%). A minority of students indicated that use of the ARS was distracting (11.8%). Conclusions. Implementation of an ARS was associated with positive student perceptions of engagement and may improve feelings of connectedness among students at schools with multiple sites. Use of ARSs could also represent a cognitive intercession strategy to help reduce communication apprehension. PMID:22412205

Cardiac β-adrenergic responsiveness of obese Zucker rats: The role of AMPK.

PubMed

Bussey, Carol T; Thaung, Hp Aye; Hughes, Gillian; Bahn, Andrew; Lamberts, Regis R

2018-06-05

What is the central question of the study? What is the main finding and its importance? 1. Is the reduced signalling of AMPK, a key regulator of energy homeostasis in the heart, responsible for the reduced β-adrenergic responsiveness of the heart in obesity? 2. Inhibition of AMPK in isolated hearts prevented the reduced cardiac β-adrenergic responsiveness of obese rats, which was accompanied by reduced phosphorylation of AMPK, a proxy of AMPK activity. This suggests a direct functional link between β-adrenergic responsiveness and AMPK signalling in the heart, and that AMPK might be an important target to restore the β-adrenergic responsiveness in the heart in obesity. The obesity epidemic impacts heavily on cardiovascular health, in part due to changes in cardiac metabolism. AMP-activated protein kinase (AMPK) is a key regulator of energy homeostasis in the heart, and is regulated by β-adrenoceptors (AR) under normal conditions. In obesity, chronic sympathetic overactivation leads to impaired cardiac β-AR responsiveness, although it is unclear whether AMPK signalling, downstream of β-AR, contributes to this dysfunction. Therefore, we aimed to determine whether reduced AMPK signalling is responsible for the reduced β-AR responsiveness in obesity. In isolated hearts of lean and obese Zucker rats, we tested β-AR responsiveness to β 1 -AR agonist isoproterenol (ISO, 1 × 10 -10 - 5 × 10 -8  M) in the absence and presence of the AMPK inhibitor compound C (CC, 10 μM). β 1 -AR expression and AMPK phosphorylation were assessed by Western blot. β-Adrenergic responsiveness was reduced in the hearts of obese rats (LogEC50 of ISO-developed pressure dose-response curves: lean -8.53 ± 0.13 vs. obese -8.35 ± 0.10 10 x M; p < 0.05 lean vs. obese, n = 6 per group). This difference was not apparent after AMPK inhibition (LogEC50 of ISO-developed pressure curves: lean CC -8.19 ± 0.12 vs. obese CC 8.17 ± 0.13 10 x M, p > 0.05, n = 6 per group). β 1 -AR expression and AMPK phosphorylation were reduced in hearts of obese rats (AMPK at Thr 172 : lean 1.73 ± 0.17 vs. lean CC 0.81 ± 0.13, and obese 1.18 ± 0.09 vs. obese CC 0.81 ± 0.16 arbitrary units, p < 0.05, n = 6 per group). Thus, a direct functional link between β-adrenergic responsiveness and AMPK signalling in the heart exists, and AMPK might be an important target to restore the reduced cardiac β-adrenergic responsiveness in obesity. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

GSNO Reductase and β2 Adrenergic Receptor Gene-gene Interaction: Bronchodilator Responsiveness to Albuterol

PubMed Central

Choudhry, Shweta; Que, Loretta G.; Yang, Zhonghui; Liu, Limin; Eng, Celeste; Kim, Sung O.; Kumar, Gunjan; Thyne, Shannon; Chapela, Rocio; Rodriguez-Santana, Jose R.; Rodriguez-Cintron, William; Avila, Pedro C.; Stamler, Jonathan S.; Burchard, Esteban G.

2010-01-01

Background Short-acting inhaled β2-agonists such as albuterol are used for bronchodilation and are the mainstay of asthma treatment worldwide. There is significant variation in bronchodilator responsiveness to albuterol not only between individuals but also across racial/ethnic groups. The β2-adrenergic receptor (β2AR) is the target for β2-agonist drugs. The enzyme S-nitrosoglutathione reductase (GSNOR), which regulates levels of the endogenous bronchodilator S-nitrosoglutathione, has been shown to modulate the response to β2-agonists. Objective We hypothesized that there are pharmacogenetic interactions between GSNOR and β2AR gene variants which are associated with variable response to albuterol. Methods We performed family-based analyses to test for association between GSNOR gene variants and asthma and related phenotypes in 609 Puerto Rican and Mexican families with asthma. In addition, we tested these subjects for pharmacogenetic interaction between GSNOR and β2AR gene variants and responsiveness to albuterol using linear regression. Cell transfection experiments were performed to test the potential effect of the GSNOR gene variants. Results Among Puerto Ricans, several GSNOR SNPs and a haplotype in the 3′UTR were significantly associated with increased risk for asthma and lower bronchodilator responsiveness (p = 0.04 to 0.007). The GSNOR risk haplotype affects expression of GSNOR mRNA and protein, suggesting a gain of function. Furthermore, gene-gene interaction analysis provided evidence of pharmacogenetic interaction between GSNOR and β2AR gene variants and the response to albuterol in Puerto Rican (p = 0.03), Mexican (p = 0.15) and combined Puerto Rican and Mexican asthmatics (p = 0.003). Specifically, GSNOR+17059*β2AR+46 genotype combinations (TG+GG*AG and TG+GG*GG) were associated with lower bronchodilator response. Conclusion Genotyping of GSNOR and β2AR genes may be a useful in identifying Latino subjects, who might benefit from adjuvant therapy for refractory asthma. PMID:20335826

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

Adherence to AHA Guidelines When Adapted for Augmented Reality Glasses for Assisted Pediatric Cardiopulmonary Resuscitation: A Randomized Controlled Trial.

PubMed

Siebert, Johan N; Ehrler, Frederic; Gervaix, Alain; Haddad, Kevin; Lacroix, Laurence; Schrurs, Philippe; Sahin, Ayhan; Lovis, Christian; Manzano, Sergio

2017-05-29

The American Heart Association (AHA) guidelines for cardiopulmonary resuscitation (CPR) are nowadays recognized as the world's most authoritative resuscitation guidelines. Adherence to these guidelines optimizes the management of critically ill patients and increases their chances of survival after cardiac arrest. Despite their availability, suboptimal quality of CPR is still common. Currently, the median hospital survival rate after pediatric in-hospital cardiac arrest is 36%, whereas it falls below 10% for out-of-hospital cardiac arrest. Among emerging information technologies and devices able to support caregivers during resuscitation and increase adherence to AHA guidelines, augmented reality (AR) glasses have not yet been assessed. In order to assess their potential, we adapted AHA Pediatric Advanced Life Support (PALS) guidelines for AR glasses. The study aimed to determine whether adapting AHA guidelines for AR glasses increased adherence by reducing deviation and time to initiation of critical life-saving maneuvers during pediatric CPR when compared with the use of PALS pocket reference cards. We conducted a randomized controlled trial with two parallel groups of voluntary pediatric residents, comparing AR glasses to PALS pocket reference cards during a simulation-based pediatric cardiac arrest scenario-pulseless ventricular tachycardia (pVT). The primary outcome was the elapsed time in seconds in each allocation group, from onset of pVT to the first defibrillation attempt. Secondary outcomes were time elapsed to (1) initiation of chest compression, (2) subsequent defibrillation attempts, and (3) administration of drugs, as well as the time intervals between defibrillation attempts and drug doses, shock doses, and number of shocks. All these outcomes were assessed for deviation from AHA guidelines. Twenty residents were randomized into 2 groups. Time to first defibrillation attempt (mean: 146 s) and adherence to AHA guidelines in terms of time to other critical resuscitation endpoints and drug dose delivery were not improved using AR glasses. However, errors and deviations were significantly reduced in terms of defibrillation doses when compared with the use of the PALS pocket reference cards. In a total of 40 defibrillation attempts, residents not wearing AR glasses used wrong doses in 65% (26/40) of cases, including 21 shock overdoses >100 J, for a cumulative defibrillation dose of 18.7 Joules per kg. These errors were reduced by 53% (21/40, P<.001) and cumulative defibrillation dose by 37% (5.14/14, P=.001) with AR glasses. AR glasses did not decrease time to first defibrillation attempt and other critical resuscitation endpoints when compared with PALS pocket cards. However, they improved adherence and performance among residents in terms of administering the defibrillation doses set by AHA. ©Johan N Siebert, Frederic Ehrler, Alain Gervaix, Kevin Haddad, Laurence Lacroix, Philippe Schrurs, Ayhan Sahin, Christian Lovis, Sergio Manzano. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 29.05.2017.

Prey composition modulates exposure risk to anticoagulant rodenticides in a sentinel predator, the barn owl.

PubMed

Geduhn, Anke; Esther, Alexandra; Schenke, Detlef; Gabriel, Doreen; Jacob, Jens

2016-02-15

Worldwide, small rodents are main prey items for many mammalian and avian predators. Some rodent species have pest potential and are managed with anticoagulant rodenticides (ARs). ARs are consumed by target and non-target small mammals and can lead to secondary exposure of predators. The development of appropriate risk mitigation strategies is important and requires detailed knowledge of AR residue pathways. From July 2011 to October 2013 we collected 2397 regurgitated barn owl (Tyto alba) pellets to analyze diet composition of owls on livestock farms in western Germany. 256 of them were fresh pellets that were collected during brodifacoum baiting. Fresh pellets and 742 liver samples of small mammals that were trapped during baiting in the same area were analyzed for residues of ARs. We calculated exposure risk of barn owls to ARs by comparing seasonal diet composition of owls with AR residue patterns in prey species. Risk was highest in autumn, when barn owls increasingly preyed on Apodemus that regularly showed AR residues, sometimes at high concentrations. The major prey species (Microtus spp.) that was consumed most frequently in summer had less potential to contribute to secondary poisoning of owls. There was no effect of AR application on prey composition. We rarely detected ARs in pellets (2 of 256 samples) but 13% of 38 prey individuals in barn owl nests were AR positive and substantiated the expected pathway. AR residues were present in 55% of 11 barn owl carcasses. Fluctuation in non-target small mammal abundance and differences in AR residue exposure patterns in prey species drives exposure risk for barn owls and probably other predators of small mammals. Exposure risk could be minimized through spatial and temporal adaption of AR applications (avoiding long baiting and non-target hot spots at farms) and through selective bait access for target animals. Copyright © 2015 Elsevier B.V. All rights reserved.

Breathing hot humid air induces airway irritation and cough in patients with allergic rhinitis.

PubMed

Khosravi, Mehdi; Collins, Paul B; Lin, Ruei-Lung; Hayes, Don; Smith, Jaclyn A; Lee, Lu-Yuan

2014-07-01

We studied the respiratory responses to an increase in airway temperature in patients with allergic rhinitis (AR). Responses to isocapnic hyperventilation (40% of maximal voluntary ventilation) for 4min of humidified hot air (HA; 49°C) and room air (RA; 21°C) were compared between AR patients (n=7) and healthy subjects (n=6). In AR patients, cough frequency increased pronouncedly from 0.10±0.07 before to 2.37±0.73 during, and 1.80±0.79coughs/min for the first 8min after the HA challenge, but not during the RA challenge. In contrast, neither HA nor RA had any significant tussive effect in healthy subjects. The HA challenge also caused respiratory discomfort (mainly throat irritation) measured by the handgrip dynamometry in AR patients, but not in healthy subjects. Bronchoconstriction was not detected after the HA challenge in either group of subjects. In conclusion, hyperventilation of HA triggered vigorous cough response and throat irritation in AR patients, indicating the involvement of sensory nerves innervating upper airways. Copyright © 2014 Elsevier B.V. All rights reserved.

α1- and α2-adrenergic receptors in the retrotrapezoid nucleus differentially regulate breathing in anesthetized adult rats.

PubMed

Oliveira, Luiz M; Moreira, Thiago S; Kuo, Fu-Shan; Mulkey, Daniel K; Takakura, Ana C

2016-09-01

Norepinephrine (NE) is a potent modulator of breathing that can increase/decrease respiratory activity by α1-/α2-adrenergic receptor (AR) activation, respectively. The retrotrapezoid nucleus (RTN) is known to contribute to central chemoreception, inspiration, and active expiration. Here we investigate the sources of catecholaminergic inputs to the RTN and identify respiratory effects produced by activation of ARs in this region. By injecting the retrograde tracer Fluoro-Gold into the RTN, we identified back-labeled catecholaminergic neurons in the A7 region. In urethane-anesthetized, vagotomized, and artificially ventilated male Wistar rats unilateral injection of NE or moxonidine (α2-AR agonist) blunted diaphragm muscle activity (DiaEMG) frequency and amplitude, without changing abdominal muscle activity. Those inhibitory effects were reduced by preapplication of yohimbine (α2-AR antagonist) into the RTN. Conversely, unilateral RTN injection of phenylephrine (α1-AR agonist) increased DiaEMG amplitude and frequency and facilitated active expiration. This response was blocked by prior RTN injection of prazosin (α1-AR antagonist). Interestingly, RTN injection of propranolol (β-AR antagonist) had no effect on respiratory inhibition elicited by applications of NE into the RTN; however, the combined blockade of α2- and β-ARs (coapplication of propranolol and yohimbine) revealed an α1-AR-dependent excitatory response to NE that resulted in increase in DiaEMG frequency and facilitation of active expiration. However, blockade of α1-, α2-, or β-ARs in the RTN had minimal effect on baseline respiratory activity, on central or peripheral chemoreflexes. These results suggest that NE signaling can modulate RTN chemoreceptor function; however, endogenous NE signaling does not contribute to baseline breathing or the ventilatory response to central or peripheral chemoreceptor activity in urethane-anesthetized rats. Copyright © 2016 the American Physiological Society.

Adenosine A2A Receptor Activation and Macrophage-mediated Experimental Glomerulonephritis

PubMed Central

Garcia, Gabriela E.; Truong, Luan D.; Li, Ping; Zhang, Ping; Du, Jie; Chen, Jiang-Fan; Feng, Lili

2010-01-01

In immune-induced inflammation, leukocytes are key mediators of tissue damage. Since A2A adenosine receptors (A2AR) are endogenous suppressors of inflammation, we examined cellular and molecular mechanisms of kidney damage to determine whether selective activation of A2AR will suppress inflammation in a rat model of glomerulonephritis. Activation of A2AR reduced the degree of kidney injury in both the acute inflammatory phase and the progressive phase of glomerulonephritis. This protection against acute and chronic inflammation was associated with suppression of the glomerular expression of the MDC/CCL22 chemokine and down-regulation of MIP-1α/CCL3, RANTES/CCL5, MIP-1β/CCL4, and MCP-1/CCL2 chemokines. The expression of anti-inflammatory cytokines, IL-4 and IL-10, also increased. The mechanism for these anti-inflammatory responses to the A2AR agonist was suppression of macrophages function. A2AR expression was increased in macrophages, macrophage-derived chemokines were reduced in response to the A2AR agonist, and chemokines not expressed in macrophages did not respond to A2AR activation. Thus, activation of the A2AR on macrophages inhibits immune-associated inflammation. In glomerulonephritis, A2AR activation modulates inflammation and tissue damage even in the progressive phase of glomerulonephritis. Accordingly, pharmacological activation of A2AR could be developed into a novel treatment for glomerulonephritis and other macrophage-related inflammatory diseases. PMID:17898087

Assessing the Integration of Audience Response System Technology in Teaching of Anatomical Sciences

PubMed Central

Alexander, Cara J.; Crescini, Weronika M.; Juskewitch, Justin E.; Lachman, Nirusha; Pawlina, Wojciech

2009-01-01

The goals of our study were to determine the predictive value and usability of an audience response system (ARS) as a knowledge assessment tool in an undergraduate medical curriculum. Over a three year period (2006–2008), data were collected from first year didactic blocks in Genetics/Histology and Anatomy/Radiology (n=42–50 per class). During each block, students answered clinically oriented multiple choice questions using the ARS. Students’ performances were recorded and cumulative ARS scores were compared with final examination performances. Correlation coefficients between these variables were calculated to assess the existence and direction of an association between ARS and final examination score. If associations existed, univariate models were then constructed using ARS as a predictor of final examination score. Student and faculty perception of ARS difficulty, usefulness, effect on performance, and preferred use were evaluated using a questionnaire. There was a statistically significant positive correlation between ARS and final examination scores in all didactic blocks and predictive univariate models were constructed for each relationship (all P < 0.0001). Students and faculty agreed that ARS was easy to use and are liable tool for providing real-time feedback that improved their performance and participation. In conclusion, we found ARS to be an effective assessment tool benefiting the faculty and the students in a curriculum focused on interaction and self-directed learning. PMID:19670428

Assessing the integration of audience response system technology in teaching of anatomical sciences.

PubMed

Alexander, Cara J; Crescini, Weronika M; Juskewitch, Justin E; Lachman, Nirusha; Pawlina, Wojciech

2009-01-01

The goals of our study were to determine the predictive value and usability of an audience response system (ARS) as a knowledge assessment tool in an undergraduate medical curriculum. Over a three year period (2006-2008), data were collected from first year didactic blocks in Genetics/Histology and Anatomy/Radiology (n = 42-50 per class). During each block, students answered clinically oriented multiple choice questions using the ARS. Students' performances were recorded and cumulative ARS scores were compared with final examination performances. Correlation coefficients between these variables were calculated to assess the existence and direction of an association between ARS and final examination score. If associations existed, univariate models were then constructed using ARS as a predictor of final examination score. Student and faculty perception of ARS difficulty, usefulness, effect on performance, and preferred use were evaluated using a questionnaire. There was a statistically significant positive correlation between ARS and final examination scores in all didactic blocks and predictive univariate models were constructed for each relationship (all P < 0.0001). Students and faculty agreed that ARS was easy to use and a reliable tool for providing real-time feedback that improved their performance and participation. In conclusion, we found ARS to be an effective assessment tool benefiting the faculty and the students in a curriculum focused on interaction and self-directed learning. 2009 American Association of Anatomists

Comparison of fMRI data from passive listening and active-response story processing tasks in children

PubMed Central

Vannest, Jennifer J.; Karunanayaka, Prasanna R.; Altaye, Mekibib; Schmithorst, Vincent J.; Plante, Elena M.; Eaton, Kenneth J.; Rasmussen, Jerod M.; Holland, Scott K.

2009-01-01

Purpose To use functional MRI methods to visualize a network of auditory and language-processing brain regions associated with processing an aurally-presented story. We compare a passive listening (PL) story paradigm to an active-response (AR) version including on-line performance monitoring and a sparse acquisition technique. Materials/Methods Twenty children (ages 11−13) completed PL and AR story processing tasks. The PL version presented alternating 30-second blocks of stories and tones; the AR version presented story segments, comprehension questions, and 5s tone sequences, with fMRI acquisitions between stimuli. fMRI data was analyzed using a general linear model approach and paired t-test identifying significant group activation. Results Both tasks activated in primary auditory cortex, superior temporal gyrus bilaterally, left inferior frontal gyrus. The AR task demonstrated more extensive activation, including dorsolateral prefrontal cortex and anterior/posterior cingulate cortex. Comparison of effect size in each paradigm showed a larger effect for the AR paradigm in a left inferior frontal ROI. Conclusion Activation patterns for story processing in children are similar in passive listening and active-response tasks. Increases in extent and magnitude of activation in the AR task are likely associated with memory and attention resources engaged across acquisition intervals. PMID:19306445

ORNL rod-bundle heat-transfer test data. Volume 2. Thermal-Hydraulic Test Facility experimental data report for test 3. 03. 6AR - transient film boiling in upflow

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

Mullins, C. B.; Felde, D. K.; Sutton, A. G.

1982-04-01

Reduced instrument responses are presented for Thermal-Hydraulic Test Facility (THTF) Test 3.03.6AR. This test was conducted by members of the ORNL Pressurized-Water-Reactor (PWR) Blowdown Heat Transfer (BDHT) Separate-Effects Program on May 21, 1980. Objective was to investigate heat transfer phenomena believed to occur in PWRs during accidents, including small and large break loss-of-coolant accidents. Test 3.03.6AR was conducted to obtain transient film boiling data in rod bundle geometry under reactor accident-type conditions. The primary purpose of this report is to make the reduced instrument responses for THTF Test 3.03.6AR available. Included in the report are uncertainties in the instrument responses,more » calculated mass flows, and calculated rod powers.« less

Control of βAR- and N-methyl-D-aspartate (NMDA) Receptor-Dependent cAMP Dynamics in Hippocampal Neurons

PubMed Central

Chay, Andrew; Zamparo, Ilaria; Koschinski, Andreas; Zaccolo, Manuela; Blackwell, Kim T.

2016-01-01

Norepinephrine, a neuromodulator that activates β-adrenergic receptors (βARs), facilitates learning and memory as well as the induction of synaptic plasticity in the hippocampus. Several forms of long-term potentiation (LTP) at the Schaffer collateral CA1 synapse require stimulation of both βARs and N-methyl-D-aspartate receptors (NMDARs). To understand the mechanisms mediating the interactions between βAR and NMDAR signaling pathways, we combined FRET imaging of cAMP in hippocampal neuron cultures with spatial mechanistic modeling of signaling pathways in the CA1 pyramidal neuron. Previous work implied that cAMP is synergistically produced in the presence of the βAR agonist isoproterenol and intracellular calcium. In contrast, we show that when application of isoproterenol precedes application of NMDA by several minutes, as is typical of βAR-facilitated LTP experiments, the average amplitude of the cAMP response to NMDA is attenuated compared with the response to NMDA alone. Models simulations suggest that, although the negative feedback loop formed by cAMP, cAMP-dependent protein kinase (PKA), and type 4 phosphodiesterase may be involved in attenuating the cAMP response to NMDA, it is insufficient to explain the range of experimental observations. Instead, attenuation of the cAMP response requires mechanisms upstream of adenylyl cyclase. Our model demonstrates that Gs-to-Gi switching due to PKA phosphorylation of βARs as well as Gi inhibition of type 1 adenylyl cyclase may underlie the experimental observations. This suggests that signaling by β-adrenergic receptors depends on temporal pattern of stimulation, and that switching may represent a novel mechanism for recruiting kinases involved in synaptic plasticity and memory. PMID:26901880

Comparative Proteomic Analysis of Differential Responses of Pinus massoniana and Taxus wallichiana var. mairei to Simulated Acid Rain

PubMed Central

Hu, Wen-Jun; Chen, Juan; Liu, Ting-Wu; Simon, Martin; Wang, Wen-Hua; Chen, Juan; Wu, Fei-Hua; Liu, Xiang; Shen, Zhi-Jun; Zheng, Hai-Lei

2014-01-01

Acid rain (AR), a serious environmental issue, severely affects plant growth and development. As the gymnosperms of conifer woody plants, Pinus massoniana (AR-sensitive) and Taxus wallichiana var. mairei (AR-resistant) are widely distributed in southern China. Under AR stress, significant necrosis and collapsed lesions were found in P. massoniana needles with remarkable yellowing and wilting tips, whereas T. wallichiana var. mairei did not exhibit chlorosis and visible damage. Due to the activation of a large number of stress-related genes and the synthesis of various functional proteins to counteract AR stress, it is important to study the differences in AR-tolerance mechanisms by comparative proteomic analysis of tolerant and sensitive species. This study revealed a total of 65 and 26 differentially expressed proteins that were identified in P. massoniana and T. wallichiana var. mairei, respectively. Among them, proteins involved in metabolism, photosynthesis, signal transduction and transcription were drastically down-regulated in P. massoniana, whereas most of the proteins participating in metabolism, cell structure, photosynthesis and transcription were increased in T. wallichiana var. mairei. These results suggest the distinct patterns of protein expression in the two woody species in response to AR, allowing a deeper understanding of diversity on AR tolerance in forest tree species. PMID:24625662

Audience response system: a new learning tool for urologic conferences.

PubMed

Leung, Cynthia P; Klausner, Adam P; Habibi, Joseph R; King, Ashley B; Feldman, Adam

2013-12-01

Audience response systems (ARS) have not been used to gauge knowledge transfer and retention in the setting of large medical conferences. In this study, we explore the utility of an ARS as an educational tool in the setting of a large urology conference. At the 2011 joint meeting of the Mid-Atlantic and New England sections of the American Urological Association, conference attendees were able to use a web-based and cell-phone accessed ARS. At the meeting, six ARS questions were asked during five point-counterpoint debate topics covering areas of prostate cancer, incontinence, pediatrics, stone disease, and renal cancer. Questions were presented by expert representatives from each of the sections; questions were structured as management options for predefined cases. At the beginning and end of each 15-minute session, attendees were asked to use the ARS to select the best management option. In five out of the six questions (83%) more than 10% of responses were changed following the presentation of the point-counterpoint session and a > 25% change in response was noted in two out of the six questions (33%). A statistically significant change was noted for one question relating to management of urolithiasis in pregnancy (p = 0.037). This is the first study which demonstrates the potential utility of an ARS in a large urology conference. With further research it may be possible to use this technology to identify high-yield topics for medical education and improve outcomes during lecture-based educational activities.

The role of the brown adipose tissue in β3-adrenergic receptor activation-induced sleep, metabolic and feeding responses.

PubMed

Szentirmai, Éva; Kapás, Levente

2017-04-19

Brown adipose tissue (BAT) is regulated by the sympathetic nervous system via β3-adrenergic receptors (β3-AR). Here we tested the hypothesis that pharmacological stimulation of β3-ARs leads to increased sleep in mice and if this change is BAT dependent. In wild-type (WT) animals, administration of CL-316,243, a selective β3-AR agonist, induced significant increases in non-rapid-eye movement sleep (NREMS) lasting for 4-10 h. Simultaneously, electroencephalographic slow-wave activity (SWA) was significantly decreased and body temperature was increased with a delay of 5-6 h. In uncoupling protein 1 (UCP-1) knockout mice, the middle and highest doses of the β3-AR agonist increased sleep and suppressed SWA, however, these effects were significantly attenuated and shorter-lasting as compared to WT animals. To determine if somnogenic signals arising from BAT in response to β3-AR stimulation are mediated by the sensory afferents of BAT, we tested the effects of CL-316,243 in mice with the chemical deafferentation of the intra-scapular BAT pads. Sleep responses to CL-316,243 were attenuated by ~50% in intra-BAT capsaicin-treated mice. Present findings indicate that the activation of BAT via β3-AR leads to increased sleep in mice and that this effect is dependent on the presence of UCP-1 protein and sleep responses require the intact sensory innervation of BAT.

7 CFR 3415.6 - Grant awards.

Code of Federal Regulations, 2010 CFR

2010-01-01

... of CSREES or ARS shall make grants to those responsible, eligible applicants whose proposals are... CSREES or ARS under this Part shall be expended solely for the purpose for which the funds are granted in... purpose of the grant award; and (ix) Other information or provisions deemed necessary by CSREES or ARS to...

Evaluation of the Acceptance of Audience Response System by Corporations Using the Technology Acceptance Model

NASA Astrophysics Data System (ADS)

Chu, Hsing-Hui; Lu, Ta-Jung; Wann, Jong-Wen

The purpose of this research is to explore enterprises' acceptance of Audience Response System (ARS) using Technology Acceptance Model (TAM). The findings show that (1) IT characteristics and facilitating conditions could be external variables of TAM. (2) The degree of E-business has positive significant correlation with behavioral intention of employees. (3) TAM is a good model to predict and explain IT acceptance. (4) Demographic variables, industry and firm characteristics have no significant correlation with ARS acceptance. The results provide useful information to managers and ARS providers that (1) ARS providers should focus more on creating different usages to enhance interactivity and employees' using intention. (2) Managers should pay attention to build sound internal facilitating conditions for introducing IT. (3) According to the degree of E-business, managers should set up strategic stages of introducing IT. (4) Providers should increase product promotion and also leverage academic and government to promote ARS.

Tips for using mobile audience response systems in medical education

PubMed Central

Gousseau, Michael; Sommerfeld, Connor; Gooi, Adrian

2016-01-01

Background With growing evidence on the benefits of active learning, audience response systems (ARSs) have been increasingly used in conferences, business, and education. With the introduction of mobile ARS as an alternative to physical clickers, there are increasing opportunities to use this tool to improve interactivity in medical education. Aim The aim of this study is to provide strategies on using mobile ARS in medical education by discussing steps for implementation and pitfalls to avoid. Method The tips presented reflect our commentary of the literature and our experiences using mobile ARS in medical education. Results This article offers specific strategies for the preparation, implementation, and assessment of medical education teaching sessions using mobile ARS. Conclusion We hope these tips will help instructors use mobile ARS as a tool to improve student interaction, teaching effectiveness, and participant enjoyment in medical education. PMID:27942242

Evaluation of an audience response system in a preclinical operative dentistry course.

PubMed

Elashvili, Ana; Denehy, Gerald E; Dawson, Deborah V; Cunningham, Marsha A

2008-11-01

Student performance was compared on written and psychomotor skill tests of freshman dental students receiving conventional lectures versus the same lectures containing interactive components using TurningPoint, a wireless audience response system (ARS). The research design was a controlled crossover study with seventy-seven freshman dental students conducted in a preclinical operative dentistry course. Two randomized groups alternated the two study lectures, one with ARS and the other without ARS. Student knowledge retention was measured through written examination using immediate posttest, as well as questions on the unit and final examinations. Psychomotor skill tests were given on both lecture topics. Statistically significant differences indicating superiority of ARS were identified for performance on the immediate posttest and psychomotor skill test only for the lecture "Principles of Dental Bonding." The other examinations/skill testing showed no significant difference. These results indicate that ARS is a promising teaching tool for dental education.

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.

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.

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.

Individual differences in the cortisol and salivary α-amylase awakening responses in early childhood: relations to age, sex, and sleep.

PubMed

Bright, Melissa A; Frick, Janet E; Out, Dorothee; Granger, Douglas A

2014-09-01

Recent studies have examined post-waking changes in cortisol as a marker of HPA functioning, but questions remain about the stability of this response, as well as its relation to sleep and other ANS markers. The purposes of this study were to a) examine the presence and developmental changes in the cortisol awakening response (CAR) and salivary α-amylase awakening (sAA-AR) in a toddler sample and b) determine whether and how sleep relates to these responses in this age group. We measured cortisol and sAA upon awakening (and 30 min post-waking) and sleep characteristics using actigraphy (e.g., total sleep time, sleep efficiency, number of awakenings) in toddlers (N = 47; 36% female, ages 12-24 months). Forty-six percent of toddlers demonstrated a CAR and 52% demonstrated a sAA-AR. Strength of either response did not change linearly with age. Additionally, likelihood of demonstrating the CAR and sAA-AR was unrelated to age, sex, awakening time, time between samples, and time since feeding. Higher waking cortisol levels were associated with a shorter total sleep time and an earlier awakening. No associations were observed between sleep characteristics and the sAA-AR, ps > .05. Our findings suggest that these awakening responses function independently of sleep in toddlers. Additionally, the lack of change in percentage of children showing a CAR or sAA-AR across these ages suggests that these responses are stable and not emerging reliably across the second year of life. © 2014 Wiley Periodicals, Inc.

PC-based control unit for a head-mounted operating microscope for augmented-reality visualization in surgical navigation

NASA Astrophysics Data System (ADS)

Figl, Michael; Birkfellner, Wolfgang; Watzinger, Franz; Wanschitz, Felix; Hummel, Johann; Hanel, Rudolf A.; Ewers, Rolf; Bergmann, Helmar

2002-05-01

Two main concepts of Head Mounted Displays (HMD) for augmented reality (AR) visualization exist, the optical and video-see through type. Several research groups have pursued both approaches for utilizing HMDs for computer aided surgery. While the hardware requirements for a video see through HMD to achieve acceptable time delay and frame rate seem to be enormous the clinical acceptance of such a device is doubtful from a practical point of view. Starting from previous work in displaying additional computer-generated graphics in operating microscopes, we have adapted a miniature head mounted operating microscope for AR by integrating two very small computer displays. To calibrate the projection parameters of this so called Varioscope AR we have used Tsai's Algorithm for camera calibration. Connection to a surgical navigation system was performed by defining an open interface to the control unit of the Varioscope AR. The control unit consists of a standard PC with a dual head graphics adapter to render and display the desired augmentation of the scene. We connected this control unit to a computer aided surgery (CAS) system by the TCP/IP interface. In this paper we present the control unit for the HMD and its software design. We tested two different optical tracking systems, the Flashpoint (Image Guided Technologies, Boulder, CO), which provided about 10 frames per second, and the Polaris (Northern Digital, Ontario, Canada) which provided at least 30 frames per second, both with a time delay of one frame.

When stress and development go hand in hand: main hormonal controls of adventitious rooting in cuttings

PubMed Central

da Costa, Cibele T.; de Almeida, Márcia R.; Ruedell, Carolina M.; Schwambach, Joseli; Maraschin, Felipe S.; Fett-Neto, Arthur G.

2013-01-01

Adventitious rooting (AR) is a multifactorial response leading to new roots at the base of stem cuttings, and the establishment of a complete and autonomous plant. AR has two main phases: (a) induction, with a requirement for higher auxin concentration; (b) formation, inhibited by high auxin and in which anatomical changes take place. The first stages of this process in severed organs necessarily include wounding and water stress responses which may trigger hormonal changes that contribute to reprogram target cells that are competent to respond to rooting stimuli. At severance, the roles of jasmonate and abscisic acid are critical for wound response and perhaps sink strength establishment, although their negative roles on the cell cycle may inhibit root induction. Strigolactones may also inhibit AR. A reduced concentration of cytokinins in cuttings results from the separation of the root system, whose tips are a relevant source of these root induction inhibitors. The combined increased accumulation of basipetally transported auxins from the shoot apex at the cutting base is often sufficient for AR in easy-to-root species. The role of peroxidases and phenolic compounds in auxin catabolism may be critical at these early stages right after wounding. The events leading to AR strongly depend on mother plant nutritional status, both in terms of minerals and carbohydrates, as well as on sink establishment at cutting bases. Auxins play a central role in AR. Auxin transporters control auxin canalization to target cells. There, auxins act primarily through selective proteolysis and cell wall loosening, via their receptor proteins TIR1 (transport inhibitor response 1) and ABP1 (Auxin-Binding Protein 1). A complex microRNA circuitry is involved in the control of auxin response factors essential for gene expression in AR. After root establishment, new hormonal controls take place, with auxins being required at lower concentrations for root meristem maintenance and cytokinins needed for root tissue differentiation. PMID:23717317

When stress and development go hand in hand: main hormonal controls of adventitious rooting in cuttings.

PubMed

da Costa, Cibele T; de Almeida, Márcia R; Ruedell, Carolina M; Schwambach, Joseli; Maraschin, Felipe S; Fett-Neto, Arthur G

2013-01-01

Adventitious rooting (AR) is a multifactorial response leading to new roots at the base of stem cuttings, and the establishment of a complete and autonomous plant. AR has two main phases: (a) induction, with a requirement for higher auxin concentration; (b) formation, inhibited by high auxin and in which anatomical changes take place. The first stages of this process in severed organs necessarily include wounding and water stress responses which may trigger hormonal changes that contribute to reprogram target cells that are competent to respond to rooting stimuli. At severance, the roles of jasmonate and abscisic acid are critical for wound response and perhaps sink strength establishment, although their negative roles on the cell cycle may inhibit root induction. Strigolactones may also inhibit AR. A reduced concentration of cytokinins in cuttings results from the separation of the root system, whose tips are a relevant source of these root induction inhibitors. The combined increased accumulation of basipetally transported auxins from the shoot apex at the cutting base is often sufficient for AR in easy-to-root species. The role of peroxidases and phenolic compounds in auxin catabolism may be critical at these early stages right after wounding. The events leading to AR strongly depend on mother plant nutritional status, both in terms of minerals and carbohydrates, as well as on sink establishment at cutting bases. Auxins play a central role in AR. Auxin transporters control auxin canalization to target cells. There, auxins act primarily through selective proteolysis and cell wall loosening, via their receptor proteins TIR1 (transport inhibitor response 1) and ABP1 (Auxin-Binding Protein 1). A complex microRNA circuitry is involved in the control of auxin response factors essential for gene expression in AR. After root establishment, new hormonal controls take place, with auxins being required at lower concentrations for root meristem maintenance and cytokinins needed for root tissue differentiation.

Targeting congestion in allergic rhinitis: the importance of intranasal corticosteroids.

PubMed

Marple, Bradley F

2008-01-01

The cardinal nasal symptoms of allergic rhinitis (AR) are sustained by an underlying inflammatory process. Congestion is one of the most prominent and distressing symptoms for patients and is strongly associated with a broadly deteriorated quality of life and significant losses in productivity. The purpose of this study was to explore the role of intranasal corticosteroids (INSs) in down-regulating the inflammatory response to allergen and their clinical efficacy on AR symptoms, particularly congestion. AR is characterized by an influx of inflammatory cells and mediators into the nasal mucosa after antigen exposure. The response is biphasic, encompassing an early and a late phase. Antigen exposure has a priming effect, decreasing the threshold for subsequent allergic reaction on rechallenge and increasing the responsiveness of the nasal mucosa. INSs are a mainstay of therapy for AR and the most effective intervention for nasal congestion and other nasal symptoms, with established superiority to antihistamines, decongestants, and leukotriene antagonists. In addition to symptom relief, INSs suppress numerous stages of the inflammatory cascade, inhibiting the influx of inflammatory cells and mediators. Topical nasal corticosteroids have a low incidence of local adverse effects, negligible systemic absorption, and excellent safety. Congestion is one of the most bothersome symptoms of AR. INS therapy improves AR symptoms, with particular efficacy in relieving congestion, by attenuating nasal hyperresponsiveness. Pretreatment with INSs has been shown to relieve early and late-phase clinical symptoms of AR. Modification of the disease process results in significant relief of symptoms and leads to fewer disease exacerbations.

Effects of a alpha 2C-adrenoreceptor gene polymorphism on neural responses to facial expressions in depression.

PubMed

Neumeister, Alexander; Drevets, Wayne C; Belfer, Inna; Luckenbaugh, David A; Henry, Shannan; Bonne, Omer; Herscovitch, Peter; Goldman, David; Charney, Dennis S

2006-08-01

Alterations in processing of emotionally salient information have been reported in individuals with major depressive disorder (MDD). Evidence suggests a role for noradrenaline in the regulation of a cortico-limbic-striatal circuit that has also been implicated in the pathophysiology of MDD. Herein, we studied the physiological consequences of a common coding polymorphism of the gene for the alpha(2C)-adrenoreceptor (AR) subtype--the deletion of four consecutive amino acids at codons 322-325 of the alpha2C-AR (alpha2CDel322-325-AR) in medication-free, remitted individuals with MDD (rMDD), and healthy control subjects. After injection of 10 mCi of H2(15)O, positron emission tomography (PET) measures of neural activity were acquired while subjects were viewing unmasked sad, happy, and fearful faces. The neural responses to sad facial expressions were increased in the amygdala and decreased in the left ventral striatum in rMDD patients relative to healthy control subjects. Furthermore, we report that rMDD carriers of one or two copies of the alpha2CDel322-325-AR exhibit greater amygdala as well as pregenual and subgenual anterior cingulate gyrus neuronal activity in response to sad faces than healthy alpha2CDel322-325-AR carriers and rMDD noncarriers. These results suggest that the alpha2CDel322-325-AR confers a change in brain function implicating this alpha2-AR subtype into the pathophysiology of MDD.

The effect of polymorphisms of the beta(2)-adrenergic receptor on the response to regular use of albuterol in asthma.

PubMed

Israel, E; Drazen, J M; Liggett, S B; Boushey, H A; Cherniack, R M; Chinchilli, V M; Cooper, D M; Fahy, J V; Fish, J E; Ford, J G; Kraft, M; Kunselman, S; Lazarus, S C; Lemanske, R F; Martin, R J; McLean, D E; Peters, S P; Silverman, E K; Sorkness, C A; Szefler, S J; Weiss, S T; Yandava, C N

2000-07-01

Inhaled beta-adrenergic agonists are the most commonly used medications for the treatment of asthma although there is evidence that regular use may produce adverse effects in some patients. Polymorphisms of the beta(2)-adrenergic receptor (beta(2)-AR) can affect regulation of the receptor. Smaller studies examining the effects of such polymorphisms on the response to beta-agonist therapy have produced inconsistent results. We examined whether polymorphisms at codon 16 (beta(2)-AR-16) and codon 27 (beta(2)-AR-27) of the beta(2)-AR might affect the response to regular versus as-needed use of albuterol by genotyping the 190 asthmatics who had participated in a trial examining the effects of regular versus as needed albuterol use. During the 16-wk treatment period there was a small decline in morning peak expiratory flow in patients homozygous for arginine at B(2)-AR-16 (Arg/Arg) who used albuterol regularly. This effect was magnified during a 4-wk run out period, during which all patients returned to using as-needed albuterol, so that by the end of the study Arg Arg patients who had regularly used albuterol had a morning peak expiratory flow 30. 5 +/- 12.1 L/min lower (p = 0.012) than Arg/Arg patients who had used albuterol on an as needed basis. There was no decline in peak flow with regular use of albuterol in patients who were homozygous for glycine at beta(2)-AR-16. Evening peak expiratory flow also declined in the Arg/Arg patients who used albuterol regularly but not in those who used albuterol on an as-needed basis. No significant differences in outcomes between regular and as-needed treatment were associated with polymorphisms at position 27 of the beta(2)-AR. No other differences in asthma outcomes that we investigated occurred in relation to these beta(2)-AR polymorphisms. Polymorphisms of the beta(2)-AR may influence airway responses to regular inhaled beta-agonist treatment.

Promoting active learning using audience response system in large bioscience classes.

PubMed

Efstathiou, Nikolaos; Bailey, Cara

2012-01-01

This paper considers the challenges of bioscience teaching and learning in pre-registration nurse education. Effective learning requires active student participation which is problematic when teaching large groups of students. New technologies, such as the audience response system (ARS), have been introduced to increase student participation and support them in the understanding of complex bioscience concepts. Within one university department, an evaluation was undertaken to identify the perceptions of pre-registration nurse students on the use of ARS in the teaching and learning of bioscience. Our findings concur with others that ARS increases student participation and aids in identifying misconceptions and in correcting them. Students found ARS very useful and wanted ARS to be used in additional modules too. Although ARS did not seem to motivate students to study adequately before attending the relevant sessions, it increased discussion among students and awareness of their level of knowledge compared to their peers. Further research is required to identify the effectiveness of ARS in the teaching and learning of bioscience and its impact on the performance of the students in their final assessments. Copyright © 2011 Elsevier Ltd. All rights reserved.

Night Vision Manual for the Flight Surgeon

DTIC Science & Technology

1992-08-01

may cause night blindness are glaucoma, progressive cone/rod dystrophies (e.g., retinitis pigmentosa , Stargardt’s disease), drug toxicity (e.g...Alabama, July 1989. 38. Berson EL, Rabin AR, Mehaffey L. Advances in night vision twchnology: A pocketscope for patients with retinitis pigmentosa ... retinal sensitivity to dim light. Regeneration of the photopigments occurs during dark adaptation. The fully dark-adapted eye, in which photopigment

Transcriptome analysis identifies genes involved in ethanol response of Saccharomyces cerevisiae in Agave tequilana juice.

PubMed

Ramirez-Córdova, Jesús; Drnevich, Jenny; Madrigal-Pulido, Jaime Alberto; Arrizon, Javier; Allen, Kirk; Martínez-Velázquez, Moisés; Alvarez-Maya, Ikuri

2012-08-01

During ethanol fermentation, yeast cells are exposed to stress due to the accumulation of ethanol, cell growth is altered and the output of the target product is reduced. For Agave beverages, like tequila, no reports have been published on the global gene expression under ethanol stress. In this work, we used microarray analysis to identify Saccharomyces cerevisiae genes involved in the ethanol response. Gene expression of a tequila yeast strain of S. cerevisiae (AR5) was explored by comparing global gene expression with that of laboratory strain S288C, both after ethanol exposure. Additionally, we used two different culture conditions, cells grown in Agave tequilana juice as a natural fermentation media or grown in yeast-extract peptone dextrose as artificial media. Of the 6368 S. cerevisiae genes in the microarray, 657 genes were identified that had different expression responses to ethanol stress due to strain and/or media. A cluster of 28 genes was found over-expressed specifically in the AR5 tequila strain that could be involved in the adaptation to tequila yeast fermentation, 14 of which are unknown such as yor343c, ylr162w, ygr182c, ymr265c, yer053c-a or ydr415c. These could be the most suitable genes for transforming tequila yeast to increase ethanol tolerance in the tequila fermentation process. Other genes involved in response to stress (RFC4, TSA1, MLH1, PAU3, RAD53) or transport (CYB2, TIP20, QCR9) were expressed in the same cluster. Unknown genes could be good candidates for the development of recombinant yeasts with ethanol tolerance for use in industrial tequila fermentation.

Accurate Attitude Estimation Using ARS under Conditions of Vehicle Movement Based on Disturbance Acceleration Adaptive Estimation and Correction

PubMed Central

Xing, Li; Hang, Yijun; Xiong, Zhi; Liu, Jianye; Wan, Zhong

2016-01-01

This paper describes a disturbance acceleration adaptive estimate and correction approach for an attitude reference system (ARS) so as to improve the attitude estimate precision under vehicle movement conditions. The proposed approach depends on a Kalman filter, where the attitude error, the gyroscope zero offset error and the disturbance acceleration error are estimated. By switching the filter decay coefficient of the disturbance acceleration model in different acceleration modes, the disturbance acceleration is adaptively estimated and corrected, and then the attitude estimate precision is improved. The filter was tested in three different disturbance acceleration modes (non-acceleration, vibration-acceleration and sustained-acceleration mode, respectively) by digital simulation. Moreover, the proposed approach was tested in a kinematic vehicle experiment as well. Using the designed simulations and kinematic vehicle experiments, it has been shown that the disturbance acceleration of each mode can be accurately estimated and corrected. Moreover, compared with the complementary filter, the experimental results have explicitly demonstrated the proposed approach further improves the attitude estimate precision under vehicle movement conditions. PMID:27754469

Accurate Attitude Estimation Using ARS under Conditions of Vehicle Movement Based on Disturbance Acceleration Adaptive Estimation and Correction.

PubMed

Xing, Li; Hang, Yijun; Xiong, Zhi; Liu, Jianye; Wan, Zhong

2016-10-16

This paper describes a disturbance acceleration adaptive estimate and correction approach for an attitude reference system (ARS) so as to improve the attitude estimate precision under vehicle movement conditions. The proposed approach depends on a Kalman filter, where the attitude error, the gyroscope zero offset error and the disturbance acceleration error are estimated. By switching the filter decay coefficient of the disturbance acceleration model in different acceleration modes, the disturbance acceleration is adaptively estimated and corrected, and then the attitude estimate precision is improved. The filter was tested in three different disturbance acceleration modes (non-acceleration, vibration-acceleration and sustained-acceleration mode, respectively) by digital simulation. Moreover, the proposed approach was tested in a kinematic vehicle experiment as well. Using the designed simulations and kinematic vehicle experiments, it has been shown that the disturbance acceleration of each mode can be accurately estimated and corrected. Moreover, compared with the complementary filter, the experimental results have explicitly demonstrated the proposed approach further improves the attitude estimate precision under vehicle movement conditions.

A novel mechanism of renal blood flow autoregulation and the autoregulatory role of A1 adenosine receptors in mice.

PubMed

Just, Armin; Arendshorst, William J

2007-11-01

Autoregulation of renal blood flow (RBF) is mediated by a fast myogenic response (MR; approximately 5 s), a slower tubuloglomerular feedback (TGF; approximately 25 s), and potentially additional mechanisms. A1 adenosine receptors (A1AR) mediate TGF in superficial nephrons and contribute to overall autoregulation, but the impact on the other autoregulatory mechanisms is unknown. We studied dynamic autoregulatory responses of RBF to rapid step increases of renal artery pressure in mice. MR was estimated from autoregulation within the first 5 s, TGF from that at 5-25 s, and a third mechanism from 25-100 s. Genetic deficiency of A1AR (A1AR-/-) reduced autoregulation at 5-25 s by 50%, indicating a residual fourth mechanism resembling TGF kinetics but independent of A1AR. MR and third mechanism were unaltered in A1AR-/-. Autoregulation in A1AR-/- was faster at 5-25 than at 25-100 s suggesting two separate mechanisms. Furosemide in wild-type mice (WT) eliminated the third mechanism and enhanced MR, indicating TGF-MR interaction. In A1AR-/-, furosemide did not further impair autoregulation at 5-25 s, but eliminated the third mechanism and enhanced MR. The resulting time course was the same as during furosemide in WT, indicating that A1AR do not affect autoregulation during furosemide inhibition of TGF. We conclude that at least one novel mechanism complements MR and TGF in RBF autoregulation, that is slower than MR and TGF and sensitive to furosemide, but not mediated by A1AR. A fourth mechanism with kinetics similar to TGF but independent of A1AR and furosemide might also contribute. A1AR mediate classical TGF but not TGF-MR interaction.

The bright side of being blue: Depression as an adaptation for analyzing complex problems

PubMed Central

Andrews, Paul W.; Thomson, J. Anderson

2009-01-01

Depression ranks as the primary emotional problem for which help is sought. Depressed people often have severe, complex problems, and rumination is a common feature. Depressed people often believe that their ruminations give them insight into their problems, but clinicians often view depressive rumination as pathological because it is difficult to disrupt and interferes with the ability to concentrate on other things. Abundant evidence indicates that depressive rumination involves the analysis of episode-related problems. Because analysis is time consuming and requires sustained processing, disruption would interfere with problem-solving. The analytical rumination (AR) hypothesis proposes that depression is an adaptation that evolved as a response to complex problems and whose function is to minimize disruption of rumination and sustain analysis of complex problems. It accomplishes this by giving episode-related problems priority access to limited processing resources, by reducing the desire to engage in distracting activities (anhedonia), and by producing psychomotor changes that reduce exposure to distracting stimuli. Because processing resources are limited, the inability to concentrate on other things is a tradeoff that must be made to sustain analysis of the triggering problem. The AR hypothesis is supported by evidence from many levels, including genes, neurotransmitters and their receptors, neurophysiology, neuroanatomy, neuroenergetics, pharmacology, cognition and behavior, and the efficacy of treatments. In addition, we address and provide explanations for puzzling findings in the cognitive and behavioral genetics literatures on depression. In the process, we challenge the belief that serotonin transmission is low in depression. Finally, we discuss implications of the hypothesis for understanding and treating depression. PMID:19618990

Stimulation of bone formation by dietary boron in an orthopedically expanded suture in rabbits.

PubMed

Uysal, Tancan; Ustdal, Ayca; Sonmez, Mehmet Fatih; Ozturk, Figen

2009-09-01

To evaluate the effects of dietary boron on bone regeneration in rabbits in response to expansion of the midpalatal suture during different retention periods. Twenty-eight 12-week-old New Zealand white male rabbits were separated into four equal groups: group 1 (B+10) and group 2 (B-10) had retention periods of 10 days with or without boron intake, respectively. Group 3 (B+20, with boron) and group 4 (B-20, without boron) were retained for 20 days. All groups had a 5-day expansion period. For both B+ groups, boron was prepared in distilled water and given to the rabbits during their (1) nursery phase (40 days), (2) expansion phase, and (3) retention period at a dosage of 3 mg/kg daily by oral gavage. Bone regeneration in the midpalatal suture was evaluated by a bone histomorphometric method, and the mineralized area (Md.Ar), fibrosis area (Fb.Ar), mineralized area/fibrosis area (Md.Ar/Fb.Ar), bone area (B.Ar) and osteoblast number (N.Ob) parameters were evaluated. Statistical analysis showed significant differences between groups for all investigated measurements. Md.Ar (P < .01), Md.Ar/Fb.Ar (P < .001), B.Ar (P < .01), and N.Ob (P < .01) parameters were increased and Fb.Ar (P < .01) was decreased in groups B+10 and B+20. No significant differences were observed during an additional 10-day retention period in all groups (P < .05). Boron has a positive effect on the early phase of bone regeneration of the midpalatal suture in response to expansion and may be beneficial in routine maxillary expansion procedures.

Recovery sleep after extended wakefulness restores elevated A1 adenosine receptor availability in the human brain

PubMed Central

Elmenhorst, Eva-Maria; Hennecke, Eva; Kroll, Tina; Matusch, Andreas; Aeschbach, Daniel; Bauer, Andreas

2017-01-01

Adenosine and functional A1 adenosine receptor (A1AR) availability are supposed to mediate sleep–wake regulation and cognitive performance. We hypothesized that cerebral A1AR availability after an extended wake period decreases to a well-rested state after recovery sleep. [18F]CPFPX positron emission tomography was used to quantify A1AR availability in 15 healthy male adults after 52 h of sleep deprivation and following 14 h of recovery sleep. Data were additionally compared with A1AR values after 8 h of baseline sleep from an earlier dataset. Polysomnography, cognitive performance, and sleepiness were monitored. Recovery from sleep deprivation was associated with a decrease in A1AR availability in several brain regions, ranging from 11% (insula) to 14% (striatum). A1AR availabilities after recovery did not differ from baseline sleep in the control group. The degree of performance impairment, sleepiness, and homeostatic sleep-pressure response to sleep deprivation correlated negatively with the decrease in A1AR availability. Sleep deprivation resulted in a higher A1AR availability in the human brain. The increase that was observed after 52 h of wakefulness was restored to control levels during a 14-h recovery sleep episode. Individuals with a large increase in A1AR availability were more resilient to sleep-loss effects than those with a subtle increase. This pattern implies that differences in endogenous adenosine and A1AR availability might be causal for individual responses to sleep loss. PMID:28373571

Incorporating an audience response system into veterinary dermatology lectures: effect on student knowledge retention and satisfaction.

PubMed

Plant, Jon D

2007-01-01

Veterinary educators are charged with delivering large amounts of information to adult students, who benefit from a more interactive learning environment than is often achieved through didactic lectures. Audience response systems (ARS) with wireless keypad technology facilitate interactive learning and have been used successfully in the education of health professionals. The objectives of this pilot study were to determine the effect of an ARS on the knowledge retention of veterinary dermatology students and to survey student attitudes concerning its use. A cohort-controlled trial was conducted to evaluate the potential benefits of ARS for short-term and long-term knowledge retention. Students also participated in four hours of student-directed case simulations using ARS technology. Students were surveyed regarding opinions on the use of the ARS. The mean short-term knowledge-retention test scores of groups A (ARS+) and B (ARS-) were 81% and 78%, respectively. The mean long-term knowledge-retention test scores of groups A and B were 54% and 55%, respectively. The differences between groups were not significant for either time period (p = 0.32, p = 0.77). Although benefits to short-term and long-term knowledge retention were not detected in this pilot study, all students responding to the survey perceived a benefit and supported the use of ARS in the clinical veterinary curriculum. ARS technology provides a tool for lecturers to create an interactive learning environment well suited for teaching veterinary dermatology.

Efficacy of Cabazitaxel in Castration-resistant Prostate Cancer Is Independent of the Presence of AR-V7 in Circulating Tumor Cells.

PubMed

Onstenk, Wendy; Sieuwerts, Anieta M; Kraan, Jaco; Van, Mai; Nieuweboer, Annemieke J M; Mathijssen, Ron H J; Hamberg, Paul; Meulenbeld, Hielke J; De Laere, Bram; Dirix, Luc Y; van Soest, Robert J; Lolkema, Martijn P; Martens, John W M; van Weerden, Wytske M; Jenster, Guido W; Foekens, John A; de Wit, Ronald; Sleijfer, Stefan

2015-12-01

Androgen receptor splice variant 7 (AR-V7) in circulating tumor cells (CTCs) from patients with metastatic castration-resistant prostate cancer (mCRPC) was recently demonstrated to be associated with resistance to abiraterone and enzalutamide. Cabazitaxel might, however, remain effective in AR-V7-positive patients. To investigate the association between AR-V7 expression in CTCs and resistance to cabazitaxel. We selected patients with mCRPC from the multicenter, randomized, phase 2, randomized, open-label, multicenter study in mCRPC on the pharmacodynamic effects of budesonide on cabazitaxel (Jevtana) (CABARESC). Before the start of the first and third cabazitaxel cycle, CTCs were enumerated using the CellSearch System. In patients with ≥10 CTCs in 7.5 ml blood at baseline, the expression of AR-V7 was assessed by quantitative polymerase chain reaction. The primary end point was the association between the AR-V7 status and the CTC response rate (decrease to fewer than five CTCs in 7.5 ml blood during treatment). Secondary end points were the prostate-specific antigen (PSA) response rate (RR) and overall survival (OS). Analyses were performed using chi-square and log-rank tests. AR-V7 was detected in 16 of 29 patients (55%) with ≥10 CTCs and was more frequently found in abiraterone pretreated patients (5 of 5 [100%] treated vs 7 of 20 [35%] untreated; p=0.009). We found no differences in CTC and PSA RRs. The presence of AR-V7 in CTCs was not associated with progression-free survival (hazard ratio [HR]: 0.8; 95% confidence interval [CI], 0.4-1.8) or overall survival (HR 1.6; 95% CI, 0.6-4.4). The response to cabazitaxel seems to be independent of the AR-V7 status of CTCs from mCRPC patients. Consequently, cabazitaxel might be a valid treatment option for patients with AR-V7-positive CTCs. Tools are needed to select specific treatments for specific patients at specific times. The presence of the gene AR-V7 in CTCs has been associated with resistance to anti-androgen receptor treatments. We investigated whether this holds true for cabazitaxel, but we found cabazitaxel to be effective independent of the presence of AR-V7. Copyright © 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Investigations on GSK-3β/NF-kB signaling in stress and stress adaptive behavior in electric foot shock subjected mice.

PubMed

Bali, Anjana; Jaggi, Amteshwar Singh

2016-04-01

The present study was designed to explore the role of GSK-3β and NF-kB signaling in electric foot shock-induced stress and stress adaptation. Mice were subjected to foot shocks of 0.5mA intensity and 1s duration of 1h to produce acute stress. Animals were exposed to the same stressor for 5 days to induce stress adaptation. The behavioral alterations were assessed using the actophotometer, hole board, open field and social interaction tests. The serum corticosterone levels were assessed as a marker of the HPA axis. The levels of total GSK-3β, p-GSK-3β-S9 and p-NF-kB were determined in the hippocampus, frontal cortex and amygdala. Acute electric foot shock stress produced behavioral and biochemical changes; decreased the levels of p-GSK-3β-S9, produced no change in total GSK-3β levels and increased p-NF-kB levels in the brain. However, repeated exposure of foot shock stress restored the behavioral and biochemical changes along with normalization of p-GSK-3β-S9 and p-NF-kB levels. Administration of AR-A01, a selective GSK-3β inhibitor, or diethyldithiocarbamic acid (DDTC), a selective NF-kB inhibitor, diminished acute stress-induced behavioral and biochemical changes. Furthermore, AR-A014418 normalized acute stress-induced alterations in p-GSK-3β-S9 and p-NF-kB levels, however, DDTC selectively restored NF-kB levels without any change in p-GSK-3β-S9 levels. It probably suggests that NF-kB is a downstream mediator of the GSK-3 signaling cascade. It may conclude that acute stress associated decrease in p-GSK-3β-S9 and increase in p-NF-kB levels in the brain contribute in the development of behavioral and biochemical alterations and normalization of GSK-3β/NF-kB signaling may contribute in stress adaptive behavior in response to repeated electric foot shock-subjected mice. Copyright © 2016 Elsevier B.V. All rights reserved.

Audience Response Systems in Higher Education: Applications and Cases

ERIC Educational Resources Information Center

Banks, David

2006-01-01

Taking advantage of user-friendly technology, Audience Response Systems (ARS) facilitates greater interaction with participants engaged in a variety of group activities. Each participant has an input device that permits them to express a view in complete anonymity, and the composite view of the total group appears on a public screen. ARS can then…

[Development of an Atypical Response Scale.

ERIC Educational Resources Information Center

Mendelsohn, Mark; Linden, James

The development of an objective diagnostic scale to measure atypical behavior is discussed. The Atypical Response Scale (ARS) is a structured projective test consisting of 17 items, each weighted 1, 2, or 3, that were tested for convergence and reliability. ARS may be individually or group administered in 10-15 minutes; hand scoring requires 90…

Enhance Learning in Athletic Training Education with Audience Response Systems

ERIC Educational Resources Information Center

Harman, Chris T.

2010-01-01

Audience Response Systems (ARS) are now being used to enhance learning in various higher education disciplines. With several ARS brands available, it is most important to consider various facets of this interactive technology prior to implementing it into athletic training courses. This article will outline strategies to incorporate this learning…

A transcriptomic study reveals differentially expressed genes and pathways respond to simulated acid rain in Arabidopsis thaliana.

PubMed

Liu, Ting-Wu; Niu, Li; Fu, Bin; Chen, Juan; Wu, Fei-Hua; Chen, Juan; Wang, Wen-Hua; Hu, Wen-Jun; He, Jun-Xian; Zheng, Hai-Lei

2013-01-01

Acid rain, as a worldwide environmental issue, can cause serious damage to plants. In this study, we provided the first case study on the systematic responses of arabidopsis (Arabidopsis thaliana (L.) Heynh.) to simulated acid rain (SiAR) by transcriptome approach. Transcriptomic analysis revealed that the expression of a set of genes related to primary metabolisms, including nitrogen, sulfur, amino acid, photosynthesis, and reactive oxygen species metabolism, were altered under SiAR. In addition, transport and signal transduction related pathways, especially calcium-related signaling pathways, were found to play important roles in the response of arabidopsis to SiAR stress. Further, we compared our data set with previously published data sets on arabidopsis transcriptome subjected to various stresses, including wound, salt, light, heavy metal, karrikin, temperature, osmosis, etc. The results showed that many genes were overlapped in several stresses, suggesting that plant response to SiAR is a complex process, which may require the participation of multiple defense-signaling pathways. The results of this study will help us gain further insights into the response mechanisms of plants to acid rain stress.

Characterisation of endogenous A2A and A2B receptor-mediated cyclic AMP responses in HEK 293 cells using the GloSensor™ biosensor: Evidence for an allosteric mechanism of action for the A2B-selective antagonist PSB 603.

PubMed

Goulding, Joelle; May, Lauren T; Hill, Stephen J

2018-01-01

Endogenous adenosine A 2B receptors (A 2B AR) mediate cAMP accumulation in HEK 293 cells. Here we have used a biosensor to investigate the mechanism of action of the A 2B AR antagonist PSB 603 in HEK 293 cells. The A 2A agonist CGS 21680 elicited a small response in these cells (circa 20% of that obtained with NECA), suggesting that they also contain a small population of A 2A receptors. The responses to NECA and adenosine were antagonised by PSB 603, but not by the selective A 2A AR antagonist SCH 58261. In contrast, CGS 21680 responses were not antagonised by high concentrations of PSB 603, but were sensitive to inhibition by SCH 58261. Analysis of the effect of increasing concentrations of PSB 603 on the response to NECA indicated a non-competitive mode of action yielding a marked reduction in the NECA E MAX with no significant effect on EC 50 values. Kinetics analysis of the effect of PSB 603 on the A 2B AR-mediated NECA responses confirmed a saturable effect that was consistent with an allosteric mode of antagonism. The possibility that PSB 603 acts as a negative allosteric modulator of A 2B AR suggests new approaches to the development of therapeutic agents to treat conditions where adenosine levels are high. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

Androgen resistance in squirrel monkeys (Saimiri spp.).

PubMed

Gross, Katherine L; Westberry, Jenne M; Hubler, Tina R; Sadosky, Patti W; Singh, Ravinder J; Taylor, Robert L; Scammell, Jonathan G

2008-08-01

The goal of this study was to understand the basis for high androgen levels in squirrel monkeys (Saimiri spp.). Mass spectrometry was used to analyze serum testosterone, androstenedione, and dihydrotestosterone of male squirrel monkeys during the nonbreeding (n = 7) and breeding (n = 10) seasons. All hormone levels were elevated compared with those of humans, even during the nonbreeding season; the highest levels occurred during the breeding season. The ratio of testosterone to dihydrotestosterone in squirrel monkeys is high during the breeding season compared to man. Squirrel monkeys may have high testosterone to compensate for inefficient metabolism to dihydrotestosterone. We also investigated whether squirrel monkeys have high androgens to compensate for low-activity androgen receptors (AR). The response to dihydrotestosterone in squirrel monkey cells transfected with AR and AR-responsive reporter plasmids was 4-fold, compared with 28-fold in human cells. This result was not due to overexpression of cellular FKBP51, which causes glucocorticoid and progestin resistance in squirrel monkeys, because overexpression of FKBP51 had no effect on dihydrotestosterone-stimulated reporter activity in a human fibroblast cell line. To test whether the inherently low levels of FKBP52 in squirrel monkeys contribute to androgen insensitivity, squirrel monkey cells were transfected with an AR expression plasmid, an AR-responsive reporter plasmid, and a plasmid expressing FKBP52. Expression of FKBP52 decreased the EC50 or increased the maximal response to dihydrotestosterone. Therefore, the high androgen levels in squirrel monkeys likely compensate for their relatively low 5 alpha-reductase activity during the breeding season and AR insensitivity resulting from low cellular levels of FKBP52.

Human PIRH2 Enhances Androgen Receptor Signaling through Inhibition of Histone Deacetylase 1 and Is Overexpressed in Prostate Cancer

PubMed Central

Logan, Ian R.; Gaughan, Luke; McCracken, Stuart R. C.; Sapountzi, Vasileia; Leung, Hing Y.; Robson, Craig N.

2006-01-01

The androgen receptor (AR) is a hormone-dependent transcription factor critically involved in human prostate carcinogenesis. Optimal transcriptional control of androgen-responsive genes by AR may require complex interaction among multiple coregulatory proteins. We have previously shown that the AR coregulator TIP60 can interact with human PIRH2 (hPIRH2). In this study, we uncover important new functional role(s) for hPIRH2 in AR signaling: (i) hPIRH2 interacts with AR and enhances AR-mediated transcription with a dynamic pattern of recruitment to androgen response elements in the prostate-specific antigen (PSA) gene; (ii) hPIRH2 interacts with the AR corepressor HDAC1, leading to reduced HDAC1 protein levels and inhibition of transcriptional repression; (iii) hPIRH2 is required for optimal PSA expression; and (iv) hPIRH2 is involved in prostate cancer cell proliferation. In addition, overexpression of hPIRH2 protein was detected in 73 of 82 (89%) resected prostate cancers, with a strong correlation between increased hPIRH2 expression and aggressive disease, as signified by high Gleason sum scores and the presence of metastatic disease (P = <0.0001 and 0.0004, respectively). Collectively, our data establish hPIRH2 as a key modulator of AR function, opening a new direction for targeted therapy in aggressive human prostate cancer. PMID:16914734

Human PIRH2 enhances androgen receptor signaling through inhibition of histone deacetylase 1 and is overexpressed in prostate cancer.

PubMed

Logan, Ian R; Gaughan, Luke; McCracken, Stuart R C; Sapountzi, Vasileia; Leung, Hing Y; Robson, Craig N

2006-09-01

The androgen receptor (AR) is a hormone-dependent transcription factor critically involved in human prostate carcinogenesis. Optimal transcriptional control of androgen-responsive genes by AR may require complex interaction among multiple coregulatory proteins. We have previously shown that the AR coregulator TIP60 can interact with human PIRH2 (hPIRH2). In this study, we uncover important new functional role(s) for hPIRH2 in AR signaling: (i) hPIRH2 interacts with AR and enhances AR-mediated transcription with a dynamic pattern of recruitment to androgen response elements in the prostate-specific antigen (PSA) gene; (ii) hPIRH2 interacts with the AR corepressor HDAC1, leading to reduced HDAC1 protein levels and inhibition of transcriptional repression; (iii) hPIRH2 is required for optimal PSA expression; and (iv) hPIRH2 is involved in prostate cancer cell proliferation. In addition, overexpression of hPIRH2 protein was detected in 73 of 82 (89%) resected prostate cancers, with a strong correlation between increased hPIRH2 expression and aggressive disease, as signified by high Gleason sum scores and the presence of metastatic disease (P = <0.0001 and 0.0004, respectively). Collectively, our data establish hPIRH2 as a key modulator of AR function, opening a new direction for targeted therapy in aggressive human prostate cancer.

Cerebral Artery Alpha-1 AR Subtypes: High Altitude Long-Term Acclimatization Responses

PubMed Central

Goyal, Ravi; Goyal, Dipali; Chu, Nina; Van Wickle, Jonathan; Longo, Lawrence D.

2014-01-01

In response to hypoxia and other stress, the sympathetic (adrenergic) nervous system regulates arterial contractility and blood flow, partly through differential activities of the alpha1 (α1) - adrenergic receptor (AR) subtypes (α1A-, α1B-, and α1D-AR). Thus, we tested the hypothesis that with acclimatization to long-term hypoxia (LTH), contractility of middle cerebral arteries (MCA) is regulated by changes in expression and activation of the specific α1-AR subtypes. We conducted experiments in MCA from adult normoxic sheep maintained near sea level (300 m) and those exposed to LTH (110 days at 3801 m). Following acclimatization to LTH, ovine MCA showed a 20% reduction (n = 5; P<0.05) in the maximum tension achieved by 10−5 M phenylephrine (PHE). LTH-acclimatized cerebral arteries also demonstrated a statistically significant (P<0.05) inhibition of PHE-induced contractility in the presence of specific α1-AR subtype antagonists. Importantly, compared to normoxic vessels, there was significantly greater (P<0.05) α1B-AR subtype mRNA and protein levels in LTH acclimatized MCA. Also, our results demonstrate that extracellular regulated kinase 1 and 2 (ERK1/2)-mediated negative feedback regulation of PHE-induced contractility is modulated by α1B-AR subtype. Overall, in ovine MCA, LTH produces profound effects on α1-AR subtype expression and function. PMID:25393740

Cerebral artery alpha-1 AR subtypes: high altitude long-term acclimatization responses.

PubMed

Goyal, Ravi; Goyal, Dipali; Chu, Nina; Van Wickle, Jonathan; Longo, Lawrence D

2014-01-01

In response to hypoxia and other stress, the sympathetic (adrenergic) nervous system regulates arterial contractility and blood flow, partly through differential activities of the alpha1 (α1) - adrenergic receptor (AR) subtypes (α1A-, α1B-, and α1D-AR). Thus, we tested the hypothesis that with acclimatization to long-term hypoxia (LTH), contractility of middle cerebral arteries (MCA) is regulated by changes in expression and activation of the specific α1-AR subtypes. We conducted experiments in MCA from adult normoxic sheep maintained near sea level (300 m) and those exposed to LTH (110 days at 3801 m). Following acclimatization to LTH, ovine MCA showed a 20% reduction (n = 5; P<0.05) in the maximum tension achieved by 10-5 M phenylephrine (PHE). LTH-acclimatized cerebral arteries also demonstrated a statistically significant (P<0.05) inhibition of PHE-induced contractility in the presence of specific α1-AR subtype antagonists. Importantly, compared to normoxic vessels, there was significantly greater (P<0.05) α1B-AR subtype mRNA and protein levels in LTH acclimatized MCA. Also, our results demonstrate that extracellular regulated kinase 1 and 2 (ERK1/2)-mediated negative feedback regulation of PHE-induced contractility is modulated by α1B-AR subtype. Overall, in ovine MCA, LTH produces profound effects on α1-AR subtype expression and function.

Coastal sea level projections with improved accounting for vertical land motion

PubMed Central

Han, Guoqi; Ma, Zhimin; Chen, Nan; Yang, Jingsong; Chen, Nancy

2015-01-01

Regional and coastal mean sea level projections in the Intergovernmental Panel for Climate Change (IPCC) Fifth Assessment Report (AR5) account only for vertical land motion (VLM) associated with glacial isostatic adjustment (GIA), which may significantly under- or over-estimate sea level rise. Here we adjust AR5-like regional projections with the VLM from Global Positioning Satellite (GPS) measurements and/or from a combination of altimetry and tide-gauge data, which include both GIA and non-GIA VLM. Our results at selected tide-gauge locations on the North American and East Asian coasts show drastically different projections with and without non-GIA VLM being accounted for. The present study points to the importance of correcting IPCC AR5 coastal projections for the non-GIA VLM in making adaptation decisions. PMID:26526287

Coastal sea level projections with improved accounting for vertical land motion.

PubMed

Han, Guoqi; Ma, Zhimin; Chen, Nan; Yang, Jingsong; Chen, Nancy

2015-11-03

Regional and coastal mean sea level projections in the Intergovernmental Panel for Climate Change (IPCC) Fifth Assessment Report (AR5) account only for vertical land motion (VLM) associated with glacial isostatic adjustment (GIA), which may significantly under- or over-estimate sea level rise. Here we adjust AR5-like regional projections with the VLM from Global Positioning Satellite (GPS) measurements and/or from a combination of altimetry and tide-gauge data, which include both GIA and non-GIA VLM. Our results at selected tide-gauge locations on the North American and East Asian coasts show drastically different projections with and without non-GIA VLM being accounted for. The present study points to the importance of correcting IPCC AR5 coastal projections for the non-GIA VLM in making adaptation decisions.

Augmented Reality Tool for the Situational Awareness Improvement of UAV Operators

PubMed Central

Ruano, Susana; Cuevas, Carlos; Gallego, Guillermo; García, Narciso

2017-01-01

Unmanned Aerial Vehicles (UAVs) are being extensively used nowadays. Therefore, pilots of traditional aerial platforms should adapt their skills to operate them from a Ground Control Station (GCS). Common GCSs provide information in separate screens: one presents the video stream while the other displays information about the mission plan and information coming from other sensors. To avoid the burden of fusing information displayed in the two screens, an Augmented Reality (AR) tool is proposed in this paper. The AR system has two functionalities for Medium-Altitude Long-Endurance (MALE) UAVs: route orientation and target identification. Route orientation allows the operator to identify the upcoming waypoints and the path that the UAV is going to follow. Target identification allows a fast target localization, even in the presence of occlusions. The AR tool is implemented following the North Atlantic Treaty Organization (NATO) standards so that it can be used in different GCSs. The experiments show how the AR tool improves significantly the situational awareness of the UAV operators. PMID:28178189

Augmented Reality Tool for the Situational Awareness Improvement of UAV Operators.

PubMed

Ruano, Susana; Cuevas, Carlos; Gallego, Guillermo; García, Narciso

2017-02-06

Unmanned Aerial Vehicles (UAVs) are being extensively used nowadays. Therefore, pilots of traditional aerial platforms should adapt their skills to operate them from a Ground Control Station (GCS). Common GCSs provide information in separate screens: one presents the video stream while the other displays information about the mission plan and information coming from other sensors. To avoid the burden of fusing information displayed in the two screens, an Augmented Reality (AR) tool is proposed in this paper. The AR system has two functionalities for Medium-Altitude Long-Endurance (MALE) UAVs: route orientation and target identification. Route orientation allows the operator to identify the upcoming waypoints and the path that the UAV is going to follow. Target identification allows a fast target localization, even in the presence of occlusions. The AR tool is implemented following the North Atlantic Treaty Organization (NATO) standards so that it can be used in different GCSs. The experiments show how the AR tool improves significantly the situational awareness of the UAV operators.

Oxytocin differently regulates pressor responses to stress in WKY and SHR rats: the role of central oxytocin and V1a receptors.

PubMed

Wsol, A; Szczepanska-Sadowska, E; Kowalewski, S; Puchalska, L; Cudnoch-Jedrzejewska, A

2014-01-01

The role of central oxytocin in the regulation of cardiovascular parameters under resting conditions and during acute stress was investigated in male normotensive Wistar-Kyoto (WKY; n = 40) and spontaneously hypertensive rats (SHR; n = 28). In Experiment 1, mean arterial blood pressure (MABP) and heart rate (HR) were recorded in WKY and SHR rats at rest and after an air-jet stressor during intracerebroventricular (ICV) infusions of vehicle, oxytocin or oxytocin receptor (OTR) antagonist. In Experiment 2, the effects of vehicle, oxytocin and OTR antagonist were determined in WKY rats after prior administration of a V1a vasopressin receptor (V1aR) antagonist. Resting MABP and HR were not affected by any of the ICV infusions either in WKY or in SHR rats. In control experiments (vehicle), the pressor response to stress was significantly higher in SHR. Oxytocin enhanced the pressor response to stress in the WKY rats but reduced it in SHR. During V1aR blockade, oxytocin infusion entirely abolished the pressor response to stress in WKY rats. Combined blockade of V1aR and OTR elicited a significantly greater MABP response to stress than infusion of V1a antagonist and vehicle. This study reveals significant differences in the regulation of blood pressure in WKY and SHR rats during alarming stress. Specifically, the augmentation of the pressor response to stress by exogenous oxytocin in WKY rats is caused by its interaction with V1aR, and endogenous oxytocin regulates the magnitude of the pressor response to stress in WKY rats by simultaneous interaction with OTR and V1aR.

Survival and expression of acid resistance genes in Shiga toxin-producing Escherichia coli acid adapted in pineapple juice and exposed to synthetic gastric fluid

USDA-ARS?s Scientific Manuscript database

Aims: The aim of this research was to examine relative transcriptional expression of acid resistance (AR) genes, rpoS, gadA and adiA, in O157:H7 and non-O157 Shiga toxin-producing Escherichia coli (STEC) serotypes after adaptation to pineapple juice (PJ) and subsequently to determine survival with e...

Prostate Cancer Characteristics Associated with Response to Pre-Receptor Targeting of the Androgen Axis

PubMed Central

Mostaghel, Elahe A.; Morgan, Andrew; Zhang, Xiaotun; Marck, Brett T.; Xia, Jing; Hunter-Merrill, Rachel; Gulati, Roman; Plymate, Stephen; Vessella, Robert L.; Corey, Eva; Higano, Celestia S.; Matsumoto, Alvin M.; Montgomery, R. Bruce; Nelson, Peter S.

2014-01-01

Background Factors influencing differential responses of prostate tumors to androgen receptor (AR) axis-directed therapeutics are poorly understood, and predictors of treatment efficacy are needed. We hypothesized that the efficacy of inhibiting DHT ligand synthesis would associate with intra-tumoral androgen ratios indicative of relative dependence on DHT-mediated growth. Methods We characterized two androgen-sensitive prostate cancer xenograft models after androgen suppression by castration in combination with the SRD5A inhibitor, dutasteride, as well as a panel of castration resistant metastases obtained via rapid autopsy. Results In LuCaP35 tumors (intra-tumoral T:DHT ratio 2∶1) dutasteride suppressed DHT to 0.02 ng/gm and prolonged survival vs. castration alone (337 vs.152 days, HR 2.8, p = 0.0015). In LuCaP96 tumors (T:DHT 10∶1), survival was not improved despite similar DHT reduction (0.02 ng/gm). LuCaP35 demonstrated higher expression of steroid biosynthetic enzymes maintaining DHT levels (5-fold higher SRD5A1, 41 fold higher, 99-fold higher RL-HSD, p<0.0001 for both), reconstitution of intra-tumoral DHT (to ∼30% of untreated tumors), and ∼2 fold increased expression of full length AR. In contrast, LuCaP96 demonstrated higher levels of steroid catabolizing enzymes (6.9-fold higher AKR1C2, 3000-fold higher UGT2B15, p = 0.002 and p<0.0001 respectively), persistent suppression of intra-tumoral DHT, and 6–8 fold induction of full length AR and the ligand independent V7 AR splice variant. Human metastases demonstrated bio-active androgen levels and AR full length and AR splice-variant expression consistent with the range observed in xenografts. Conclusions Intrinsic differences in basal steroidogenesis, as well as variable expression of full length and splice-variant AR, associate with response and resistance to pre-receptor AR ligand suppression. Expression of steroidogenic enzymes and AR isoforms may serve as potential biomarkers of sensitivity to potent AR-axis inhibition and should be validated in additional models. PMID:25356728

Prostate cancer characteristics associated with response to pre-receptor targeting of the androgen axis.

PubMed

Mostaghel, Elahe A; Morgan, Andrew; Zhang, Xiaotun; Marck, Brett T; Xia, Jing; Hunter-Merrill, Rachel; Gulati, Roman; Plymate, Stephen; Vessella, Robert L; Corey, Eva; Higano, Celestia S; Matsumoto, Alvin M; Montgomery, R Bruce; Nelson, Peter S

2014-01-01

Factors influencing differential responses of prostate tumors to androgen receptor (AR) axis-directed therapeutics are poorly understood, and predictors of treatment efficacy are needed. We hypothesized that the efficacy of inhibiting DHT ligand synthesis would associate with intra-tumoral androgen ratios indicative of relative dependence on DHT-mediated growth. We characterized two androgen-sensitive prostate cancer xenograft models after androgen suppression by castration in combination with the SRD5A inhibitor, dutasteride, as well as a panel of castration resistant metastases obtained via rapid autopsy. In LuCaP35 tumors (intra-tumoral T:DHT ratio 2:1) dutasteride suppressed DHT to 0.02 ng/gm and prolonged survival vs. castration alone (337 vs.152 days, HR 2.8, p = 0.0015). In LuCaP96 tumors (T:DHT 10:1), survival was not improved despite similar DHT reduction (0.02 ng/gm). LuCaP35 demonstrated higher expression of steroid biosynthetic enzymes maintaining DHT levels (5-fold higher SRD5A1, 41 fold higher, 99-fold higher RL-HSD, p<0.0001 for both), reconstitution of intra-tumoral DHT (to ∼30% of untreated tumors), and ∼2 fold increased expression of full length AR. In contrast, LuCaP96 demonstrated higher levels of steroid catabolizing enzymes (6.9-fold higher AKR1C2, 3000-fold higher UGT2B15, p = 0.002 and p<0.0001 respectively), persistent suppression of intra-tumoral DHT, and 6-8 fold induction of full length AR and the ligand independent V7 AR splice variant. Human metastases demonstrated bio-active androgen levels and AR full length and AR splice-variant expression consistent with the range observed in xenografts. Intrinsic differences in basal steroidogenesis, as well as variable expression of full length and splice-variant AR, associate with response and resistance to pre-receptor AR ligand suppression. Expression of steroidogenic enzymes and AR isoforms may serve as potential biomarkers of sensitivity to potent AR-axis inhibition and should be validated in additional models.

Comparison of fMRI data from passive listening and active-response story processing tasks in children.

PubMed

Vannest, Jennifer J; Karunanayaka, Prasanna R; Altaye, Mekibib; Schmithorst, Vincent J; Plante, Elena M; Eaton, Kenneth J; Rasmussen, Jerod M; Holland, Scott K

2009-04-01

To use functional MRI (fMRI) methods to visualize a network of auditory and language-processing brain regions associated with processing an aurally-presented story. We compare a passive listening (PL) story paradigm to an active-response (AR) version including online performance monitoring and a sparse acquisition technique. Twenty children (ages 11-13 years) completed PL and AR story processing tasks. The PL version presented alternating 30-second blocks of stories and tones; the AR version presented story segments, comprehension questions, and 5-second tone sequences, with fMRI acquisitions between stimuli. fMRI data was analyzed using a general linear model approach and paired t-test identifying significant group activation. Both tasks showed activation in the primary auditory cortex, superior temporal gyrus bilaterally, and left inferior frontal gyrus (IFG). The AR task demonstrated more extensive activation, including the dorsolateral prefrontal cortex and anterior/posterior cingulate cortex. Comparison of effect size in each paradigm showed a larger effect for the AR paradigm in a left inferior frontal region-of-interest (ROI). Activation patterns for story processing in children are similar in PL and AR tasks. Increases in extent and magnitude of activation in the AR task are likely associated with memory and attention resources engaged across acquisition intervals.

The ArTéMiS wide-field sub-millimeter camera: preliminary on-sky performance at 350 microns

NASA Astrophysics Data System (ADS)

Revéret, Vincent; André, Philippe; Le Pennec, Jean; Talvard, Michel; Agnèse, Patrick; Arnaud, Agnès.; Clerc, Laurent; de Breuck, Carlos; Cigna, Jean-Charles; Delisle, Cyrille; Doumayrou, Eric; Duband, Lionel; Dubreuil, Didier; Dumaye, Luc; Ercolani, Eric; Gallais, Pascal; Groult, Elodie; Jourdan, Thierry; Leriche, Bernadette; Maffei, Bruno; Lortholary, Michel; Martignac, Jérôme; Rabaud, Wilfried; Relland, Johan; Rodriguez, Louis; Vandeneynde, Aurélie; Visticot, François

2014-07-01

ArTeMiS is a wide-field submillimeter camera operating at three wavelengths simultaneously (200, 350 and 450 μm). A preliminary version of the instrument equipped with the 350 μm focal plane, has been successfully installed and tested on APEX telescope in Chile during the 2013 and 2014 austral winters. This instrument is developed by CEA (Saclay and Grenoble, France), IAS (France) and University of Manchester (UK) in collaboration with ESO. We introduce the mechanical and optical design, as well as the cryogenics and electronics of the ArTéMiS camera. ArTeMiS detectors consist in Si:P:B bolometers arranged in 16×18 sub-arrays operating at 300 mK. These detectors are similar to the ones developed for the Herschel PACS photometer but they are adapted to the high optical load encountered at APEX site. Ultimately, ArTeMiS will contain 4 sub-arrays at 200 μm and 2×8 sub-arrays at 350 and 450 μm. We show preliminary lab measurements like the responsivity of the instrument to hot and cold loads illumination and NEP calculation. Details on the on-sky commissioning runs made in 2013 and 2014 at APEX are shown. We used planets (Mars, Saturn, Uranus) to determine the flat-field and to get the flux calibration. A pointing model was established in the first days of the runs. The average relative pointing accuracy is 3 arcsec. The beam at 350 μm has been estimated to be 8.5 arcsec, which is in good agreement with the beam of the 12 m APEX dish. Several observing modes have been tested, like "On- The-Fly" for beam-maps or large maps, spirals or raster of spirals for compact sources. With this preliminary version of ArTeMiS, we concluded that the mapping speed is already more than 5 times better than the previous 350 μm instrument at APEX. The median NEFD at 350 μm is 600 mJy.s1/2, with best values at 300 mJy.s1/2. The complete instrument with 5760 pixels and optimized settings will be installed during the first half of 2015.

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

Evaluation of partial beta-adrenoceptor agonist activity.

PubMed

Lipworth, B J; Grove, A

1997-01-01

A partial beta-adrenoceptor (beta-AR) agonist will exhibit opposite agonist and antagonist activity depending on the prevailing degree of adrenergic tone or the presence of a beta-AR agonist with higher intrinsic activity. In vivo partial beta-AR agonist activity will be evident at rest with low endogenous adrenergic tone, as for example with chronotropicity (beta 1/beta 2), inotropicity (beta 1) or peripheral vasodilatation and finger tremor (beta 2). beta-AR blocking drugs which have partial agonist activity may exhibit a better therapeutic profile when used for hypertension because of maintained cardiac output without increased systemic vascular resistance, along with an improved lipid profile. In the presence of raised endogenous adrenergic tone such as exercise or an exogenous full agonist, beta-AR subtype antagonist activity will become evident in terms of effects on exercise induced heart rate (beta 1) and potassium (beta 2) responses. Reduction of exercise heart rate will occur to a lesser degree in the case of a beta-adrenoceptor blocker with partial beta 1-AR agonist activity compared with a beta-adrenoceptor blocker devoid of partial agonist activity. This may result in reduced therapeutic efficacy in the treatment of angina on effort when using beta-AR blocking drugs with partial beta 1-AR agonist activity. Effects on exercise hyperkalaemia are determined by the balance between beta 2-AR partial agonist activity and endogenous adrenergic activity. For predominantly beta 2-AR agonist such as salmeterol and salbutamol, potentiation of exercise hyperkalaemia occurs. For predominantly beta 2-AR antagonists such as carteolol, either potentiation or attenuation of exercise hyperkalaemia occurs at low and high doses respectively. beta 2-AR partial agonist activity may also be expressed as antagonism in the presence of an exogenous full agonist, as for example attenuation of fenoterol induced responses by salmeterol. Studies are required to investigate whether this phenomenon is relevant in the setting of acute severe asthma.

7 CFR 520.4 - Responsibilities.

Code of Federal Regulations, 2010 CFR

2010-01-01

... compliance with the provisions of NEPA and related laws, policies, plans, programs, and projects. The ARS... Administrator for assuring that ARS programs are in compliance with the policies and procedures of NEPA. ...

7 CFR 520.4 - Responsibilities.

Code of Federal Regulations, 2012 CFR

2012-01-01

... compliance with the provisions of NEPA and related laws, policies, plans, programs, and projects. The ARS... Administrator for assuring that ARS programs are in compliance with the policies and procedures of NEPA. ...

7 CFR 520.4 - Responsibilities.

Code of Federal Regulations, 2011 CFR

2011-01-01

... compliance with the provisions of NEPA and related laws, policies, plans, programs, and projects. The ARS... Administrator for assuring that ARS programs are in compliance with the policies and procedures of NEPA. ...

Cross-cultural adaptation, reliability and validity of the Arabic version of the reduced Western Ontario and McMaster Universities Osteoarthritis index in patients with knee osteoarthritis.

PubMed

Alghadir, Ahmad; Anwer, Shahnawaz; Iqbal, Zaheen Ahmed; Alsanawi, Hisham Abdulaziz

2016-01-01

We adapted the reduced Western Ontario and McMaster Universities Osteoarthritis (WOMAC) index for the Arabic language and tested its metric properties in patients with knee osteoarthritis (OA). One hundred and twenty-one consecutive patients who were referred for physiotherapy to the outpatient department were asked to answer the Arabic version of the reduced WOMAC index (ArWOMAC). After the completion of the ArWOMAC, the intensity of knee pain and general health status were assessed using the visual analog scale (VAS) and the 12-item short form health survey (SF-12), respectively. A second assessment was performed at least 48 h after the first session to assess test-retest reliability. The test-retest reliability was quantified using the intra-class correlation coefficient (ICC), and Cronbach's alpha was calculated to assess the internal consistency of the Arabic questionnaire. The construct validity was assessed using Spearman rank correlation coefficients. The total ArWOMAC scale and pain and function subscales were internally consistent with Cronbach's coefficient alpha of 0.91, 0.89 and 0.90, respectively. Test-retest reliability was good to excellent with ICC of 0.91, 0.89 and 0.90, respectively. SF-12 and VAS score significantly correlated with ArWOMAC index (p < 0.01), which support the construct validity. The standard error of measurement (SEM) of the total scale was 2.94, based on repeated measurements for test-retest. The minimum detectable change based on the SEM for test-retest was 8.15. The ArWOMAC index is a reliable and valid instrument for evaluating the severity of knee OA, with metric properties in agreement with the original version. Although, the reduced WOMAC index has been clinically utilized within the Saudi population, the Arabic version of this instrument is not validated for an Arab population to measure lower limb functional disability caused by OA. The Arabic version of reduced WOMAC (ArWOMAC) index is a reliable and valid scale to measure lower limb functional disability in patients with knee OA. The ArWOMAC index could be suitable in Saudi Arabia and other Arab countries where the language, culture and the life style are similar.

Arousal effect of caffeine depends on adenosine A2A receptors in the shell of the nucleus accumbens

PubMed Central

Lazarus, Michael; Shen, Hai-Ying; Cherasse, Yoan; Qu, Wei-Min; Huang, Zhi-Li; Bass, Caroline E.; Winsky-Sommerer, Raphaelle; Semba, Kazue; Fredholm, Bertil B.; Boison, Detlev; Hayaishi, Osamu; Urade, Yoshihiro; Chen, Jiang-Fan

2011-01-01

Caffeine, the most widely used psychoactive compound, is an adenosine receptor antagonist. It promotes wakefulness by blocking adenosine A2A receptors (A2ARs) in the brain, but the specific neurons on which caffeine acts to produce arousal have not been identified. Using selective gene deletion strategies based on the Cre/loxP technology in mice and focal RNA interference to silence the expression of A2ARs in rats by local infection with adeno-associated virus carrying short-hairpin RNA, we report that the A2ARs in the shell region of the nucleus accumbens (NAc) are responsible for the effect of caffeine on wakefulness. Caffeine-induced arousal was not affected in rats when A2ARs were focally removed from the NAc core or other A2AR-positive areas of the basal ganglia. Our observations suggest that caffeine promotes arousal by activating pathways that traditionally have been associated with motivational and motor responses in the brain. PMID:21734299

Development of a Browser-Based Mobile Audience Response System for Large Classrooms

ERIC Educational Resources Information Center

Andergassen, Monika; Guerra, Victor; Ledermüller, Karl; Neumann, Gustaf

2013-01-01

Didactical advantages of audience response systems (ARS) have been discussed extensively ever since they have been used in classes. However, conventional ARS bear some drawbacks, such as requiring specific hardware, generating costs (text messaging based and web service fees) and creating a dependency on external hosts. In this paper we present a…

An Audience Response System May Influence Student Performance on Anatomy Examination Questions

ERIC Educational Resources Information Center

Hoyt, Amy; McNulty, John A.; Gruener, Gregory; Chandrasekhar, Arcot; Espiritu, Baltazar; Ensminger, David; Price, Ron, Jr.; Naheedy, Ross

2010-01-01

This study integrated an in-house audience response system (ARS) in the human anatomy course over two years to determine whether students performed better on high-stakes examinations following exposure to similar interactive questions in a large lecture format. Questions in an interactive ARS format were presented in lectures via PowerPoint…

Using Audience Response Systems to Encourage Student Engagement and Reflection on Ethical Orientation and Behavior

ERIC Educational Resources Information Center

Micheletto, Melinda J.

2011-01-01

The purpose of this study was to use an audience response system (ARS) to engage students in classroom discussions concerning sensitive and controversial topics (e.g., business ethics), assess student's ethical orientation and conduct in unethical behaviors, and encourage reflection on their personal level of ethicality. Students used ARS devices…

Effect of ED-71, a New Active Vitamin D Analog, on Bone Formation in an Orthopedically Expanded Suture in Rats. A Histomorphometric Study

PubMed Central

Uysal, Tancan; Amasyali, Mihri; Enhos, Sukru; Sonmez, Mehmet Fatih; Sagdic, Deniz

2009-01-01

Objectives The aim of this experimental study was to evaluate the effects of ED-71, a new active vitamin D analog, on bone regeneration in response to expansion of the mid-palatal suture, in rats, histomorphometrically. Methods Sixteen male 50–60 days old Wistar rats were separated into two equal groups (control and experimental). Both groups were subjected to expansion, and 30 grams of force was applied to the maxillary incisors with a helical-spring. Experimental group was treated with single-dose ED-71 (0.8 μg/kg body weight) in the mid-palatal suture locally and eight control animals received vehicle solution. Bone regeneration in the mid-palatal suture was evaluated by bone histomorphometric method and mineralized area (Md.Ar), fibrosis area (Fb.Ar), mineralized area/fibrosis area (Md.Ar/Fb.Ar), bone area (B.Ar) and osteoblast number (N.Ob) parameters were evaluated. Mann Whitney-U test was used for statistical evaluation at P<.05 level. Results Statistical analysis showed significant differences between groups for all investigated histomorphometric parameters. Md.Ar (P<.001), Md.Ar/Fb.Ar (P<.001), B.Ar (P<.01) and N.Ob (P<.001) parameters were significantly increased and Fb.Ar (P<.001) measurement was significantly decreased in experimental group. ED-71 group with a mean of 24.55±6.47 showed statistically higher N.Ob than the control group (mean N.Ob: 12.82±5.81). Conclusions ED-71 has positive effects on early phase of bone regeneration in the mid-palatal suture in response to expansion and may be beneficial in routine maxillary expansion procedures. PMID:19756189

Mesenchymal stem cell therapy for acute radiation syndrome: innovative medical approaches in military medicine.

PubMed

Eaton, Erik B; Varney, Timothy R

2015-01-01

After a radiological or nuclear event, acute radiation syndrome (ARS) will present complex medical challenges that could involve the treatment of hundreds to thousands of patients. Current medical doctrine is based on limited clinical data and remains inadequate. Efforts to develop medical innovations that address ARS complications are unlikely to be generated by industry because of market uncertainties specific to this type of injury. A prospective strategy could be the integration of cellular therapy to meet the medical demands of ARS. The most clinically advanced cellular therapy to date is the administration of mesenchymal stem cells (MSCs). Results of currently published investigations describing MSC safety and efficacy in a variety of injury and disease models demonstrate the unique qualities of this reparative cell population in adapting to the specific requirements of the damaged tissue in which the cells integrate. This report puts forward a rationale for the further evaluation of MSC therapy to address the current unmet medical needs of ARS. We propose that the exploration of this novel therapy for the treatment of the multivariate complications of ARS could be of invaluable benefit to military medicine.

Stress-induced activation of brown adipose tissue prevents obesity in conditions of low adaptive thermogenesis

PubMed Central

Razzoli, Maria; Frontini, Andrea; Gurney, Allison; Mondini, Eleonora; Cubuk, Cankut; Katz, Liora S.; Cero, Cheryl; Bolan, Patrick J.; Dopazo, Joaquin; Vidal-Puig, Antonio; Cinti, Saverio; Bartolomucci, Alessandro

2015-01-01

Background Stress-associated conditions such as psychoemotional reactivity and depression have been paradoxically linked to either weight gain or weight loss. This bi-directional effect of stress is not understood at the functional level. Here we tested the hypothesis that pre-stress level of adaptive thermogenesis and brown adipose tissue (BAT) functions explain the vulnerability or resilience to stress-induced obesity. Methods We used wt and triple β1,β2,β3−Adrenergic Receptors knockout (β-less) mice exposed to a model of chronic subordination stress (CSS) at either room temperature (22 °C) or murine thermoneutrality (30 °C). A combined behavioral, physiological, molecular, and immunohistochemical analysis was conducted to determine stress-induced modulation of energy balance and BAT structure and function. Immortalized brown adipocytes were used for in vitro assays. Results Departing from our initial observation that βARs are dispensable for cold-induced BAT browning, we demonstrated that under physiological conditions promoting low adaptive thermogenesis and BAT activity (e.g. thermoneutrality or genetic deletion of the βARs), exposure to CSS acted as a stimulus for BAT activation and thermogenesis, resulting in resistance to diet-induced obesity despite the presence of hyperphagia. Conversely, in wt mice acclimatized to room temperature, and therefore characterized by sustained BAT function, exposure to CSS increased vulnerability to obesity. Exposure to CSS enhanced the sympathetic innervation of BAT in wt acclimatized to thermoneutrality and in β-less mice. Despite increased sympathetic innervation suggesting adrenergic-mediated browning, norepinephrine did not promote browning in βARs knockout brown adipocytes, which led us to identify an alternative sympathetic/brown adipocytes purinergic pathway in the BAT. This pathway is downregulated under conditions of low adaptive thermogenesis requirements, is induced by stress, and elicits activation of UCP1 in wt and β-less brown adipocytes. Importantly, this purinergic pathway is conserved in human BAT. Conclusion Our findings demonstrate that thermogenesis and BAT function are determinant of the resilience or vulnerability to stress-induced obesity. Our data support a model in which adrenergic and purinergic pathways exert complementary/synergistic functions in BAT, thus suggesting an alternative to βARs agonists for the activation of human BAT. PMID:26844204

Progressive skeletal benefits of physical activity when young as assessed at the midshaft humerus in male baseball players.

PubMed

Warden, S J; Weatherholt, A M; Gudeman, A S; Mitchell, D C; Thompson, W R; Fuchs, R K

2017-07-01

Physical activity benefits the skeleton, but there is contrasting evidence regarding whether benefits differ at different stages of growth. The current study demonstrates that physical activity should be encouraged at the earliest age possible and be continued into early adulthood to gain most skeletal benefits. The current study explored physical activity-induced bone adaptation at different stages of somatic maturity by comparing side-to-side differences in midshaft humerus properties between male throwing athletes and controls. Throwers present an internally controlled model, while inclusion of control subjects removes normal arm dominance influences. Throwing athletes (n = 90) and controls (n = 51) were categorized into maturity groups (pre, peri, post-early, post-mid, and post-late) based on estimated years from peak height velocity (<-2, -2 to 2, 2 to 4, 4 to 10, and >10 years). Side-to-side percent differences in midshaft humerus cortical volumetric bone mineral density (Ct.vBMD) and bone mineral content (Ct.BMC); total (Tt.Ar), medullary (Me.Ar), and cortical (Ct.Ar) areas; average cortical thickness (Ct.Th); and polar Strength Strain Index (SSI P ) were assessed. Significant interactions between physical activity and maturity on side-to-side differences in Ct.BMC, Tt.Ar, Ct.Ar, Me.Ar, Ct.Th, and SSI P resulted from the following: (1) greater throwing-to-nonthrowing arm differences than dominant-to-nondominant arm differences in controls (all p < 0.05) and (2) throwing-to-nonthrowing arm differences in throwers being progressively greater across maturity groups (all p < 0.05). Regional analyses revealed greatest adaptation in medial and lateral sectors, particularly in the three post-maturity groups. Years throwing predicted 59% of the variance of the variance in throwing-to-nonthrowing arm difference in SSI P (p < 0.001). These data suggest that physical activity has skeletal benefits beginning prior to and continuing beyond somatic maturation and that a longer duration of exposure to physical activity has cumulative skeletal benefits. Thus, physical activity should be encouraged at the earliest age possible and be continued into early adulthood to optimize skeletal benefits.

Variations in the perception of trauma-related complications between attending surgeons, surgery residents, critical care nurses, and medical students.

PubMed

Dissanaike, Sharmila; Berry, Matthew; Ginos, Jason; Paige, Robert; McNabb, Wendi; Griswold, John

2009-06-01

The morbidity and mortality conference (M&M) is a key component of the performance improvement process. The audience response system (ARS) has been shown to improve audience participation and promote more truthful responses in various settings. We implemented the ARS in our trauma M&M and evaluated the responses we received from different categories of participants. This was a prospective observational study undertaken between November 2006 and July 2007. Cases were graded based on the American College of Surgeons scoring system. We evaluated the responses of attending surgeons, residents, critical care nurses, and medical students using the ARS. We had 695 responses for complications and 936 responses for deaths. Residents consistently scored complications as more severe than other groups (P = .03). There was no difference in the scoring of deaths. Surgical residents assign higher severity to trauma-related complications than other groups when using an anonymous automated scoring system.

Quantitative evaluation of root canal surface roughness after filing with adaptive reciprocating and continuous rotary instruments.

PubMed

Sakhaei Manesh, Vahid; Giacomin, Paul; Stoll, Richard

2017-06-01

Obtaining clean and smooth root canal walls is the ideal clinical outcome of the cleaning and shaping stage in root canal treatment. This study compares the surface roughness of root canal surfaces instrumented with a NiTi filing system with either adaptive reciprocating (AR) or continuous rotation (CR). Root canal cleaning and shaping was carried out on the mesial canals of 24 extracted first molars roots with either AR or CR. Roots were split in half and the surface roughness of their canals was evaluated in 12 three dimensional roughness reconstructions using a scanning electron microscope. Rz (nm) values were calculated in three areas of each reconstruction and analyzed (α = 0.05). Mann-Whitney tests showed that surface roughness was significantly higher overall in the AR group (Rz = 967 ± 250 nm) compared with the CR group (Rz = 739 ± 239 nm; p = 0.044). The roughness values generally increased from apical towards the coronal third in both groups. A less aggressive finishing file or a continuous rotary system to end the cleaning and shaping stage may be beneficial to reduce roughness of the root canal surface. © 2017 Wiley Periodicals, Inc.

Identification and characterization of human UDP-glucuronosyltransferases responsible for the in-vitro glucuronidation of arctigenin.

PubMed

Xin, Hong; Xia, Yang-Liu; Hou, Jie; Wang, Ping; He, Wei; Yang, Ling; Ge, Guang-Bo; Xu, Wei

2015-12-01

This study aimed to characterize the glucuronidation pathway of arctigenin (AR) in human liver microsomes (HLM) and human intestine microsomes (HIM). HLM and HIM incubation systems were employed to catalyse the formation of AR glucuronide. The glucuronidation activity of commercially recombinant UGT isoforms towards AR was screened. A combination of chemical inhibition assay and kinetic analysis was used to determine the UGT isoforms involved in the glucuronidation of AR in HLM and HIM. AR could be extensively metabolized to one mono-glucuronide in HLM and HIM. The mono-glucuronide was biosynthesized and characterized as 4'-O-glucuronide. UGT1A1, 1A3, 1A7, 1A8, 1A9, 1A10, 2B4, 2B7 and 2B17 participated in the formation of 4'-O-G, while UGT2B17 demonstrated the highest catalytic activity in this biotransformation. Both kinetic analysis and chemical inhibition assays demonstrated that UGT1A9, UGT2B7 and UGT2B17 played important roles in AR-4'-O-glucuronidation in HLM. Furthermore, HIM demonstrated moderate efficiency for AR-4'-O-glucuronidation, implying that AR may undergo a first-pass metabolism during the absorption process. UGT1A9, UGT2B7 and UGT2B17 were the major isoforms responsible for the 4'-O-glucuronidation of AR in HLM, while UGT2B7 and UGT2B17 were the major contributors to this biotransformation in HIM. © 2015 Royal Pharmaceutical Society.

7 CFR 520.4 - Responsibilities.

Code of Federal Regulations, 2014 CFR

2014-01-01

... compliance with the provisions of NEPA and related laws, policies, plans, programs, and projects. The ARS... Administrator for assuring that ARS programs are in compliance with the policies and procedures of NEPA. [51 FR...

7 CFR 520.4 - Responsibilities.

Code of Federal Regulations, 2013 CFR

2013-01-01

... compliance with the provisions of NEPA and related laws, policies, plans, programs, and projects. The ARS... Administrator for assuring that ARS programs are in compliance with the policies and procedures of NEPA. [51 FR...

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

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.

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

Comparing Student Learning in the Team-Based Learning Classroom with Different Team Reporting Methods

ERIC Educational Resources Information Center

Johnson, Staci Neas

2017-01-01

The increase in classroom technology has resulted in the use of clickers and other audience response systems (ARS) for simultaneous reporting of choices in the teambased learning (TBL) classroom. A variety of techniques and practices using ARS technology in TBL courses has been noted. Learning gains in the TBL classroom with ARS reporting has not…

[Measurement of 75Se-SeHCAT abdominal retention in the initial diagnosis of Bile Acid Absorption (BAM)].

PubMed

Notta, P C; Ramal, D; Maisterra, S; Rodríguez Gasen, A; Maymó, S; Sabaté, A; Girbau, A; Guardiola, J; Martín-Comín, J

2011-01-01

To evaluate the usefulness of the (75)SeHCAT abdominal retention (AR) measurement in the early diagnosis of diarrhea syndrome (DS). Thirty-seven patients with diarrhea syndrome within the first month of evolution were prospectively evaluated. The (75)Se-SeHCAT abdominal retention was measured 4 and 7 days post-administration of 0.01 mCi of (75)SeHCAT. The test was performed prior to treatment and at 3 months when the baseline study was positive. The test was considered positive if the RA was <25% at 4(th) and <10% on the 7th day. The patients were visited at 3 months. Depending on the response, 3 groups were established: a) complete response: normalization of stool frequency, b) partial response, decrease of frequency or c) no response. Group A: The AR of (75)Se-SEHCAT was normal in 21 patients. Six were diagnosed of colonic diverticulosis, 8 of irritable bowel syndrome, 1 of lymphocytic colitis, 1 of post-gastroenteritis syndrome, 1 of celiac disease and 1 of stenosis of the cardia. Four are still under study. Group B: The AR of (75)Se-SEHCAT decreased in 16 patients. All showed abnormal AR at day 7 and all but 1 at day 4. Following administration of cholestyramine resin, 8 (50%) presented partial response and 8 (50%) complete response. At 3 months, AR had increased at day 4 and 9 at day 7. The measurement of (75)SEHCAT abdominal retention allows the early diagnosis of bile acid malabsorption in 43% of the patients with DS. Measurement at 7 days seems more accurate than that at 4 days. Copyright © 2010 Elsevier España, S.L. y SEMNIM. All rights reserved.

How the Scientific Community Reacts to Newly Submitted Preprints: Article Downloads, Twitter Mentions, and Citations

PubMed Central

Shuai, Xin; Pepe, Alberto; Bollen, Johan

2012-01-01

We analyze the online response to the preprint publication of a cohort of 4,606 scientific articles submitted to the preprint database arXiv.org between October 2010 and May 2011. We study three forms of responses to these preprints: downloads on the arXiv.org site, mentions on the social media site Twitter, and early citations in the scholarly record. We perform two analyses. First, we analyze the delay and time span of article downloads and Twitter mentions following submission, to understand the temporal configuration of these reactions and whether one precedes or follows the other. Second, we run regression and correlation tests to investigate the relationship between Twitter mentions, arXiv downloads, and article citations. We find that Twitter mentions and arXiv downloads of scholarly articles follow two distinct temporal patterns of activity, with Twitter mentions having shorter delays and narrower time spans than arXiv downloads. We also find that the volume of Twitter mentions is statistically correlated with arXiv downloads and early citations just months after the publication of a preprint, with a possible bias that favors highly mentioned articles. PMID:23133597

A Specific Transitory Increase in Intracellular Calcium Induced by Progesterone Promotes Acrosomal Exocytosis in Mouse Sperm1

PubMed Central

Romarowski, Ana; Sánchez-Cárdenas, Claudia; Ramírez-Gómez, Héctor V.; Puga Molina, Lis del C.; Treviño, Claudia L.; Hernández-Cruz, Arturo; Darszon, Alberto; Buffone, Mariano G

2016-01-01

During capacitation, sperm acquire the ability to undergo the acrosome reaction (AR), an essential step in fertilization. Progesterone produced by cumulus cells has been associated with various physiological processes in sperm, including stimulation of AR. An increase in intracellular Ca2+ ([Ca2+]i) is necessary for AR to occur. In this study, we investigated the spatiotemporal correlation between the changes in [Ca2+]i and AR in single mouse spermatozoa in response to progesterone. We found that progesterone stimulates an [Ca2+]i increase in five different patterns: gradual increase, oscillatory, late transitory, immediate transitory, and sustained. We also observed that the [Ca2+]i increase promoted by progesterone starts at either the flagellum or the head. We validated the use of FM4-64 as an indicator for the occurrence of the AR by simultaneously detecting its fluorescence increase and the loss of EGFP in transgenic EGFPAcr sperm. For the first time, we have simultaneously visualized the rise in [Ca2+]i and the process of exocytosis in response to progesterone and found that only a specific transitory increase in [Ca2+]i originating in the sperm head promotes the initiation of AR. PMID:26819478

Image analysis of androgen receptor immunostaining in metastatic prostate cancer. Heterogeneity as a predictor of response to hormonal therapy.

PubMed

Sadi, M V; Barrack, E R

1993-04-15

Reliable predictors of the response of prostate cancer to androgen ablation therapy are lacking. The goals of this study were to determine whether nuclear androgen receptor (AR) concentrations in metastatic prostate cancer varied within and between specimens and to correlate this information with the response to therapy. AR concentration was evaluated by computer-assisted image analysis of immunohistochemical staining intensity in 200 malignant epithelial nuclei of each of 17 specimens of Stage D2 prostate cancer obtained before hormonal therapy. The data were correlated with the time to tumor progression (relapse) after hormonal therapy. AR staining intensity varied within specimens, and the variance of staining intensity was significantly greater (P = 0.03) in the poor responders (n = 8; time to progression, < 20 months) than in the good responders (n = 9; time to progression, > or = 20 months). The kurtosis was significantly lower in poor responders (P = 0.04). However, the mean AR staining intensity was not significantly different among patients. The frequency distribution plots of good responders were generally uniform and unimodal, but those of poor responders were flattened (more platykurtic), dispersed, and highly variable. Thus, the AR concentration per cell was significantly more heterogeneous in poor responders. Variance was a significant predictor of response. Five of 6 patients with a high variance (defined as variance greater than the mean) were poor responders, whereas 8 of 11 patients with a low variance were good responders (an overall classification accuracy of 13 of 17, 76%). The greater AR heterogeneity in poor responders may reflect a greater genetic instability in tumors that have progressed further toward androgen independence and may be a valuable predictor of progression.

An aryl hydrocarbon receptor ligand acts on dendritic cells and T cells to suppress the Th17 response in allergic rhinitis patients.

PubMed

Wei, Ping; Hu, Guo-Hua; Kang, Hou-Yong; Yao, Hong-Bing; Kou, Wei; Liu, Hong; Zhang, Cheng; Hong, Su-Ling

2014-05-01

A predominant Th17 population is a marker of allergic rhinitis (AR). The aryl hydrocarbon receptor (AhR) exhibits strong immunomodulation potential via regulation of the differentiation of T lymphocytes and dendritic cells (DCs) after activation by its ligand, such as 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE). The aim of this study was to analyze the effect of AhR on Th17 differentiation by investigating the action of ITE on DCs and CD4(+) T cells from patients with AR. In all, 26 AR patients and 12 healthy controls were included in this study. The expression of interleukin (IL)-1β, IL-6, IL-10, and IL-17 in the culture supernatant and the presence of Th17 cells in CD4(+) T cells and DC-CD4(+) T-cell co-culture system were measured before and after treatment with ITE. We show that ITE significantly induced cell secretion of IL-10 and inhibited IL-1β and IL-6 production in DCs, and promoted IL-10 production and suppressed IL-17 expression in CD4(+) T cells in vitro. It also suppressed the expansion of Th17 cells in vitro. Our work demonstrates that ITE acts on DCs and CD4(+) T cells to inhibit the Th17 response that suppresses AR; the AhR-DC-Th17 axis may be an important pathway in the treatment of AR. ITE, a nontoxic AhR ligand, attenuated the Th17 response; thus, it appears to be a promising therapeutic candidate for suppressing the inflammatory responses associated with AR.

AR-v7 liquid biopsy for treatment stratification in prostate cancer: how close are we?

PubMed

Fletcher, Claire

2017-09-01

Recent clinical introduction of the novel antiandrogen, Enzalutamide (Enza), CYP17 inhibitor, Abiraterone (Abi), and the second-generation chemotherapeutic, Cabazitaxel, has increased survival of patients with advanced, metastatic castration-resistant prostate cancer (mCRPC). However, de novo and acquired resistance rates are high. A liquid biopsy that can rapidly, sensitively and robustly identify which patients will respond to treatment in a minimally invasive manner is urgently required to permit switch to a potentially more efficacious drug regimen, thus increasing survival whilst avoiding debilitating side effects associated with unnecessary treatment. This review will highlight recent developments in detection of AR-v7 in circulating mRNA/whole blood and circulating tumour cells (CTCs) as a liquid biopsy for patient-stratification in mCRPC. Continued androgen receptor (AR) activity in mCRPC has been linked to the expression of a number of truncated but constitutively active AR isoforms. One such variant, AR-v7, can drive drug resistance in preclinical models and is correlated with disease progression whilst showing dynamic response to AR-targeting treatments when assessed in blood. It has thus been proposed as an Abi/Enza treatment-response biomarker. AR-v7 liquid biopsy has the potential to transform clinical management of mCRPC and increase patient survival. This review will explore recent efforts to validate AR-v7 as a robust, clinically informative biomarker. I will also address potential limitations of detection and quantification that could frustrate its adoption into routine clinical practise.

OnlineTED.com--a novel web-based audience response system for higher education. A pilot study to evaluate user acceptance.

PubMed

Kühbeck, Felizian; Engelhardt, Stefan; Sarikas, Antonio

2014-01-01

Audience response (AR) systems are increasingly used in undergraduate medical education. However, high costs and complexity of conventional AR systems often limit their use. Here we present a novel AR system that is platform independent and does not require hardware clickers or additional software to be installed. "OnlineTED" was developed at Technische Universität München (TUM) based on Hypertext Preprocessor (PHP) with a My Structured Query Language (MySQL)-database as server- and Javascript as client-side programming languages. "OnlineTED" enables lecturers to create and manage question sets online and start polls in-class via a web-browser. Students can participate in the polls with any internet-enabled device (smartphones, tablet-PCs or laptops). A paper-based survey was conducted with undergraduate medical students and lecturers at TUM to compare "OnlineTED" with conventional AR systems using clickers. "OnlineTED" received above-average evaluation results by both students and lecturers at TUM and was seen on par or superior to conventional AR systems. The survey results indicated that up to 80% of students at TUM own an internet-enabled device (smartphone or tablet-PC) for participation in web-based AR technologies. "OnlineTED" is a novel web-based and platform-independent AR system for higher education that was well received by students and lecturers. As a non-commercial alternative to conventional AR systems it may foster interactive teaching in undergraduate education, in particular with large audiences.

Ralstonia solanacearum novel E3 ubiquitin ligase (NEL) effectors RipAW and RipAR suppress pattern-triggered immunity in plants.

PubMed

Nakano, Masahito; Oda, Kenji; Mukaihara, Takafumi

2017-07-01

Ralstonia solanacearum is the causal agent of bacterial wilt in solanaceous crops. This pathogen injects more than 70 effector proteins into host plant cells via the Hrp type III secretion system to cause a successful infection. However, the function of these effectors in plant cells, especially in the suppression of plant immunity, remains largely unknown. In this study, we characterized two Ralstonia solanacearum effectors, RipAW and RipAR, which share homology with the IpaH family of effectors from animal and plant pathogenic bacteria, that have a novel E3 ubiquitin ligase (NEL) domain. Recombinant RipAW and RipAR show E3 ubiquitin ligase activity in vitro. RipAW and RipAR localized to the cytoplasm of plant cells and significantly suppressed pattern-triggered immunity (PTI) responses such as the production of reactive oxygen species and the expression of defence-related genes when expressed in leaves of Nicotiana benthamiana. Mutation in the conserved cysteine residue in the NEL domain of RipAW completely abolished the E3 ubiquitin ligase activity in vitro and the ability to suppress PTI responses in plant leaves. These results indicate that RipAW suppresses plant PTI responses through the E3 ubiquitin ligase activity. Unlike other members of the IpaH family of effectors, RipAW and RipAR had no leucine-rich repeat motifs in their amino acid sequences. A conserved C-terminal region of RipAW is indispensable for PTI suppression. Transgenic Arabidopsis plants expressing RipAW and RipAR showed increased disease susceptibility, suggesting that RipAW and RipAR contribute to bacterial virulence in plants.

Indole-3-butyric acid promotes adventitious rooting in Arabidopsis thaliana thin cell layers by conversion into indole-3-acetic acid and stimulation of anthranilate synthase activity.

PubMed

Fattorini, L; Veloccia, A; Della Rovere, F; D'Angeli, S; Falasca, G; Altamura, M M

2017-07-11

Indole-3-acetic acid (IAA), and its precursor indole-3-butyric acid (IBA), control adventitious root (AR) formation in planta. Adventitious roots are also crucial for propagation via cuttings. However, IBA role(s) is/are still far to be elucidated. In Arabidopsis thaliana stem cuttings, 10 μM IBA is more AR-inductive than 10 μM IAA, and, in thin cell layers (TCLs), IBA induces ARs when combined with 0.1 μM kinetin (Kin). It is unknown whether arabidopsis TCLs produce ARs under IBA alone (10 μM) or IAA alone (10 μM), and whether they contain endogenous IAA/IBA at culture onset, possibly interfering with the exogenous IBA/IAA input. Moreover, it is unknown whether an IBA-to-IAA conversion is active in TCLs, and positively affects AR formation, possibly through the activity of the nitric oxide (NO) deriving from the conversion process. Revealed undetectable levels of both auxins at culture onset, showing that arabidopsis TCLs were optimal for investigating AR-formation under the total control of exogenous auxins. The AR-response of TCLs from various ecotypes, transgenic lines and knockout mutants was analyzed under different treatments. It was shown that ARs are better induced by IBA than IAA and IBA + Kin. IBA induced IAA-efflux (PIN1) and IAA-influx (AUX1/LAX3) genes, IAA-influx carriers activities, and expression of ANTHRANILATE SYNTHASE -alpha1 (ASA1), a gene involved in IAA-biosynthesis. ASA1 and ANTHRANILATE SYNTHASE -beta1 (ASB1), the other subunit of the same enzyme, positively affected AR-formation in the presence of exogenous IBA, because the AR-response in the TCLs of their mutant wei2wei7 was highly reduced. The AR-response of IBA-treated TCLs from ech2ibr10 mutant, blocked into IBA-to-IAA-conversion, was also strongly reduced. Nitric oxide, an IAA downstream signal and a by-product of IBA-to-IAA conversion, was early detected in IAA- and IBA-treated TCLs, but at higher levels in the latter explants. Altogether, results showed that IBA induced AR-formation by conversion into IAA involving NO activity, and by a positive action on IAA-transport and ASA1/ASB1-mediated IAA-biosynthesis. Results are important for applications aimed to overcome rooting recalcitrance in species of economic value, but mainly for helping to understand IBA involvement in the natural process of adventitious rooting.

Targeting the androgen receptor pathway in castration-resistant prostate cancer: progresses and prospects

PubMed Central

Ferraldeschi, R; Welti, J; Luo, J; Attard, G; de Bono, JS

2015-01-01

Androgen receptor (AR) signaling is a critical pathway for prostate cancer cells, and androgen-deprivation therapy (ADT) remains the principal treatment for patients with locally advanced and metastatic disease. However, over time, most tumors become resistant to ADT. The view of castration-resistant prostate cancer (CRPC) has changed dramatically in the last several years. Progress in understanding the disease biology and mechanisms of castration resistance led to significant advancements and to paradigm shift in the treatment. Accumulating evidence showed that prostate cancers develop adaptive mechanisms for maintaining AR signaling to allow for survival and further evolution. The aim of this review is to summarize molecular mechanisms of castration resistance and provide an update in the development of novel agents and strategies to more effectively target the AR signaling pathway. PMID:24837363

Functional characterization of the beta-adrenergic receptor subtypes expressed by CA1 pyramidal cells in the rat hippocampus.

PubMed

Hillman, Kristin L; Doze, Van A; Porter, James E

2005-08-01

Recent studies have demonstrated that activation of the beta-adrenergic receptor (AR) using the selective beta-AR agonist isoproterenol (ISO) facilitates pyramidal cell long-term potentiation in the cornu ammonis 1 (CA1) region of the rat hippocampus. We have previously analyzed beta-AR genomic expression patterns of 17 CA1 pyramidal cells using single cell reverse transcription-polymerase chain reaction, demonstrating that all samples expressed the beta2-AR transcript, with four of the 17 cells additionally expressing mRNA for the beta1-AR subtype. However, it has not been determined which beta-AR subtypes are functionally expressed in CA1 for these same pyramidal neurons. Using cell-attached recordings, we tested the ability of ISO to increase pyramidal cell action potential (AP) frequency in the presence of subtype-selective beta-AR antagonists. ICI-118,551 [(+/-)-1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl)amino]-2-butanol] and butoxamine [alpha-[1-(t-butylamino)ethyl]-2,5-dimethoxybenzyl alcohol) hydrochloride], agents that selectively block the beta2-AR, produced significant parallel rightward shifts in the concentration-response curves for ISO. From these curves, apparent equilibrium dissociation constant (K(b)) values of 0.3 nM for ICI-118,551 and 355 nM for butoxamine were calculated using Schild regression analysis. Conversely, effective concentrations of the selective beta1-AR antagonists CGP 20712A [(+/-)-2-hydroxy-5-[2-([2-hydroxy-3-(4-[1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl]phenoxy)propyl]amino)ethoxy]-benzamide methanesulfonate] and atenolol [4-[2'-hydroxy-3'-(isopropyl-amino)propoxy]phenylacetamide] did not significantly affect the pyramidal cell response to ISO. However, at higher concentrations, atenolol significantly decreased the potency for ISO-mediated AP frequencies. From these curves, an apparent atenolol K(b) value of 3162 nM was calculated. This pharmacological profile for subtype-selective beta-AR antagonists indicates that beta2-AR activation is mediating the increased AP frequency. Knowledge of functional AR expression in CA1 pyramidal neurons will aid future long-term potentiation studies by allowing selective manipulation of specific beta-AR subtypes.

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.

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

Prevention of adenosine A2A receptor activation diminishes beat-to-beat alternation in human atrial myocytes.

PubMed

Molina, Cristina E; Llach, Anna; Herraiz-Martínez, Adela; Tarifa, Carmen; Barriga, Montserrat; Wiegerinck, Rob F; Fernandes, Jacqueline; Cabello, Nuria; Vallmitjana, Alex; Benitéz, Raúl; Montiel, José; Cinca, Juan; Hove-Madsen, Leif

2016-01-01

Atrial fibrillation (AF) has been associated with increased spontaneous calcium release from the sarcoplasmic reticulum and linked to increased adenosine A2A receptor (A2AR) expression and activation. Here we tested whether this may favor atrial arrhythmogenesis by promoting beat-to-beat alternation and irregularity. Patch-clamp and confocal calcium imaging was used to measure the beat-to-beat response of the calcium current and transient in human atrial myocytes. Responses were classified as uniform, alternating or irregular and stimulation of Gs-protein coupled receptors decreased the frequency where a uniform response could be maintained from 1.0 ± 0.1 to 0.6 ± 0.1 Hz; p < 0.01 for beta-adrenergic receptors and from 1.4 ± 0.1 to 0.5 ± 0.1 Hz; p < 0.05 for A2ARs. The latter was linked to increased spontaneous calcium release and after-depolarizations. Moreover, A2AR activation increased the fraction of non-uniformly responding cells in HL-1 myocyte cultures from 19 ± 3 to 51 ± 9 %; p < 0.02, and electrical mapping in perfused porcine atria revealed that adenosine induced electrical alternans at longer cycle lengths, doubled the fraction of electrodes showing alternation, and increased the amplitude of alternations. Importantly, protein kinase A inhibition increased the highest frequency where uniform responses could be maintained from 0.84 ± 0.12 to 1.86 ± 0.11 Hz; p < 0.001 and prevention of A2AR-activation with exogenous adenosine deaminase selectively increased the threshold from 0.8 ± 0.1 to 1.2 ± 0.1 Hz; p = 0.001 in myocytes from patients with AF. In conclusion, A2AR-activation promotes beat-to-beat irregularities in the calcium transient in human atrial myocytes, and prevention of A2AR activation may be a novel means to maintain uniform beat-to-beat responses at higher beating frequencies in patients with atrial fibrillation.

Beta2-adrenergic receptor genotype affects the renin-angiotensin-aldosterone system response to the Dietary Approaches to Stop Hypertension (DASH) dietary pattern.

PubMed

Sun, Bei; Williams, Jonathan S; Svetkey, Laura P; Kolatkar, Nikheel S; Conlin, Paul R

2010-08-01

Beta(2)-adrenergic receptor (beta2-AR) is a susceptibility locus for hypertension, and polymorphisms at this site relate to salt sensitivity and low plasma renin activity (PRA). The Dietary Approaches to Stop Hypertension (DASH) dietary pattern lowers blood pressure and appears to interact with the renin-angiotensin-aldosterone system (RAAS). We hypothesized that the DASH diet associates with increased RAAS activity, and genotype status at beta2-AR G46A modifies this response. We genotyped participants in the DASH-Sodium study (n = 372) at beta2-AR G46A to determine the association with blood pressure, RAAS components, and consumption of the DASH diet. We used 2-way mixed linear regression and an additive model for all primary analyses. Mean (+/-SEM) PRA was significantly higher in participants in the DASH group than in participants in the control group (0.68 +/- 0.03 compared with 0.54 +/- 0.03 ng x mL(-1) x h(-1), P = 0.002). Serum aldosterone, urinary aldosterone, and urinary potassium concentrations were also significantly higher in the DASH group (P < 0.01 for all). We observed significant gene-diet interactions for changes in systolic blood pressure (SBP) and concentrations of aldosterone and urinary potassium (P for interaction = 0.048, 0.017, and 0.001 for SBP and aldosterone and urinary potassium concentrations, respectively). There was an association between the A allele of beta2-AR G46A and greater blood pressure reduction and blunted aldosterone and PRA responses to the DASH diet. Our results indicate that the DASH diet lowers blood pressure and increases PRA and aldosterone concentrations. There is an association between the G46A polymorphism of beta2-AR and blood pressure and RAAS responses to the DASH diet, which suggests that beta2-AR may be a genetic modifier of DASH-diet responsiveness. This trial was registered at clinicaltrials.gov as NCT00000608.

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

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.

Transcriptional activation of LON Gene by a new form of mitochondrial stress: A role for the nuclear respiratory factor 2 in StAR overload response (SOR).

PubMed

Bahat, Assaf; Perlberg, Shira; Melamed-Book, Naomi; Isaac, Sara; Eden, Amir; Lauria, Ines; Langer, Thomas; Orly, Joseph

2015-06-15

High output of steroid hormone synthesis in steroidogenic cells of the adrenal cortex and the gonads requires the expression of the steroidogenic acute regulatory protein (StAR) that facilitates cholesterol mobilization to the mitochondrial inner membrane where the CYP11A1/P450scc enzyme complex converts the sterol to the first steroid. Earlier studies have shown that StAR is active while pausing on the cytosolic face of the outer mitochondrial membrane while subsequent import of the protein into the matrix terminates the cholesterol mobilization activity. Consequently, during repeated activity cycles, high level of post-active StAR accumulates in the mitochondrial matrix. To prevent functional damage due to such protein overload effect, StAR is degraded by a sequence of three to four ATP-dependent proteases of the mitochondria protein quality control system, including LON and the m-AAA membranous proteases AFG3L2 and SPG7/paraplegin. Furthermore, StAR expression in both peri-ovulatory ovarian cells, or under ectopic expression in cell line models, results in up to 3-fold enrichment of the mitochondrial proteases and their transcripts. We named this novel form of mitochondrial stress as StAR overload response (SOR). To better understand the SOR mechanism at the transcriptional level we analyzed first the unexplored properties of the proximal promoter of the LON gene. Our findings suggest that the human nuclear respiratory factor 2 (NRF-2), also known as GA binding protein (GABP), is responsible for 88% of the proximal promoter activity, including the observed increase of transcription in the presence of StAR. Further studies are expected to reveal if common transcriptional determinants coordinate the SOR induced transcription of all the genes encoding the SOR proteases. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Resident and attending physician attitudes regarding an audience response system.

PubMed

Kung, Justin W; Slanetz, Priscilla J; Chen, Po-Hao; Lee, Karen S; Donohoe, Kevin; Eisenberg, Ronald L

2012-11-01

Audience response system (ARS) technology is increasingly being incorporated into radiology education. The aim of this study was to gauge resident and attending physician attitudes regarding the use of an ARS in resident conferences. An anonymous survey was sent to 38 residents and 57 attending physicians to gauge their attitudes regarding the use of an ARS in resident lectures using a 5-point, Likert-type scale (1 = strongly disagree, 2 = disagree, 3 = neither agree nor disagree, 4 = agree, and 5 = strongly agree). A total of 30 of 38 residents (78.9%) and 26 of 57 attending radiologists (45.6%) responded. Residents viewed the incorporation of an ARS into lectures positively, replying that they learned better from lectures incorporating an ARS (mean, 4.03; 95% confidence interval [CI], 3.74-4.32), felt more comfortable answering questions using it (mean, 4.53; 95% CI, 4.25-4.81), and were more likely to attend a lecture that incorporated its use (mean, 3.70; 95% CI, 3.37-4.03). The use of an ARS by attending physicians was limited (9 of 26 [34.6%]), with respondents citing a lack of adequate training. Those attending physicians who used it viewed the system positively, stating that residents were more engaged when they used an ARS (mean, 4.33; 95% CI, 3.87-4.79). An ARS somewhat helped the faculty members gauge resident understanding of the lecture material (mean, 3.67; 95% CI, 2.95-4.40) and prepare future lectures (mean, 3.33; 95% CI 2.68-3.98). Both residents and attending physicians favorably view audience response technology as a means to enhance education in didactic and case-based settings. Increased training on how to incorporate its use into teaching may drive additional utilization. Copyright © 2012 American College of Radiology. Published by Elsevier Inc. All rights reserved.

MURC/Cavin-4 facilitates recruitment of ERK to caveolae and concentric cardiac hypertrophy induced by α1-adrenergic receptors.

PubMed

Ogata, Takehiro; Naito, Daisuke; Nakanishi, Naohiko; Hayashi, Yukiko K; Taniguchi, Takuya; Miyagawa, Kotaro; Hamaoka, Tetsuro; Maruyama, Naoki; Matoba, Satoaki; Ikeda, Koji; Yamada, Hiroyuki; Oh, Hidemasa; Ueyama, Tomomi

2014-03-11

The actions of catecholamines on adrenergic receptors (ARs) induce sympathetic responses, and sustained activation of the sympathetic nervous system results in disrupted circulatory homeostasis. In cardiomyocytes, α1-ARs localize to flask-shaped membrane microdomains known as "caveolae." Caveolae require both caveolin and cavin proteins for their biogenesis and function. However, the functional roles and molecular interactions of caveolar components in cardiomyocytes are poorly understood. Here, we showed that muscle-restricted coiled-coil protein (MURC)/Cavin-4 regulated α1-AR-induced cardiomyocyte hypertrophy through enhancement of ERK1/2 activation in caveolae. MURC/Cavin-4 was expressed in the caveolae and T tubules of cardiomyocytes. MURC/Cavin-4 overexpression distended the caveolae, whereas MURC/Cavin-4 was not essential for their formation. MURC/Cavin-4 deficiency attenuated cardiac hypertrophy induced by α1-AR stimulation in the presence of caveolae. Interestingly, MURC/Cavin-4 bound to α1A- and α1B-ARs as well as ERK1/2 in caveolae, and spatiotemporally modulated MEK/ERK signaling in response to α1-AR stimulation. Thus, MURC/Cavin-4 facilitates ERK1/2 recruitment to caveolae and efficient α1-AR signaling mediated by caveolae in cardiomyocytes, which provides a unique insight into the molecular mechanisms underlying caveola-mediated signaling in cardiac hypertrophy.

Minireview: The Androgen Receptor in Breast Tissues: Growth Inhibitor, Tumor Suppressor, Oncogene?

PubMed Central

Hickey, T. E.; Robinson, J. L. L.; Carroll, J. S.

2012-01-01

Androgen receptor (AR) signaling exerts an antiestrogenic, growth-inhibitory influence in normal breast tissue, and this role may be sustained in estrogen receptor α (ERα)-positive luminal breast cancers. Conversely, AR signaling may promote growth of a subset of ERα-negative, AR-positive breast cancers with a molecular apocrine phenotype. Understanding the molecular mechanisms whereby androgens can elicit distinct gene expression programs and opposing proliferative responses in these two breast cancer phenotypes is critical to the development of new therapeutic strategies to target the AR in breast cancer. PMID:22745190

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

Correlative Gene Expression to Protective Seroconversion in Rift Valley Fever Vaccinates.

PubMed

Laughlin, Richard C; Drake, Kenneth L; Morrill, John C; Adams, L Garry

2016-01-01

Rift Valley fever Virus (RVFV), a negative-stranded RNA virus, is the etiological agent of the vector-borne zoonotic disease, Rift Valley fever (RVF). In both humans and livestock, protective immunity can be achieved through vaccination. Earlier and more recent vaccine trials in cattle and sheep demonstrated a strong neutralizing antibody and total IgG response induced by the RVF vaccine, authentic recombinant MP-12 (arMP-12). From previous work, protective immunity in sheep and cattle vaccinates normally occurs from 7 to 21 days after inoculation with arMP-12. While the serology and protective response induced by arMP-12 has been studied, little attention has been paid to the underlying molecular and genetic events occurring prior to the serologic immune response. To address this, we isolated RNA from whole blood of vaccinated calves over a time course of 21 days before and after vaccination with arMP-12. The time course RNAs were sequenced by RNASeq and bioinformatically analyzed. Our results revealed time-dependent activation or repression of numerous gene ontologies and pathways related to the vaccine induced immune response and its regulation. Additional bioinformatic analyses identified a correlative relationship between specific host immune response genes and protective immunity prior to the detection of protective serum neutralizing antibody responses. These results contribute an important proof of concept for identifying molecular and genetic components underlying the immune response to RVF vaccination and protection prior to serologic detection.

A Fresh Look at Potential Mechanisms of Change in Applied Relaxation for Generalized Anxiety Disorder: A Case Series

PubMed Central

Hayes-Skelton, Sarah A.; Usmani, Aisha; Lee, Jonathan K.; Roemer, Lizabeth; Orsillo, Susan M.

2013-01-01

Applied Relaxation (AR), which involves noticing early signs of anxiety and responding with a relaxation response, is an empirically supported treatment for Generalized Anxiety Disorder (GAD). However, research on hypothesized mechanisms of AR (e.g., reduced muscle tension) has been mixed, making it likely that additional mechanisms are contributing to the efficacy of AR. Stemming from more recent conceptualizations of GAD, it is hypothesized that mindfulness, decentering, and acceptance may be potential mechanisms of change in AR. Outcome, mechanism data, and case descriptions from three individuals diagnosed with GAD who received 16 weeks of AR as part of a larger randomized controlled trial are presented to demonstrate the ways that AR may lead to clinical improvement through mindfulness, decentering, and acceptance. PMID:23888107

Dating paleo-seismic faulting in the Taiwan Mountain Belt

NASA Astrophysics Data System (ADS)

Lo, C. H.; Wu, C. Y.; Chu, H. T.; Yui, T. F.

2017-12-01

In-situ 40Ar/39Ar laser microprobe dating was carried out on the Hoping pseudotachylite from a mylonite-fault zone in the metamorphosed basement complex of the active Taiwan Mountain Belt to determine the timing of the responsible earthquake(s). The dating results, distributed between 3.2 to 1.6 Ma with errors ranging 0.2 1.1 Ma, were derived from a combination of two Ar isotopic system end-members with inverse isochron ages of 1.55±0.05 and 2.87±0.07 Ma, respectively. Fault melt was found mixed with ultracataclasis in petrographical observations, therefore the older inverse isochron end-member may be attributed to the relic wall rock Ar isotopic system contained in micro-breccia as published 40Ar/39Ar mylonitization ages from 4.1 to 3.0 Ma. Without significant Ar loss expected, the young 1.6 Ma end-member represents the Ar isotopic system and age of the exact pseudotachylite. Seismic faulting therefore occurred during basement rock exhumation in the Taiwanese hinterland.

Effectiveness of an audience response system on orthodontic knowledge retention of undergraduate dental students--a randomised control trial.

PubMed

Robson, Nicholas; Popat, Hashmat; Richmond, Stephen; Farnell, Damian J J

2015-01-01

To determine the effect of an audience response system (ARS) on knowledge retention of dental students and to gauge student perceptions of using the ARS. Randomised control study. School of Dentistry, Cardiff University. Seventy four second-year dental students were stratified by gender and randomised anonymously to one of two groups. One group received a lecture on orthodontic terminology and diagnosis in a traditional didactic format and the other received the same lecture integrated with ARS slides. Students completed an assessment of multiple-choice questions (MCQs) scored out of 20, before and immediately after the lecture. Students were also asked to complete a self-reported questionnaire on their perceptions of ARS. Both groups had statistically significant increases in MCQ scores post-lecture (ARS mean increase 3.6 SD2.0, 95% CI 2.2-3.5 and Didactic mean increase 2.9 SD2.3, 95% CI 2.8-4.3). A mixed-design analysis of variance showed that ARS led to an improved MCQ score (by 0.8 or 25%) compared to the didactic group, although this effect was not significant (P = 0.15). The effect of gender at baseline (P = 0.49), post-lecture (P = 0.73) and increase in MCQ score split by group (P = 0.46) was also not significant. Students reported that the ARS was easy to use, helped them engage with the lecture and encouraged them to work harder. The ARS did not lead to a significant increase in short-term orthodontic knowledge recall of students compared with didactic teaching. However, the use of ARS within orthodontic teaching could make lectures more interactive and engaging.

Parametric modulation of neural activity during face emotion processing in unaffected youth at familial risk for bipolar disorder.

PubMed

Brotman, Melissa A; Deveney, Christen M; Thomas, Laura A; Hinton, Kendra E; Yi, Jennifer Y; Pine, Daniel S; Leibenluft, Ellen

2014-11-01

Both patients with pediatric bipolar disorder (BD) and unaffected youth at familial risk (AR) for the illness show impairments in face emotion labeling. Few studies, however, have examined brain regions engaged in AR youth when processing emotional faces. Moreover, studies have yet to explore neural responsiveness to subtle changes in face emotion in AR youth. Sixty-four unrelated youth, including 20 patients with BD, 15 unaffected AR youth, and 29 healthy comparisons (HC), completed functional magnetic resonance imaging. Neutral faces were morphed with angry or happy faces in 25% intervals. In specific phases of the task, youth alternatively made explicit (hostility) or implicit (nose width) ratings of the faces. The slope of blood oxygenated level-dependent activity was calculated across neutral to angry and neutral to happy face stimuli. Behaviorally, both subjects with BD (p ≤ 0.001) and AR youth (p ≤ 0.05) rated faces as less hostile relative to HC. Consistent with this, in response to increasing anger on the face, patients with BD and AR youth showed decreased modulation in the amygdala and inferior frontal gyrus (IFG; BA 46) compared to HC (all p ≤ 0.05). Amygdala dysfunction was present across both implicit and explicit rating conditions, but IFG modulation deficits were specific to the explicit condition. With increasing happiness, AR youth showed aberrant modulation in the IFG, which was also sensitive to task demands (all p ≤ 0.05). Decreased amygdala and IFG modulation in patients with BD and AR youth may be pathophysiological risk markers for BD, and may underlie the social cognition and face emotion labeling deficits observed in BD and AR youth. Published 2014. This article is a U.S. Government work and is in the public domain in the USA.

Effectiveness of an audience response system on orthodontic knowledge retention of undergraduate dental students – a randomised control trial

PubMed Central

Robson, Nicholas; Popat, Hashmat; Richmond, Stephen; Farnell, Damian J. J.

2015-01-01

Objective:: To determine the effect of an audience response system (ARS) on knowledge retention of dental students and to gauge student perceptions of using the ARS. Design:: Randomised control study. Setting:: School of Dentistry, Cardiff University. Participants:: Seventy four second-year dental students were stratified by gender and randomised anonymously to one of two groups. Methods:: One group received a lecture on orthodontic terminology and diagnosis in a traditional didactic format and the other received the same lecture integrated with ARS slides. Students completed an assessment of multiple-choice questions (MCQs) scored out of 20, before and immediately after the lecture. Students were also asked to complete a self-reported questionnaire on their perceptions of ARS. Results:: Both groups had statistically significant increases in MCQ scores post-lecture (ARS mean increase 3.6 SD2.0, 95% CI 2.2–3.5 and Didactic mean increase 2.9 SD2.3, 95% CI 2.8–4.3). A mixed-design analysis of variance showed that ARS led to an improved MCQ score (by 0.8 or 25%) compared to the didactic group, although this effect was not significant (P = 0.15). The effect of gender at baseline (P = 0.49), post-lecture (P = 0.73) and increase in MCQ score split by group (P = 0.46) was also not significant. Students reported that the ARS was easy to use, helped them engage with the lecture and encouraged them to work harder. Conclusion:: The ARS did not lead to a significant increase in short-term orthodontic knowledge recall of students compared with didactic teaching. However, the use of ARS within orthodontic teaching could make lectures more interactive and engaging. PMID:26282015

Release of "Bella" white bean cultivar

USDA-ARS?s Scientific Manuscript database

"Bella" Reg. No. GP-___, PI ______) is a multiple disease resistant white bean (Phaseolus vulgaris L.) cultivar, adapted to the humid tropics that was developed and released cooperatively by the University of Puerto Rico Agricultural Experiment Station and the USDA-ARS. The breeding objective was to...

Response surface methodological approach for the decolorization of simulated dye effluent using Aspergillus fumigatus fresenius.

PubMed

Sharma, Praveen; Singh, Lakhvinder; Dilbaghi, Neeraj

2009-01-30

The aim of our research was to study, effect of temperature, pH and initial dye concentration on decolorization of diazo dye Acid Red 151 (AR 151) from simulated dye solution using a fungal isolate Aspergillus fumigatus fresenius have been investigated. The central composite design matrix and response surface methodology (RSM) have been applied to design the experiments to evaluate the interactive effects of three most important operating variables: temperature (25-35 degrees C), pH (4.0-7.0), and initial dye concentration (100-200 mg/L) on the biodegradation of AR 151. The total 20 experiments were conducted in the present study towards the construction of a quadratic model. Very high regression coefficient between the variables and the response (R(2)=0.9934) indicated excellent evaluation of experimental data by second-order polynomial regression model. The RSM indicated that initial dye concentration of 150 mg/L, pH 5.5 and a temperature of 30 degrees C were optimal for maximum % decolorization of AR 151 in simulated dye solution, and 84.8% decolorization of AR 151 was observed at optimum growth conditions.

A Pharmacokinetic/Pharmacodynamic Study of the Glucocorticoid Receptor Antagonist Mifepristone Combined with Enzalutamide in Castrate-Resistant Prostate Cancer

DTIC Science & Technology

2017-12-01

findings contained in this report are those of the author(s) and should not be construed as an official Department of the Army position, policy or...trial for patients with metastatic, castration resistant prostate cancer (CRPC). For patients with metastatic CRPC, there are few established...receptor ( AR ) targeted therapies, prostate cancer adapts. One way it adapts is by upregulating another hormone receptor, the glucocorticoid receptor (GR

Use of an Audience Response System during Peer Teaching among Physical Therapy Students in Human Gross Anatomy: Perceptions of Peer Teachers and Students

ERIC Educational Resources Information Center

Wait, Kevin R.; Cloud, Beth A.; Forster, Lindsey A.; Jones, Tiffany M.; Nokleby, Jessica J.; Wolfe, Cortney R.; Youdas, James W.

2009-01-01

An audience response system (ARS) has become popular among educators in medicine and the health professions because of the system's ability to engage listeners during a lecture presentation. No one has described the usefulness of ARS technology during planned nonlecture peer teaching sessions in gross anatomy instruction for health professionals.…

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.

The use of audience response system technology with limited-english-proficiency, low-literacy, and vulnerable populations.

PubMed

Keifer, Matthew C; Reyes, Iris; Liebman, Amy K; Juarez-Carrillo, Patricia

2014-01-01

Audience response systems (ARS) have long been used to improve the interactivity of educational activities. Most studies of ARS have addressed education of literate trainees. How well these devices work with low-literacy subjects is not well studied. Information gathering on the training audience is an important use of ARS and helpful in improving the targeting of training information. However, obtaining demographic information from vulnerable populations with reasons to be concerned about divulging information about themselves has not been tested. In addition, a culturally competent method to effectively collect demographic and evaluation data of this growing population is essential. This project investigated the use of ARS to gather information from Hispanic immigrant workers, many of whom are socially vulnerable and have limited English proficiency (LEP) and low-literacy. Workers attended focus groups and were asked to use ARS devices or clickers to respond to questions. Questions were both categorical (multiple choice) and open-ended numerical (text entry), and varied from simple queries to more sensitive points regarding immigration. Most workers answered the one-key response categorical questions with little difficulty. In contrast, some participants struggled when responding to numerical questions, especially when the response required pressing multiple clicker keys. An overwhelming majority of participants reported that the clickers were comfortable and easy to use despite the challenges presented by the more complex responses. The error rate increased as question complexity increased and the trend across three ordered categories of response complexity reached statistical significance. Results suggest that ARS is a viable method for gathering dichotomous or higher-order categorical information from LEP and low-literacy populations in a group setting while assuring anonymity. However, it is recommended that clickers be developed and tested with fewer, bigger, and more widely separated buttons, and less printing on the buttons for these populations. Further research is needed to determine the effectiveness of using clickers with simplified configurations in the workplace as a tool to collect data for surveys and assessments and to better engage LEP and low-literacy workers in training sessions.

The role of nitric oxide synthase in reduced vasocontractile responsiveness induced by prolonged α1-adrenergic receptor stimulation in rat thoracic aorta

PubMed Central

Gürdal, Hakan; Can, Alp; Uğur, Mehmet

2005-01-01

Prolonged exposure (6–12 h) of rat aorta to alpha1-adrenergic receptor (α1AR) agonist phenylephrine (Phe) leads to a decrease in α1AR-mediated vasoconstriction. This reduced responsiveness to α1AR stimulation was strongly dependent on the intactness of the endothelium. We examined the effect of Phe on nitric oxide synthase (NOS) activity by measuring the conversion of [3H]L-arginine to [3H]L-citrulline in rat aorta or in endothelial cells isolated from rat aorta. Phe stimulation increased NOS activity in control aortas. This response was antagonized by prazosin. However, Phe increased neither the activity of NOS nor intracellular Ca2+ in the isolated endothelial cells from the control aortas, whereas acetylcholine (Ach) was able to stimulate both responses in these cells. This result suggests that Phe stimulates α1AR on vascular smooth muscle cells and has an indirect influence on endothelial cells to increase NOS activity. In Phe-exposed aortic rings, basal NOS activity was found to have increased compared to vehicle-exposed control rings. Stimulation with Phe or Ach caused a small increase over basal NOS activity in these preparations. Prolonged exposure to Phe also caused an enhancement of Ach-mediated vasorelaxation in rat aorta. Immunoblot and reverse transcription–polymerase chain reaction experiments showed that prolonged exposure of rat aorta to Phe resulted in an increased expression of eNOS, but not iNOS. This increase was antagonized by nonselective antagonist prazosin. Immunohistochemical staining experiments also showed that expression of eNOS increased in endothelial cells after Phe exposure of the aortas. These results, all together, showed that prolonged exposure of rat aorta to α1AR agonist Phe enhanced the expression of eNOS and basal NOS activity, which probably causes a decreased vasocontractile response to Phe or to other agonists such as 5HT (5-hydroxytryptamine) in rat aorta. This phenomenon can be considered more as a functional antagonism of vasocontractile response to agonists mediated by endothelium than a specific desensitization of α1AR-mediated signalling in vascular smooth muscle cells. PMID:15753950

Stressed (acute) mice display neuroimmunodysregulation and defective innate immune response against coliform infection.

PubMed

Mehrzad, Jalil; Shajari, Majid; Saleh-Moghaddam, Massoud; Sarmad-Nabavi, Mohammad

2015-09-01

We examined the impact of acute restraint stress (ARS) with(out) intraperitoneal E. coli infection on TLR4 mRNA abundance in brain and spleen, clinical signs, cytokines and oxidative loads and peritoneal E. coli growth in balb/c mice. ARS exacerbated E. coli virulence and behavioral abnormality. At different post-stress hour the pattern and intensity of TLR4 activity differed in brain and spleen. While TLR4 stimulation in spleen of E. coli-infected mice was maximal, it superseded in brain of post-stressed E. coli-infected mice. ARS and E. coli infection elicited systemic pro-inflammatory and pro-oxidant status, with defective peritoneal E. coli clearance in post-ARS mice. Continuous TLR4 activation in post-stressed mice partially disarms innate immune response, and contributes to inappropriate host-E. coli interactions and thus neuroimmune dysregulation/toxicity. The description of these observed novel effects induced by ARS will provide a basis for deeper investigations of the effects from increasingly stress-oriented rural/urban life upon neuroimmune system. Copyright © 2015 Elsevier B.V. All rights reserved.

Increasing AR by HIF-2α inhibitor (PT-2385) overcomes the side-effects of sorafenib by suppressing hepatocellular carcinoma invasion via alteration of pSTAT3, pAKT and pERK signals

PubMed Central

Xu, Junjie; Zheng, Longbo; Chen, Jiang; Sun, Yin; Lin, Hui; Jin, Ren-an; Tang, Minyue; Liang, Xiao; Cai, Xiujun

2017-01-01

Although sorafenib is currently used as a standard treatment for advanced hepatocellular carcinoma, low response rate, transient and limited efficacy, primary and acquired resistance and negative side-effects gain increasing attentions, suggesting the need for better efficacious combination therapy. Here, we demonstrated that the sorafenib-induced or hypoxia-induced hypoxia inducible factor (HIF)-2α could bind to an hypoxia responsive element within 500 bp region of androgen receptor (AR) promoter and thus transcriptionally suppress AR. Importantly, In vitro and In vivo studies suggested a specific and potent HIF-2α inhibitor, PT-2385, could significantly enhance sorafenib efficacy by suppressing HIF-2α, increasing AR and suppressing downstream pSTAT3/pAKT/pERK pathways. Clinical samples further confirmed the role of HIF-2α and AR. It is promising that PT-2385 could alleviate the undesirable side-effects of sorafenib treatment by sorafenib-PT-2385 combination therapy, which may shed light for late-stage HCC patients. PMID:29022906

Increasing AR by HIF-2α inhibitor (PT-2385) overcomes the side-effects of sorafenib by suppressing hepatocellular carcinoma invasion via alteration of pSTAT3, pAKT and pERK signals.

PubMed

Xu, Junjie; Zheng, Longbo; Chen, Jiang; Sun, Yin; Lin, Hui; Jin, Ren-An; Tang, Minyue; Liang, Xiao; Cai, Xiujun

2017-10-12

Although sorafenib is currently used as a standard treatment for advanced hepatocellular carcinoma, low response rate, transient and limited efficacy, primary and acquired resistance and negative side-effects gain increasing attentions, suggesting the need for better efficacious combination therapy. Here, we demonstrated that the sorafenib-induced or hypoxia-induced hypoxia inducible factor (HIF)-2α could bind to an hypoxia responsive element within 500 bp region of androgen receptor (AR) promoter and thus transcriptionally suppress AR. Importantly, In vitro and In vivo studies suggested a specific and potent HIF-2α inhibitor, PT-2385, could significantly enhance sorafenib efficacy by suppressing HIF-2α, increasing AR and suppressing downstream pSTAT3/pAKT/pERK pathways. Clinical samples further confirmed the role of HIF-2α and AR. It is promising that PT-2385 could alleviate the undesirable side-effects of sorafenib treatment by sorafenib-PT-2385 combination therapy, which may shed light for late-stage HCC patients.

Bacillus cereus AR156-Induced Resistance to Colletotrichum acutatum Is Associated with Priming of Defense Responses in Loquat Fruit

PubMed Central

Wang, Xiaoli; Wang, Lei; Wang, Jing; Jin, Peng; Liu, Hongxia; Zheng, Yonghua

2014-01-01

The effectiveness of a biocontrol agent Bacillus cereus AR156 for control of anthracnose rot caused by Colletotrichum acutatum in harvested loquat fruit and the possible mechanisms of its action have been investigated. Treatment of fruit with B. cereus AR156 resulted in lower disease incidence and smaller lesion diameters compared with that of untreated fruit. The treatment enhanced activities of defense-related enzymes including chitinase, β-1, 3-glucanase, phenylalanine ammonia-lyase, peroxidase and polyphenoloxidase, and promoted accumulation of H2O2. Total phenolic content and 2,2-diphenyl-1-picrylhydrazyl radical scavenging activity were also increased by treatment. Transcripts of three defense-related genes were enhanced only in fruit undergoing both B. cereus AR156 treatment and C. acutatum inoculation compared with those receiving either intervention alone. These results suggest that the disease resistance against C. acutatum in loquat fruit is enhanced by B. cereus AR156 and that the induced resistance is associated with induction and priming of defense responses in the fruit. PMID:25386680

Performance Analysis on Carrier Phase-Based Tightly-Coupled GPS/BDS/INS Integration in GNSS Degraded and Denied Environments

PubMed Central

Han, Houzeng; Wang, Jian; Wang, Jinling; Tan, Xinglong

2015-01-01

The integration of Global Navigation Satellite Systems (GNSS) carrier phases with Inertial Navigation System (INS) measurements is essential to provide accurate and continuous position, velocity and attitude information, however it is necessary to fix ambiguities rapidly and reliably to obtain high accuracy navigation solutions. In this paper, we present the notion of combining the Global Positioning System (GPS), the BeiDou Navigation Satellite System (BDS) and low-cost micro-electro-mechanical sensors (MEMS) inertial systems for reliable navigation. An adaptive multipath factor-based tightly-coupled (TC) GPS/BDS/INS integration algorithm is presented and the overall performance of the integrated system is illustrated. A twenty seven states TC GPS/BDS/INS model is adopted with an extended Kalman filter (EKF), which is carried out by directly fusing ambiguity fixed double-difference (DD) carrier phase measurements with the INS predicted pseudoranges to estimate the error states. The INS-aided integer ambiguity resolution (AR) strategy is developed by using a dynamic model, a two-step estimation procedure is applied with adaptively estimated covariance matrix to further improve the AR performance. A field vehicular test was carried out to demonstrate the positioning performance of the combined system. The results show the TC GPS/BDS/INS system significantly improves the single-epoch AR reliability as compared to that of GPS/BDS-only or single satellite navigation system integrated strategy, especially for high cut-off elevations. The AR performance is also significantly improved for the combined system with adaptive covariance matrix in the presence of low elevation multipath related to the GNSS-only case. A total of fifteen simulated outage tests also show that the time to relock of the GPS/BDS signals is shortened, which improves the system availability. The results also indicate that TC integration system achieves a few centimeters accuracy in positioning based on the comparison analysis and covariance analysis, even in harsh environments (e.g., in urban canyons), thus we can see the advantage of positioning at high cut-off elevations that the combined GPS/BDS brings. PMID:25875191

Performance analysis on carrier phase-based tightly-coupled GPS/BDS/INS integration in GNSS degraded and denied environments.

PubMed

Han, Houzeng; Wang, Jian; Wang, Jinling; Tan, Xinglong

2015-04-14

The integration of Global Navigation Satellite Systems (GNSS) carrier phases with Inertial Navigation System (INS) measurements is essential to provide accurate and continuous position, velocity and attitude information, however it is necessary to fix ambiguities rapidly and reliably to obtain high accuracy navigation solutions. In this paper, we present the notion of combining the Global Positioning System (GPS), the BeiDou Navigation Satellite System (BDS) and low-cost micro-electro-mechanical sensors (MEMS) inertial systems for reliable navigation. An adaptive multipath factor-based tightly-coupled (TC) GPS/BDS/INS integration algorithm is presented and the overall performance of the integrated system is illustrated. A twenty seven states TC GPS/BDS/INS model is adopted with an extended Kalman filter (EKF), which is carried out by directly fusing ambiguity fixed double-difference (DD) carrier phase measurements with the INS predicted pseudoranges to estimate the error states. The INS-aided integer ambiguity resolution (AR) strategy is developed by using a dynamic model, a two-step estimation procedure is applied with adaptively estimated covariance matrix to further improve the AR performance. A field vehicular test was carried out to demonstrate the positioning performance of the combined system. The results show the TC GPS/BDS/INS system significantly improves the single-epoch AR reliability as compared to that of GPS/BDS-only or single satellite navigation system integrated strategy, especially for high cut-off elevations. The AR performance is also significantly improved for the combined system with adaptive covariance matrix in the presence of low elevation multipath related to the GNSS-only case. A total of fifteen simulated outage tests also show that the time to relock of the GPS/BDS signals is shortened, which improves the system availability. The results also indicate that TC integration system achieves a few centimeters accuracy in positioning based on the comparison analysis and covariance analysis, even in harsh environments (e.g., in urban canyons), thus we can see the advantage of positioning at high cut-off elevations that the combined GPS/BDS brings.

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.

A Survey of Clinical Features of Allergic Rhinitis in Adults

PubMed Central

Frati, Franco; Dell’Albani, Ilaria; Passalacqua, Giovanni; Bonini, Sergio; Rossi, Oliviero; Senna, Gianenrico; Incorvaia, Cristoforo

2014-01-01

Background Allergic rhinitis (AR) has high prevalence and substantial socio-economic burden. Material/Methods The study included 35 Italian Centers recruiting an overall number of 3383 adult patients with rhinitis (48% males, 52% females, mean age 29.1, range 18–45 years). For each patient, the attending physician had to fill in a standardized questionnaire, covering, in particular, some issues such as the ARIA classification of allergic rhinitis (AR), the results of skin prick test (SPT), the kind of treatment, the response to treatment, and the satisfaction with treatment. Results Out of the 3383 patients with rhinitis, 2788 (82.4%) had AR: 311 (11.5%) had a mild intermittent, 229 (8.8%) a mild persistent, 636 (23.5%) a moderate-severe intermittent, and 1518 (56.1%) a moderate-severe persistent form. The most frequently used drugs were oral antihistamines (77.1%) and topical corticosteroids (60.8%). The response to treatment was judged as excellent in 12.2%, good in 41.3%, fair in 31.2%, poor in 14.5%, and very bad in 0.8% of subjects. The rate of treatment dissatisfaction was significantly higher in patients with moderate-to-severe AR than in patients with mild AR (p<0.0001). Indication to allergen immunotherapy (AIT) was significantly more frequent (p<0.01) in patients with severe AR than with mild AR. Conclusions These findings confirm the appropriateness of ARIA guidelines in classifying the AR patients and the association of severe symptoms with unsuccessful drug treatment. The optimal targeting of patients to be treated with AIT needs to be reassessed. PMID:25366169

A survey of clinical features of allergic rhinitis in adults.

PubMed

Frati, Franco; Dell'Albani, Ilaria; Passalacqua, Giovanni; Bonini, Sergio; Rossi, Oliviero; Senna, Gianenrico; Incorvaia, Cristoforo

2014-11-04

Allergic rhinitis (AR) has high prevalence and substantial socio-economic burden. The study included 35 Italian Centers recruiting an overall number of 3383 adult patients with rhinitis (48% males, 52% females, mean age 29.1, range 18-45 years). For each patient, the attending physician had to fill in a standardized questionnaire, covering, in particular, some issues such as the ARIA classification of allergic rhinitis (AR), the results of skin prick test (SPT), the kind of treatment, the response to treatment, and the satisfaction with treatment. Out of the 3383 patients with rhinitis, 2788 (82.4%) had AR: 311 (11.5%) had a mild intermittent, 229 (8.8%) a mild persistent, 636 (23.5%) a moderate-severe intermittent, and 1518 (56.1%) a moderate-severe persistent form. The most frequently used drugs were oral antihistamines (77.1%) and topical corticosteroids (60.8%). The response to treatment was judged as excellent in 12.2%, good in 41.3%, fair in 31.2%, poor in 14.5%, and very bad in 0.8% of subjects. The rate of treatment dissatisfaction was significantly higher in patients with moderate-to-severe AR than in patients with mild AR (p<0.0001). Indication to allergen immunotherapy (AIT) was significantly more frequent (p<0.01) in patients with severe AR than with mild AR. These findings confirm the appropriateness of ARIA guidelines in classifying the AR patients and the association of severe symptoms with unsuccessful drug treatment. The optimal targeting of patients to be treated with AIT needs to be reassessed.

OnlineTED.com − a novel web-based audience response system for higher education. A pilot study to evaluate user acceptance

PubMed Central

Kühbeck, Felizian; Engelhardt, Stefan; Sarikas, Antonio

2014-01-01

Background and aim: Audience response (AR) systems are increasingly used in undergraduate medical education. However, high costs and complexity of conventional AR systems often limit their use. Here we present a novel AR system that is platform independent and does not require hardware clickers or additional software to be installed. Methods and results: “OnlineTED” was developed at Technische Universität München (TUM) based on Hypertext Preprocessor (PHP) with a My Structured Query Language (MySQL)-database as server- and Javascript as client-side programming languages. “OnlineTED” enables lecturers to create and manage question sets online and start polls in-class via a web-browser. Students can participate in the polls with any internet-enabled device (smartphones, tablet-PCs or laptops). A paper-based survey was conducted with undergraduate medical students and lecturers at TUM to compare "OnlineTED" with conventional AR systems using clickers. "OnlineTED" received above-average evaluation results by both students and lecturers at TUM and was seen on par or superior to conventional AR systems. The survey results indicated that up to 80% of students at TUM own an internet-enabled device (smartphone or tablet-PC) for participation in web-based AR technologies. Summary and Conclusion: “OnlineTED” is a novel web-based and platform-independent AR system for higher education that was well received by students and lecturers. As a non-commercial alternative to conventional AR systems it may foster interactive teaching in undergraduate education, in particular with large audiences. PMID:24575156

Seizure-Onset Mapping Based on Time-Variant Multivariate Functional Connectivity Analysis of High-Dimensional Intracranial EEG: A Kalman Filter Approach.

PubMed

Lie, Octavian V; van Mierlo, Pieter

2017-01-01

The visual interpretation of intracranial EEG (iEEG) is the standard method used in complex epilepsy surgery cases to map the regions of seizure onset targeted for resection. Still, visual iEEG analysis is labor-intensive and biased due to interpreter dependency. Multivariate parametric functional connectivity measures using adaptive autoregressive (AR) modeling of the iEEG signals based on the Kalman filter algorithm have been used successfully to localize the electrographic seizure onsets. Due to their high computational cost, these methods have been applied to a limited number of iEEG time-series (<60). The aim of this study was to test two Kalman filter implementations, a well-known multivariate adaptive AR model (Arnold et al. 1998) and a simplified, computationally efficient derivation of it, for their potential application to connectivity analysis of high-dimensional (up to 192 channels) iEEG data. When used on simulated seizures together with a multivariate connectivity estimator, the partial directed coherence, the two AR models were compared for their ability to reconstitute the designed seizure signal connections from noisy data. Next, focal seizures from iEEG recordings (73-113 channels) in three patients rendered seizure-free after surgery were mapped with the outdegree, a graph-theory index of outward directed connectivity. Simulation results indicated high levels of mapping accuracy for the two models in the presence of low-to-moderate noise cross-correlation. Accordingly, both AR models correctly mapped the real seizure onset to the resection volume. This study supports the possibility of conducting fully data-driven multivariate connectivity estimations on high-dimensional iEEG datasets using the Kalman filter approach.

Study on predictive role of AR and EGFR family genes with response to neoadjuvant chemotherapy in locally advanced breast cancer in Indian women.

PubMed

Singh, L C; Chakraborty, Anurupa; Mishra, Ashwani K; Devi, Thoudam Regina; Sugandhi, Nidhi; Chintamani, Chintamani; Bhatnagar, Dinesh; Kapur, Sujala; Saxena, Sunita

2012-06-01

Locally advanced breast cancer (LABC) remains a clinical challenge as the majority of patients with this diagnosis develop distant metastases despite appropriate therapy. We analyzed expression of steroid and growth hormone receptor genes as well as gene associated with metabolism of chemotherapeutic drugs in locally advanced breast cancer before and after neoadjuvant chemotherapy (NACT) to study whether there is a change in gene expression induced by chemotherapy and whether such changes are associated with tumor response or non-response. Fifty patients were included with locally advanced breast cancer treated with cyclophosphamide, adriamycin, 5-fluorouracil (CAF)-based neoadjuvant chemotherapy before surgery. Total RNA was extracted from 50 match samples of pre- and post-NACT tumor tissues. RNA expression levels of epidermal growth factor receptor family genes including EGFR, ERBB2, ERBB3, androgen receptor (AR), and multidrug-resistance gene 1 (MDR1) were determined by quantitative real-time reverse transcriptase-polymerase chain reaction. Responders show significantly high levels of pre-NACT AR gene expression (P = 0.016), which reduces following NACT (P = 0.008), and hence can serve as a useful tool for the prediction of the success of neoadjuvant chemotherapy in individual cancer patients with locally advanced breast carcinoma. Moreover, a significant post-therapeutic increase in the expression levels of EGFR and MDR1 gene in responders (P = 0.026 and P < 0.001) as well as in non-responders (P = 0.055, P = 0.001) suggests that expression of these genes changes during therapy but they do not have any impact on tumor response, whereas a post-therapeutic reduction was observed in AR in responders. This indicates an independent predictive role of AR with response to NACT.

A brain leptin-renin angiotensin system interaction in the regulation of sympathetic nerve activity.

PubMed

Hilzendeger, Aline M; Morgan, Donald A; Brooks, Leonard; Dellsperger, David; Liu, Xuebo; Grobe, Justin L; Rahmouni, Kamal; Sigmund, Curt D; Mark, Allyn L

2012-07-15

The sympathetic nervous system, leptin, and renin-angiotensin system (RAS) have been implicated in obesity-associated hypertension. There is increasing evidence for the presence of both leptin and angiotensin II receptors in several key brain cardiovascular and metabolic control regions. We tested the hypothesis that the brain RAS plays a facilitatory role in the sympathetic nerve responses to leptin. In rats, intracerebroventricular (ICV) administration of losartan (5 μg) selectively inhibited increases in renal and brown adipose tissue (BAT) sympathetic nerve activity (SNA) produced by leptin (10 μg ICV) but did not reduce the SNA responses to corticotrophin-releasing factor (CRF) or the melanocortin receptor agonist MTII. In mice with deletion of angiotensin II type-1a receptors (AT(1a)R(-/-)), increases in renal and BAT SNA induced by leptin (2 μg ICV) were impaired whereas SNA responses to MTII were preserved. Decreases in food intake and body weight with ICV leptin did not differ in AT(1a)R(-/-) vs. AT(1a)R(+/+) mice. ICV leptin in rats increased AT(1a)R and angiotensin-converting enzyme (ACE) mRNA in the subfornical organ and AT(1a)R mRNA in the arcuate nucleus, suggesting leptin-induced upregulation of the brain RAS in specific brain regions. To evaluate the role of de novo production of brain angiotensin II in SNA responses to leptin, we treated rats with captopril (12.5 μg ICV). Captopril attenuated leptin effects on renal and BAT SNA. In conclusion, these studies provide evidence that the brain RAS selectively facilitates renal and BAT sympathetic nerve responses to leptin while sparing effects on food intake.

Increased Efferent Cardiac Sympathetic Nerve Activity and Defective Intrinsic Heart Rate Regulation in Type 2 Diabetes.

PubMed

Thaung, H P Aye; Baldi, J Chris; Wang, Heng-Yu; Hughes, Gillian; Cook, Rosalind F; Bussey, Carol T; Sheard, Phil W; Bahn, Andrew; Jones, Peter P; Schwenke, Daryl O; Lamberts, Regis R

2015-08-01

Elevated sympathetic nerve activity (SNA) coupled with dysregulated β-adrenoceptor (β-AR) signaling is postulated as a major driving force for cardiac dysfunction in patients with type 2 diabetes; however, cardiac SNA has never been assessed directly in diabetes. Our aim was to measure the sympathetic input to and the β-AR responsiveness of the heart in the type 2 diabetic heart. In vivo recording of SNA of the left efferent cardiac sympathetic branch of the stellate ganglion in Zucker diabetic fatty rats revealed an elevated resting cardiac SNA and doubled firing rate compared with nondiabetic rats. Ex vivo, in isolated denervated hearts, the intrinsic heart rate was markedly reduced. Contractile and relaxation responses to β-AR stimulation with dobutamine were compromised in externally paced diabetic hearts, but not in diabetic hearts allowed to regulate their own heart rate. Protein levels of left ventricular β1-AR and Gs (guanine nucleotide binding protein stimulatory) were reduced, whereas left ventricular and right atrial β2-AR and Gi (guanine nucleotide binding protein inhibitory regulatory) levels were increased. The elevated resting cardiac SNA in type 2 diabetes, combined with the reduced cardiac β-AR responsiveness, suggests that the maintenance of normal cardiovascular function requires elevated cardiac sympathetic input to compensate for changes in the intrinsic properties of the diabetic heart. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

Increased behavioral output but intact goal-directed and habitual responding for food reward following early-life social deprivation in rats.

PubMed

Lomanowska, Anna M; Kraemer, Gary W

2014-09-01

Early-life social adversity, such as child neglect and institutionalized rearing, is associated with later-life difficulties of inhibitory control that may reflect altered attribution of salience to external stimuli. Studies in rats demonstrate that early-life social deprivation results in enhanced responsiveness to reward stimuli and conditioned reward cues. This study examined whether these effects are related to fundamental changes in appetitive conditioning processes involving instrumental goal-directed and habitual responding for food reward. Rats were reared either by the mother (maternal rearing; MR) or in complete isolation from the mother and litter (artificial rearing; AR) and tested as adults in two appetitive conditioning tasks. AR and MR rats did not differ in the amount of goal-directed effort they exerted to obtain food reward on progressive ratio schedules of reinforcement. AR and MR rats also did not differ in the shift from goal-directed to habitual responding on a random interval schedule and they were equally sensitive to changes in reward value. The major difference between AR and MR rats was that AR rats exhibited more non-instrumental responses (empty food magazine entries, ineffective lever presses). Thus, early-life social deprivation of rats through AR affects the expression of unreinforced extraneous behaviors when motivational requirements are high, but does not affect conditioned goal-directed and habitual responding to reward. The findings have implications for understanding what aspects of responsiveness to external stimuli may be selectively affected in disorders of inhibition associated with early-life social adversity. Copyright © 2014 Elsevier B.V. All rights reserved.

Adverse outcome pathway and risks of anticoagulant rodenticides to predatory wildlife

USGS Publications Warehouse

Rattner, Barnett A.; Lazarus, Rebecca S.; Elliott, John E.; Shore, Richard F.; van den Brink, Nico

2014-01-01

Despite a long history of successful use, routine application of some anticoagulant rodenticides (ARs) may be at a crossroad due to new regulatory guidelines intended to mitigate risk. An adverse outcome pathway for ARs was developed to identify information gaps and end points to assess the effectiveness of regulations. This framework describes chemical properties of ARs, established macromolecular interactions by inhibition of vitamin K epoxide reductase, cellular responses including altered clotting factor processing and coagulopathy, organ level effects such as hemorrhage, organism responses with linkages to reduced fitness and mortality, and potential consequences to predator populations. Risk assessments have led to restrictions affecting use of some second-generation ARs (SGARs) in North America. While the European regulatory community highlighted significant or unacceptable risk of ARs to nontarget wildlife, use of SGARs in most EU member states remains authorized due to public health concerns and the absence of safe alternatives. For purposes of conservation and restoration of island habitats, SGARs remain a mainstay for eradication of invasive species. There are significant data gaps related to exposure pathways, comparative species sensitivity, consequences of sublethal effects, potential hazards of greater AR residues in genetically resistant prey, effects of low-level exposure to multiple rodenticides, and quantitative data on the magnitude of nontarget wildlife mortality.

Working alliance inventory applied to virtual and augmented reality (WAI-VAR): psychometrics and therapeutic outcomes

PubMed Central

Miragall, Marta; Baños, Rosa M.; Cebolla, Ausiàs; Botella, Cristina

2015-01-01

This study examines the psychometric properties of the Working Alliance Inventory-Short (WAI-S) adaptation to Virtual Reality (VR) and Augmented Reality (AR) therapies (WAI-VAR). The relationship between the therapeutic alliance (TA) with VR and AR and clinically significant change (CSC) is also explored. Seventy-five patients took part in this study (74.7% women, Mage = 34.41). Fear of flying and adjustment disorder patients received VR therapy, and cockroach phobia patients received AR therapy. Psychometric properties, CSC, one-way ANOVA, Spearman’s Correlations and Multiple Regression were calculated. The WAI-VAR showed a unidimensional structure, high internal consistency and adequate convergent validity. “Not changed” patients scored lower on the WAI-VAR than “improved” and “recovered” patients. Correlation between the WAI-VAR and CSC was moderate. The best fitting model for predicting CSC was a linear combination of the TA with therapist (WAI-S) and the TA with VR and AR (WAI-VAR), due to the latter variable slightly increased the percentage of variability accounted for in CSC. The WAI-VAR is the first validated instrument to measure the TA with VR and AR in research and clinical practice. This study reveals the importance of the quality of the TA with technologies in achieving positive outcomes in the therapy. PMID:26500589

Working alliance inventory applied to virtual and augmented reality (WAI-VAR): psychometrics and therapeutic outcomes.

PubMed

Miragall, Marta; Baños, Rosa M; Cebolla, Ausiàs; Botella, Cristina

2015-01-01

This study examines the psychometric properties of the Working Alliance Inventory-Short (WAI-S) adaptation to Virtual Reality (VR) and Augmented Reality (AR) therapies (WAI-VAR). The relationship between the therapeutic alliance (TA) with VR and AR and clinically significant change (CSC) is also explored. Seventy-five patients took part in this study (74.7% women, M age = 34.41). Fear of flying and adjustment disorder patients received VR therapy, and cockroach phobia patients received AR therapy. Psychometric properties, CSC, one-way ANOVA, Spearman's Correlations and Multiple Regression were calculated. The WAI-VAR showed a unidimensional structure, high internal consistency and adequate convergent validity. "Not changed" patients scored lower on the WAI-VAR than "improved" and "recovered" patients. Correlation between the WAI-VAR and CSC was moderate. The best fitting model for predicting CSC was a linear combination of the TA with therapist (WAI-S) and the TA with VR and AR (WAI-VAR), due to the latter variable slightly increased the percentage of variability accounted for in CSC. The WAI-VAR is the first validated instrument to measure the TA with VR and AR in research and clinical practice. This study reveals the importance of the quality of the TA with technologies in achieving positive outcomes in the therapy.

Hyper Accumulation of Arsenic in Mutants of Ochrobactrum tritici Silenced for Arsenite Efflux Pumps

PubMed Central

Piedade, Ana Paula; Morais, Paula V.

2015-01-01

Ochrobactrum tritici SCII24T is a highly As-resistant bacterium, with two previously described arsenic resistance operons, ars1 and ars2. Among a large number of genes, these operons contain the arsB and Acr3 genes that encode the arsenite efflux pumps responsible for arsenic resistance. Exploring the genome of O. tritici SCII24T, an additional putative operon (ars3) was identified and revealed the presence of the Acr3_2 gene that encodes for an arsenite efflux protein but which came to prove to not be required for full As resistance. The genes encoding for arsenite efflux pumps, identified in this strain, were inactivated to develop microbial accumulators of arsenic as new tools for bioremediation. Six different mutants were produced, studied and three were more useful as biotools. O. tritici wild type and the Acr3-mutants showed the highest resistance to As(III), being able to grow up to 50 mM of arsenite. On the other hand, arsB-mutants were not able to grow at concentrations higher than 1 mM As(III), and were the most As(III) sensitive mutants. In the presence of 1 mM As(III), the strain with arsB and Acr3_1 mutated showed the highest intracellular arsenic concentration (up to 17 ng(As)/mg protein), while in assays with 5 mM As(III), the single arsB-mutant was able to accumulate the highest concentration of arsenic (up to 10 ng(As)/mg protein). Therefore, arsB is the main gene responsible for arsenite resistance in O. tritici. However, both genes arsB and Acr3_1 play a crucial role in the resistance mechanism, depending on the arsenite concentration in the medium. In conclusion, at moderate arsenite concentrations, the double arsB- and Acr3_1-mutant exhibited a great ability to accumulate arsenite and can be seen as a promising bioremediation tool for environmental arsenic detoxification. PMID:26132104

AR-V7 in circulating tumor cells cluster as a predictive biomarker of abiraterone acetate and enzalutamide treatment in castration-resistant prostate cancer patients.

PubMed

Okegawa, Takatsugu; Ninomiya, Naoki; Masuda, Kazuki; Nakamura, Yu; Tambo, Mitsuhiro; Nutahara, Kikuo

2018-06-01

We examined whether androgen receptor splice variant 7 (AR-V7) in circulating tumor cell(CTC)clusters can be used to predict survival in patients with bone metastatic castration resistant-prostate cancer (mCRPC) treated with abiraterone or enzalutamide. We retrospectively enrolled 98 patients with CRPC on abiraterone or enzalutamide, and investigated the prognostic value of CTC cluster detection (+ v -) and AR-V7 detection (+ v -) using a CTC cluster detection - based AR-V7 mRNA assay. We examined ≤50% prostate-specific antigen (PSA) responses, PSA progression-free survival (PSA-PFS), clinical and radiological progression-free survival (radiologic PSF), and overall survival (OS). We then assessed whether AR-V7 expression in CTC clusters identified after On-chip multi-imaging flow cytometry was related to disease progression and survival after first-line systemic therapy. All abiraterone-treated or enzalutamide-treated patients received prior docetaxel. The median follow-up was 20.7 (range: 3.0-37.0) months in the abiraterone and enzalutamide cohorts, respectively. Forty-nine of the 98 men (50.0%) were CTC cluster (-), 23 of the 98 men (23.5%) were CTC cluster(+)/AR-V7(-), and 26 of the 98 men (26.5%) were CTC cluster(+)/AR-V7(+). CTC cluster(+)/AR-V7(+) patients were more likely to have EOD ≥3 at diagnosis (P = 0.003), pain (P = 0.023), higher alkaline phosphatase levels (P < 0.001), and visceral metastases (P < 0.001). On multivariable analysis, pretherapy CTC cluster(+), CTC cluster(+)/AR-V7(-), and ALP >UNL were independently associated with a poor PSA-PFS, radiographic PFS, and OS in abiraterone-treated patients and enzalutamide-treated patients. The CTC clusters and AR-V7-positive CTC clusters detected were important for assessing the response to abiraterone or enzalutamide therapy and for predicting disease outcome. © 2018 Wiley Periodicals, Inc.

Predicting the Pathogenicity of Aminoacyl-tRNA Synthetase Mutations

PubMed Central

Oprescu, Stephanie N.; Griffin, Laurie B.; Beg, Asim A.; Antonellis, Anthony

2016-01-01

Aminoacyl-tRNA synthetases (ARSs) are ubiquitously expressed, essential enzymes responsible for charging tRNA with cognate amino acids—the first step in protein synthesis. ARSs are required for protein translation in the cytoplasm and mitochondria of all cells. Surprisingly, mutations in 28 of the 37 nuclear-encoded human ARS genes have been linked to a variety of recessive and dominant tissue-specific disorders. Current data sustains that impaired enzyme function is a robust predictor of the pathogenicity of ARS mutations. However, experimental model systems that distinguish between pathogenic and non-pathogenic ARS variants are required for implicating newly identified ARS mutations in disease. Here, we outline strategies to assist in predicting the pathogenicity of ARS variants and urge cautious evaluation of genetic and functional data prior to linking an ARS mutation to a human disease phenotype. PMID:27876679

Brain responses to facial attractiveness induced by facial proportions: evidence from an fMRI study

PubMed Central

Shen, Hui; Chau, Desmond K. P.; Su, Jianpo; Zeng, Ling-Li; Jiang, Weixiong; He, Jufang; Fan, Jintu; Hu, Dewen

2016-01-01

Brain responses to facial attractiveness induced by facial proportions are investigated by using functional magnetic resonance imaging (fMRI), in 41 young adults (22 males and 19 females). The subjects underwent fMRI while they were presented with computer-generated, yet realistic face images, which had varying facial proportions, but the same neutral facial expression, baldhead and skin tone, as stimuli. Statistical parametric mapping with parametric modulation was used to explore the brain regions with the response modulated by facial attractiveness ratings (ARs). The results showed significant linear effects of the ARs in the caudate nucleus and the orbitofrontal cortex for all of the subjects, and a non-linear response profile in the right amygdala for only the male subjects. Furthermore, canonical correlation analysis was used to learn the most relevant facial ratios that were best correlated with facial attractiveness. A regression model on the fMRI-derived facial ratio components demonstrated a strong linear relationship between the visually assessed mean ARs and the predictive ARs. Overall, this study provided, for the first time, direct neurophysiologic evidence of the effects of facial ratios on facial attractiveness and suggested that there are notable gender differences in perceiving facial attractiveness as induced by facial proportions. PMID:27779211

Brain responses to facial attractiveness induced by facial proportions: evidence from an fMRI study.

PubMed

Shen, Hui; Chau, Desmond K P; Su, Jianpo; Zeng, Ling-Li; Jiang, Weixiong; He, Jufang; Fan, Jintu; Hu, Dewen

2016-10-25

Brain responses to facial attractiveness induced by facial proportions are investigated by using functional magnetic resonance imaging (fMRI), in 41 young adults (22 males and 19 females). The subjects underwent fMRI while they were presented with computer-generated, yet realistic face images, which had varying facial proportions, but the same neutral facial expression, baldhead and skin tone, as stimuli. Statistical parametric mapping with parametric modulation was used to explore the brain regions with the response modulated by facial attractiveness ratings (ARs). The results showed significant linear effects of the ARs in the caudate nucleus and the orbitofrontal cortex for all of the subjects, and a non-linear response profile in the right amygdala for only the male subjects. Furthermore, canonical correlation analysis was used to learn the most relevant facial ratios that were best correlated with facial attractiveness. A regression model on the fMRI-derived facial ratio components demonstrated a strong linear relationship between the visually assessed mean ARs and the predictive ARs. Overall, this study provided, for the first time, direct neurophysiologic evidence of the effects of facial ratios on facial attractiveness and suggested that there are notable gender differences in perceiving facial attractiveness as induced by facial proportions.

Everyone's answering: using technology to increase classroom participation.

PubMed

Filer, Debra

2010-01-01

A study was designed to assess the impact of a wireless technology known as an audience response system (ARS), commonly known clickers, on learning and student engagement in a nursing classroom. Students in the control group responded verbally to questions posed during lectures, while students in the intervention groups responded anonymously using the ARS. Although no significant improvement in postlecture quizzes was noted, students in ARS-enhanced lectures reported significantly higher satisfaction scores. The use of ARS promoted a sense of comfort, encouraged participation, and motivated students to answer questions and interact with the subject matter.

Cannabinoid receptor activation correlates with the proapoptotic action of the β2-adrenergic agonist (R,R')-4-methoxy-1-naphthylfenoterol in HepG2 hepatocarcinoma cells.

PubMed

Paul, Rajib K; Ramamoorthy, Anuradha; Scheers, Jade; Wersto, Robert P; Toll, Lawrence; Jimenez, Lucita; Bernier, Michel; Wainer, Irving W

2012-10-01

Inhibition of cell proliferation by fenoterol and fenoterol derivatives in 1321N1 astrocytoma cells is consistent with β(2)-adrenergic receptor (β(2)-AR) stimulation. However, the events that result in fenoterol-mediated control of cell proliferation in other cell types are not clear. Here, we compare the effect of the β(2)-AR agonists (R,R')-fenoterol (Fen) and (R,R')-4-methoxy-1-naphthylfenoterol (MNF) on signaling and cell proliferation in HepG2 hepatocarcinoma cells by using Western blotting and [(3)H]thymidine incorporation assays. Despite the expression of β(2)-AR, no cAMP accumulation was observed when cells were stimulated with isoproterenol or Fen, although the treatment elicited both mitogen-activated protein kinase and phosphatidylinositol 3-kinase/Akt activation. Unexpectedly, isoproterenol and Fen promoted HepG2 cell growth, but MNF reduced proliferation together with increased apoptosis. The mitogenic responses of Fen were attenuated by 3-(isopropylamino)-1-[(7-methyl-4-indanyl)oxy]butan-2-ol (ICI 118,551), a β(2)-AR antagonist, whereas those of MNF were unaffected. Because of the coexpression of β(2)-AR and cannabinoid receptors (CBRs) and their impact on HepG2 cell proliferation, these Gα(i)/Gα(o)-linked receptors may be implicated in MNF signaling. Cell treatment with (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-napthalenylmethanone (WIN 55,212-2), a synthetic agonist of CB(1)R and CB(2)R, led to growth inhibition, whereas inverse agonists of these receptors blocked MNF mitogenic responses without affecting Fen signaling. MNF responses were sensitive to pertussis toxin. The β(2)-AR-deficient U87MG cells were refractory to Fen, but responsive to the antiproliferative actions of MNF and WIN 55,212-2. The data indicate that the presence of the naphthyl moiety in MNF results in functional coupling to the CBR pathway, providing one of the first examples of a dually acting β(2)-AR-CBR ligand.

Cannabinoid Receptor Activation Correlates with the Proapoptotic Action of the β2-Adrenergic Agonist (R,R′)-4-Methoxy-1-Naphthylfenoterol in HepG2 Hepatocarcinoma CellsS⃞

PubMed Central

Paul, Rajib K.; Ramamoorthy, Anuradha; Scheers, Jade; Wersto, Robert P.; Toll, Lawrence; Jimenez, Lucita; Wainer, Irving W.

2012-01-01

Inhibition of cell proliferation by fenoterol and fenoterol derivatives in 1321N1 astrocytoma cells is consistent with β2-adrenergic receptor (β2-AR) stimulation. However, the events that result in fenoterol-mediated control of cell proliferation in other cell types are not clear. Here, we compare the effect of the β2-AR agonists (R,R′)-fenoterol (Fen) and (R,R′)-4-methoxy-1-naphthylfenoterol (MNF) on signaling and cell proliferation in HepG2 hepatocarcinoma cells by using Western blotting and [3H]thymidine incorporation assays. Despite the expression of β2-AR, no cAMP accumulation was observed when cells were stimulated with isoproterenol or Fen, although the treatment elicited both mitogen-activated protein kinase and phosphatidylinositol 3-kinase/Akt activation. Unexpectedly, isoproterenol and Fen promoted HepG2 cell growth, but MNF reduced proliferation together with increased apoptosis. The mitogenic responses of Fen were attenuated by 3-(isopropylamino)-1-[(7-methyl-4-indanyl)oxy]butan-2-ol (ICI 118,551), a β2-AR antagonist, whereas those of MNF were unaffected. Because of the coexpression of β2-AR and cannabinoid receptors (CBRs) and their impact on HepG2 cell proliferation, these Gαi/Gαo-linked receptors may be implicated in MNF signaling. Cell treatment with (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-napthalenylmethanone (WIN 55,212-2), a synthetic agonist of CB1R and CB2R, led to growth inhibition, whereas inverse agonists of these receptors blocked MNF mitogenic responses without affecting Fen signaling. MNF responses were sensitive to pertussis toxin. The β2-AR-deficient U87MG cells were refractory to Fen, but responsive to the antiproliferative actions of MNF and WIN 55,212-2. The data indicate that the presence of the naphthyl moiety in MNF results in functional coupling to the CBR pathway, providing one of the first examples of a dually acting β2-AR-CBR ligand. PMID:22776956

Association Between Response to Acid-Suppression Therapy and Efficacy of Antireflux Surgery in Patients With Extraesophageal Reflux.

PubMed

Krill, Joseph T; Naik, Rishi D; Higginbotham, Tina; Slaughter, James C; Holzman, Michael D; Francis, David O; Garrett, C Gaelyn; Vaezi, Michael F

2017-05-01

The effectiveness of antireflux surgery (ARS) varies among patients with extraesophageal manifestations of gastroesophageal reflux disease (GERD). By studying a cohort of patients with primary extraesophageal symptoms and abnormal physiologic markers for GERD, we aimed to identify factors associated with positive outcomes from surgery, and compare outcomes to those with typical esophageal manifestations of GERD. We performed a retrospective cohort study to compare adult patients with extraesophageal and typical reflux symptoms who underwent de novo ARS from 2004 through 2012 at a tertiary care center. All 115 patients (79 with typical GERD and 36 with extraesophageal manifestations of GERD) had evidence of abnormal distal esophageal acid exposure based on pH testing or endoscopy. The principle outcome was time to primary symptom recurrence after surgery, based on patient reports of partial or total recurrence of symptoms at follow-up visits. Patients were followed up for a median duration of 66 months (interquartile range, 52-77 mo). The median time to recurrence of symptoms in the overall cohort was 68 months (11.5 months in the extraesophageal cohort vs >132 months in the typical cohort). Symptom recurrence after ARS was associated with having primarily extraesophageal symptoms (adjusted hazard ratio, 2.34; 95% confidence interval, 1.31-4.17) and poor preoperative symptom response to acid-suppression therapy (AST) (hazard ratio, 3.85; 95% confidence interval, 2.05-7.22). Patients with primary extraesophageal symptoms who had a full or partial preoperative AST response experienced lower rates of symptom recurrence compared to patients with poor AST response (P < .01). The rate of symptom recurrence was lowest among patients with primary typical reflux symptoms who had a partial or full symptom response to AST (P < .01). The severity of acid reflux on pH testing, symptom indices, severity of esophagitis, and hiatal hernia size were not associated with symptom response. In a retrospective study, we found the effectiveness of ARS to be less predictable in patients with extraesophageal symptoms of GERD than in patients with typical GERD. Response to AST before surgery was associated with ARS effectiveness in patients with extraesophageal reflux symptoms. Caution should be exercised when advocating ARS for patients with extraesophageal symptoms that do not respond to AST. Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.

A beta1-adrenergic receptor CaM kinase II-dependent pathway mediates cardiac myocyte fetal gene induction.

PubMed

Sucharov, Carmen C; Mariner, Peter D; Nunley, Karin R; Long, Carlin; Leinwand, Leslie; Bristow, Michael R

2006-09-01

Beta-adrenergic signaling plays an important role in the natural history of dilated cardiomyopathies. Chronic activation of beta-adrenergic receptors (beta1-AR and beta2-AR) during periods of cardiac stress ultimately harms the failing heart by mechanisms that include alterations in gene expression. Here, we show that stimulation of beta-ARs with isoproterenol in neonate rat ventricular myocytes causes a "fetal" response in the relative activities of the human cardiac fetal and/or adult gene promoters that includes repression of the human and rat alpha-myosin heavy chain (alpha-MyHC) promoters with simultaneous activation of the human atrial natriuretic peptide (ANP) and rat beta-MyHC promoters. We also show that the promoter changes correlate with changes in endogenous gene expression as measured by mRNA expression. Furthermore, we show that these changes are specifically mediated by the beta1-AR, but not the beta2-AR, and are independent of alpha1-AR stimulation. We also demonstrate that the fetal gene response is independent of cAMP and protein kinase A, whereas inhibition of Ca2+/calmodulin-dependent protein kinase (CaMK) pathway blocks isoproterenol-mediated fetal gene program induction. Finally, we show that induction of the fetal program is dependent on activation of the L-type Ca2+ channel. We conclude that in neonatal rat cardiac myocytes, agonist-occupied beta1-AR mobilizes Ca2+ stores to activate fetal gene induction through cAMP independent pathways that involve CaMK.

Progenitor cells are mobilized by acute psychological stress but not beta-adrenergic receptor agonist infusion

PubMed Central

Riddell, Natalie E.; Burns, Victoria E.; Wallace, Graham R.; Edwards, Kate M.; Drayson, Mark; Redwine, Laura S.; Hong, Suzi; Bui, Jack D.; Fischer, Johannes C.; Mills, Paul J.; Bosch, Jos A.

2015-01-01

Objectives Stimuli that activate the sympathetic nervous system, such as acute psychological stress, rapidly invoke a robust mobilization of lymphocytes into the circulation. Experimental animal studies suggest that bone marrow-derived progenitor cells (PCs) also mobilize in response to sympathetic stimulation. Here we tested the effects of acute psychological stress and brief pharmacological β-adrenergic (βAR) stimulation on peripheral PC numbers in humans. Methods In two studies, we investigated PC mobilization in response to an acute speech task (n=26) and βAR-agonist (isoproterenol) infusion (n=20). A subset of 8 participants also underwent the infusion protocol with concomitant administration of the βAR-antagonist propranolol. Flow cytometry was used to enumerate lymphocyte subsets, total progenitor cells, total haematopoietic stem cells (HSC), early HSC (multi-lineage potential), late HSC (lineage committed), and endothelial PCs (EPCs). Results Both psychological stress and βAR-agonist infusion caused the expected mobilization of total monocytes and lymphocytes and CD8+ T lymphocytes. Psychological stress also induced a modest, but significant, increase in total PCs, HSCs, and EPC numbers in peripheral blood. However, infusion of a βAR-agonist did not result in a significant change in circulating PCs. Conclusion PCs are rapidly mobilized by psychological stress via mechanisms independent of βAR-stimulation, although the findings do not exclude βAR-stimulation as a possible cofactor. Considering the clinical and physiological relevance, further research into the mechanisms involved in stress-induced PC mobilization seems warranted. PMID:25747743

Progenitor cells are mobilized by acute psychological stress but not beta-adrenergic receptor agonist infusion.

PubMed

Riddell, Natalie E; Burns, Victoria E; Wallace, Graham R; Edwards, Kate M; Drayson, Mark; Redwine, Laura S; Hong, Suzi; Bui, Jack C; Fischer, Johannes C; Mills, Paul J; Bosch, Jos A

2015-10-01

Stimuli that activate the sympathetic nervous system, such as acute psychological stress, rapidly invoke a robust mobilization of lymphocytes into the circulation. Experimental animal studies suggest that bone marrow-derived progenitor cells (PCs) also mobilize in response to sympathetic stimulation. Here we tested the effects of acute psychological stress and brief pharmacological β-adrenergic (βAR) stimulation on peripheral PC numbers in humans. In two studies, we investigated PC mobilization in response to an acute speech task (n=26) and βAR-agonist (isoproterenol) infusion (n=20). A subset of 8 participants also underwent the infusion protocol with concomitant administration of the βAR-antagonist propranolol. Flow cytometry was used to enumerate lymphocyte subsets, total progenitor cells, total haematopoietic stem cells (HSC), early HSC (multi-lineage potential), late HSC (lineage committed), and endothelial PCs (EPCs). Both psychological stress and βAR-agonist infusion caused the expected mobilization of total monocytes and lymphocytes and CD8(+) T lymphocytes. Psychological stress also induced a modest, but significant, increase in total PCs, HSCs, and EPC numbers in peripheral blood. However, infusion of a βAR-agonist did not result in a significant change in circulating PCs. PCs are rapidly mobilized by psychological stress via mechanisms independent of βAR-stimulation, although the findings do not exclude βAR-stimulation as a possible cofactor. Considering the clinical and physiological relevance, further research into the mechanisms involved in stress-induced PC mobilization seems warranted. Copyright © 2015 Elsevier Inc. All rights reserved.

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

PTTG1, A novel androgen responsive gene is required for androgen-induced prostate cancer cell growth and invasion

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

Zhang, Zheng; Jin, Bo; Jin, Yaqiong

Androgens (AR) play an important role in initiation and progression of prostate cancer. It has been shown that AR exert their effects mainly through the androgen-activated AR which binds to androgen response elements (AREs) in the regulatory regions of target genes to regulate the transcription of androgen-responsive genes, thus, identification of AR downstream target gene is critical to understand androgen function in prostate cancer. In this study, our results showed that androgen treatment of LNCaP cells induced PTTG1 expression, which was blocked by the androgen receptor antagonist, Casodex. Bioinformatics analysis and experiments using PTTG1 promoter deletion mutants showed that themore » PTTG1 promoter contains a putative androgen response element (ARE), which localizes in the −851 to −836 region of the promoter. Androgen activated androgen receptor (AR) binding to this ARE was confirmed by Chromatin immunoprecipitation (ChIP) assay. Furthermore, Knockdown of PTTG1 expression using short hairpin RNA significantly reduced androgen-induced LNCaP cell growth and invasion. In addition, we showed PTTG1 is highly expressed in metastasis prostate cancer tissue. These results suggest that PTTG1 is a novel downstream target gene of androgen receptor and take part in prostate cancer proliferation and metastasis. - Highlights: • Androgen treatment of LNCaP cells induced PTTG1 expression. • Knockdown of PTTG1 expression significantly reduced androgen-induced LNCaP cell growth and invasion. • PTTG1 is highly expressed in metastasis prostate cancer tissue. • PTTG1 is a novel downstream target gene of androgen receptor.« less

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.

Adaptive cover crop implementation and evaluation in the Chesapeake Bay watersheds

USDA-ARS?s Scientific Manuscript database

Four years of applied research, led by the USDA-ARS Choptank River Conservation Reserve Assessment Project (CEAP), have demonstrated that satellite remote sensing, used in combination with cost-share program farm implementation records, can provide a powerful tool for evaluating the nutrient conserv...

Seed storage effects on germination for two forage kochia cultivars

USDA-ARS?s Scientific Manuscript database

The cultivar ‘Snowstorm’ forage kochia was released by the USDA-ARS in 2012. It is a synthetic cultivar selected for stature, forage production, and adaptation to semiarid environments. Similar to the earlier released (1984) ‘Immigrant’ cultivar it can increase rangeland productivity magnitudes when...

Herbivore exploits chink in armor of host

USDA-ARS?s Scientific Manuscript database

Mites in the genus Raoiella Hirst are obligate plant parasites that feed via stylet-like mouthparts adapted to pierce plant tissues. A species of particular interest in this genus, the red palm mite, R. indica Hirst, is currently spreading aggressively throughout the Americas on species of palm (Ar...

Overcoming mutation-based resistance to antiandrogens with rational drug design

PubMed Central

Balbas, Minna D; Evans, Michael J; Hosfield, David J; Wongvipat, John; Arora, Vivek K; Watson, Philip A; Chen, Yu; Greene, Geoffrey L; Shen, Yang; Sawyers, Charles L

2013-01-01

The second-generation antiandrogen enzalutamide was recently approved for patients with castration-resistant prostate cancer. Despite its success, the duration of response is often limited. For previous antiandrogens, one mechanism of resistance is mutation of the androgen receptor (AR). To prospectively identify AR mutations that might confer resistance to enzalutamide, we performed a reporter-based mutagenesis screen and identified a novel mutation, F876L, which converted enzalutamide into an AR agonist. Ectopic expression of AR F876L rescued the growth inhibition of enzalutamide treatment. Molecular dynamics simulations performed on antiandrogen–AR complexes suggested a mechanism by which the F876L substitution alleviates antagonism through repositioning of the coactivator recruiting helix 12. This model then provided the rationale for a focused chemical screen which, based on existing antiandrogen scaffolds, identified three novel compounds that effectively antagonized AR F876L (and AR WT) to suppress the growth of prostate cancer cells resistant to enzalutamide. DOI: http://dx.doi.org/10.7554/eLife.00499.001 PMID:23580326

β-TrCP1 Is a Vacillatory Regulator of Wnt Signaling.

PubMed

Long, Marcus John; Lin, Hong-Yu; Parvez, Saba; Zhao, Yi; Poganik, Jesse Richard; Huang, Paul; Aye, Yimon

2017-08-17

Simultaneous hyperactivation of Wnt and antioxidant response (AR) are often observed during oncogenesis. However, it remains unclear how the β-catenin-driven Wnt and the Nrf2-driven AR mutually regulate each other. The situation is compounded because many players in these two pathways are redox sensors, rendering bolus redox signal-dosing methods uninformative. Herein we examine the ramifications of single-protein target-specific AR upregulation in various knockdown lines. Our data document that Nrf2/AR strongly inhibits β-catenin/Wnt. The magnitude and mechanism of this negative regulation are dependent on the direct interaction between β-catenin N terminus and β-TrCP1 (an antagonist of both Nrf2 and β-catenin), and independent of binding between Nrf2 and β-TrCP1. Intriguingly, β-catenin positively regulates AR. Because AR is a negative regulator of Wnt regardless of β-catenin N terminus, this switch of function is likely sufficient to establish a new Wnt/AR equilibrium during tumorigenesis. Copyright © 2017 Elsevier Ltd. All rights reserved.

Effects of upright and supine position on cardiac rest and exercise response in aortic regurgitation.

PubMed

Shen, W F; Roubin, G S; Fletcher, P J; Choong, C Y; Hutton, B F; Harris, P J; Kelly, D T

1985-02-01

The effects of upright and supine position on cardiac response to exercise were assessed by radionuclide ventriculography in 15 patients with moderate to severe aortic regurgitation (AR) and in 10 control subjects. In patients with AR, heart rate was higher during upright exercise, but systolic and diastolic blood pressure and left ventricular (LV) output were similar during both forms of exercise. LV stroke volume and end-diastolic volume were not altered during supine exercise. LV end-systolic volume increased and ejection fraction decreased during supine exercise, but both were unchanged during upright exercise. Of 15 patients, 5 in the upright and 12 in the supine position had an abnormal LV ejection fraction response to exercise (p less than 0.01). Right ventricular ejection fraction increased and regurgitant index decreased with both forms of exercise and was not significantly different between the 2 positions. Thus, posture is important in determining LV response to exercise in patients with moderate to severe AR.

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.

Impact of aspirin resistance on outcomes among patients following coronary artery bypass grafting: exploratory analysis from randomized controlled trial (NCT01159639).

PubMed

Petricevic, Mate; Kopjar, Tomislav; Gasparovic, Hrvoje; Milicic, Davor; Svetina, Lucija; Zdilar, Boris; Boban, Marko; Mihaljevic, Martina Zrno; Biocina, Bojan

2015-05-01

Individual variability in the response to aspirin, has been established by various platelet function assays, however, the clinical relevance of aspirin resistance (AR) in patients undergoing coronary artery bypass grafting (CABG) has to be evaluated. Our working group conducted a randomized controlled trial (NCT01159639) with the aim to assess impact of dual antiplatelet therapy (APT) on outcomes among patients with AR following CABG. Patients that were aspirin resistant on fourth postoperative day (POD 4) were randomly assigned to receive either dual APT with clopidogrel (75 mg) plus aspirin (300 mg)-intervention arm or monotherapy with aspirin (300 mg)-control arm. This exploratory analysis compares clinical outcomes between aspirin resistant patients allocated to control arm and patients that have had adequate platelet inhibitory response to aspirin at POD 4. Both groups were treated with 300 mg of aspirin per day following surgery. We sought to evaluate the impact of early postoperative AR on outcomes among patients following CABG. Exploratory analysis included a total number of 325 patients. Of those, 215 patients with adequate response to aspirin and 110 patients with AR allocated to aspirin monotherapy following randomization protocol. The primary efficacy end point (MACCEs-major adverse cardiac and cardiovascular events) occurred in 10 and 6 % of patients with AR and with adequate aspirin response, respectively (p = 0.27). Non-significant differences were observed in bleeding events occurrence. Subgroup analysis of the primary end point revealed that aspirin resistant patients with BMI > 30 kg/m(2) tend to have a higher occurrence of MACCEs 18 versus 5 % (relative risk 0.44 [95 % CI 0.16-1.16]; p = 0.05). This exploratory analysis did not reveal significant impact of aspirin resistance on outcomes among patients undergoing CABG. Further, sufficiently powered studies are needed in order to evaluate clinical relevance of AR in patients undergoing CABG.

Potential antidepressant-like activity of silymarin in the acute restraint stress in mice: Modulation of corticosterone and oxidative stress response in cerebral cortex and hippocampus.

PubMed

Thakare, Vishnu N; Dhakane, Valmik D; Patel, Bhoomika M

2016-10-01

Silymarin is a polyphenolic flavanoid of Silybum marianum, elicited neuroprotection and antidepressant like activity in stressed model. It was found to increase 5-hydroxytryptamine (5-HT) levels in the cortex and dopamine (DA) and norepinephrine (NE) in the cerebellum in normal mice. The aim of the present study was to investigate the potential antidepressant-like activity of silymarin in the acute restraint stress (ARS) in mice. The ARS was induced by immobilizing the mice for a period of 7h using rodent restraint device preventing them for any physical movement. One hour prior to ARS, silymarin was administered at doses of 100mg/kg and 200mg/kg per oral to non stressed and ARS mice. Various behavioral parameters like immobility time in force swim test, locomotor activity in open field test, and biochemical alterations, serum corticosterone, 5-HT, DA, NE level, malondialdehyde (MDA), and antioxidant enzymes (GSH, CAT and SOD) in hippocampus and cerebral cortex in non stressed and ARS subjected mice were investigated. Experimental findings reveals mice subjected to ARS exhibited significant increase immobility time, serum corticosterone, MDA formation and impaired SOD and CAT activities in hippocampus and cerebral cortex as compared to non stressed mice. Silymarin treatment (100mg/kg and 200mg/kg) significantly attenuated immobility time, corticosterone and restored the antioxidant enzymes after ARS. The present experimental findings indicate that silymarin exhibits antidepressant like activity probably either through alleviating oxidative stress by modulation of corticosterone response, and antioxidant defense system in hippocampus and cerebral cortex in ARS mice. Copyright © 2016. Published by Elsevier Urban & Partner Sp. z o.o.

The effects of arachidonic acid on the endocrine and osmoregulatory response of tilapia (Oreochromis mossambicus) acclimated to seawater and subjected to confinement stress.

PubMed

Van Anholt, R D; Spanings, F A T; Nixon, O; Wendelaar Bonga, S E; Koven, W M

2012-06-01

In previous studies in freshwater tilapia (Oreochromis mossambicus), dietary supplementation with arachidonic acid (ArA; 20:4n - 6) had considerable, opposing effects on the main ion-transporting enzyme Na(+)/K(+)-ATPase in gills and kidneys and changed the release of osmoregulatory hormones, such as cortisol. The present study was performed to assess the influence of dietary ArA on (1) the osmoregulatory capacity of tilapia acclimated to seawater (SW) (34‰) and (2) the osmoregulatory imbalance associated with acute stress. The increased ambient salinity was associated with significant alterations in the tissue fatty acid composition, particularly the n - 6 polyunsaturated fatty acids (PUFAs). Tissue levels of ArA were further increased as a result of dietary supplementation, whereas docosahexaenoic acid (DHA, 22:6n - 3) and eicosapentaenoic acid (EPA, 20:5n - 3) decreased in gills and kidneys. Basal plasma cortisol as well as lactate levels were elevated in the ArA-supplemented SW-acclimated tilapia compared with the control group. The 5 min of confinement (transient stress) increased plasma cortisol, glucose, and lactate levels with significantly higher levels in ArA-supplemented tilapia. Confinement was also associated with significantly elevated plasma osmolality, sodium, chloride, and potassium levels. ArA-supplemented tilapia showed markedly lower ionic disturbances after confinement, suggesting that dietary ArA can attenuate the hydromineral imbalance associated with acute stress. These results emphasize the involvement of ArA and/or its metabolites in the endocrine and osmoregulatory processes and the response to confinement stress.

Synergistic activation of the androgen receptor by bombesin and low-dose androgen.

PubMed

Dai, Jie; Shen, Ruoqian; Sumitomo, Makoto; Stahl, Rosalyn; Navarro, Daniel; Gershengorn, Marvin C; Nanus, David M

2002-07-01

Neuropeptide growth factors such as bombesinare implicated in progression to androgen-independent prostate cancer (PC). We examined the impact of bombesin on androgen receptor (AR)-mediated gene expression. The AR together with the AR-responsive probasin ARR(3)tk-luc or PSA-pPUE-ELB-luc promoter was cotransfected into Swiss 3T3 and PC-3 cells, both of which express high-affinity bombesin receptors; the cells were incubated with bombesin (0-50 nM) and dihydrotestosterone (DHT; 0-10 nM), and luciferase activities were measured. DHT increased transcription approximately 40-fold at doses of 1 and 10 nM but had no effect at 10 pM. Bombesin alone, or with 1 or 10 nM DHT, did not further increase transcription. However, 5 nM bombesin and 10 pM DHT, doses that by themselves had no effect, resulted in a approximately 20 fold increase in transcription (P < 0.005). This synergistic effect was blocked by bombesin receptor antagonists and recombinant neutral endopeptidase, which hydrolyzes bombesin. Bombesin and DHT together also increased binding of nuclear extracts from PC-3 cells transfected with AR to a consensus androgen response element in mobility shift assays and increased the level of secreted prostate-specific antigen in LNCaP cell supernatant compared with DHT or bombesin alone. Immunoprecipitation of AR from (32)P-labeled LNCaP cells revealed that 5 nM bombesin + 10 pM DHT induced AR phosphorylation comparable with 1 nM DHT, whereas bombesin or 10 pM DHT alone did not. These data indicate that bombesin can synergize with low (castrate) levels of DHT to induce AR-mediated transcription and suggest that neuropeptides promote AR-mediated signaling in androgen-independent prostate cancer.

Mechanisms of protein kinase C signaling in the modulation of 3',5'-cyclic adenosine monophosphate-mediated steroidogenesis in mouse gonadal cells.

PubMed

Manna, Pulak R; Huhtaniemi, Ilpo T; Stocco, Douglas M

2009-07-01

The protein kinase C (PKC) signaling pathway plays integral roles in the expression of the steroidogenic acute regulatory (StAR) protein that regulates steroid biosynthesis in steroidogenic cells. PKC can modulate the activity of cAMP/protein kinase A signaling involved in steroidogenesis; however, its mechanism remains obscure. In the present study, we demonstrate that activation of the PKC pathway, by phorbol 12-myristate 13-acetate (PMA), was capable of potentiating dibutyryl cAMP [(Bu)(2)cAMP]-stimulated StAR expression, StAR phosphorylation, and progesterone synthesis in both mouse Leydig (MA-10) and granulosa (KK-1) tumor cells. The steroidogenic potential of PMA and (Bu)(2)cAMP was linked with phosphorylation of ERK 1/2; however, inhibition of the latter demonstrated varying effects on steroidogenesis. Transcriptional activation of the StAR gene by PMA and (Bu)(2)cAMP was influenced by several factors, its up-regulation being dependent on phosphorylation of the cAMP response element binding protein (CREB). An oligonucleotide probe containing a CREB/activating transcription factor binding region in the StAR promoter was found to bind nuclear proteins in PMA and (Bu)(2)cAMP-treated MA-10 and KK-1 cells. Chromatin immunoprecipitation studies revealed that the induction of phosphorylated CREB was tightly correlated with in vivo protein-DNA interactions and recruitment of CREB binding protein to the StAR promoter. Ectopic expression of CREB binding protein enhanced CREB-mediated transcription of the StAR gene, an event that was markedly repressed by the adenovirus E1A oncoprotein. Further studies demonstrated that the activation of StAR expression and steroid synthesis by PMA and (Bu)(2)cAMP was associated with expression of the nuclear receptor Nur77, indicating its essential role in hormone-regulated steroidogenesis. Collectively, these findings provide insight into the mechanisms by which PKC modulates cAMP/protein kinase A responsiveness involved in regulating the steroidogenic response in mouse gonadal cells.

The ethics of animal research: a survey of the public and scientists in North America.

PubMed

Joffe, Ari R; Bara, Meredith; Anton, Natalie; Nobis, Nathan

2016-03-29

To determine whether the public and scientists consider common arguments (and counterarguments) in support (or not) of animal research (AR) convincing. After validation, the survey was sent to samples of public (Sampling Survey International (SSI; Canadian), Amazon Mechanical Turk (AMT; US), a Canadian city festival and children's hospital), medical students (two second-year classes), and scientists (corresponding authors, and academic pediatricians). We presented questions about common arguments (with their counterarguments) to justify the moral permissibility (or not) of AR. Responses were compared using Chi-square with Bonferonni correction. There were 1220 public [SSI, n = 586; AMT, n = 439; Festival, n = 195; Hospital n = 107], 194/331 (59%) medical student, and 19/319 (6%) scientist [too few to report] responses. Most public respondents were <45 years (65%), had some College/University education (83%), and had never done AR (92%). Most public and medical student respondents considered 'benefits arguments' sufficient to justify AR; however, most acknowledged that counterarguments suggesting alternative research methods may be available, or that it is unclear why the same 'benefits arguments' do not apply to using humans in research, significantly weakened 'benefits arguments'. Almost all were not convinced of the moral permissibility of AR by 'characteristics of non-human-animals arguments', including that non-human-animals are not sentient, or are property. Most were not convinced of the moral permissibility of AR by 'human exceptionalism' arguments, including that humans have more advanced mental abilities, are of a special 'kind', can enter social contracts, or face a 'lifeboat situation'. Counterarguments explained much of this, including that not all humans have these more advanced abilities ['argument from species overlap'], and that the notion of 'kind' is arbitrary [e.g., why are we not of the 'kind' 'sentient-animal' or 'subject-of-a-life'?]. Medical students were more supportive (80%) of AR at the end of the survey (p < 0.05). Responses suggest that support for AR may not be based on cogent philosophical rationales, and more open debate is warranted.

Androgen Receptor Gene Polymorphisms and Alterations in Prostate Cancer: Of Humanized Mice and Men

PubMed Central

Robins, Diane M.

2011-01-01

Germline polymorphisms and somatic mutations of the androgen receptor (AR) have been intensely investigated in prostate cancer but even with genomic approaches their impact remains controversial. To assess the functional significance of AR genetic variation, we converted the mouse gene to the human sequence by germline recombination and engineered alleles to query the role of a polymorphic glutamine (Q) tract implicated in cancer risk. In a prostate cancer model, AR Q tract length influences progression and castration response. Mutation profiling in mice provides direct evidence that somatic AR variants are selected by therapy, a finding validated in human metastases from distinct treatment groups. Mutant ARs exploit multiple mechanisms to resist hormone ablation, including alterations in ligand specificity, target gene selectivity, chaperone interaction and nuclear localization. Regardless of their frequency, these variants permute normal function to reveal novel means to target wild type AR and its key interacting partners. PMID:21689727

Resolution and partial characterization of two aldehyde reductases of mammalian liver.

PubMed

Tulsiani, D R; Touster

1977-04-25

Investigation of NADP-dependent aldehyde reductase activity in mouse liver led to the finding that two distinct reductases are separable by DE52 ion exchange chromatography. Aldehyde reductase I (AR I) appears in the effluent, while aldehyde reductase II (AR II) is eluted with a salt gradient. By several procedures AR II was purified over 1100-fold from liver supernatant fraction, but AR I could be pruified only 107-fold because of its instability. The two enzymes are different in regard to pH optimum, substrate specificity, response to inhibitors, and reactivity with antibody to AR II. While both enzymes utilize aromatic aldehydes well, only AR II ACTS ON D-glucuronate, indicating that it is the aldyhyde reductase recently reported to be identical to NADP-L-gulonate dehydrogenase. The presence of two NADP-linked aldehyde reductases in liver has apparently not heretofore been reported.

The impact of seawater saturation state and bicarbonate ion concentration on calcification by new recruits of two Atlantic corals

NASA Astrophysics Data System (ADS)

de Putron, S. J.; McCorkle, D. C.; Cohen, A. L.; Dillon, A. B.

2011-06-01

Rising concentrations of atmospheric CO2 are changing the carbonate chemistry of the oceans, a process known as ocean acidification (OA). Absorption of this CO2 by the surface oceans is increasing the amount of total dissolved inorganic carbon (DIC) and bicarbonate ion (HCO3 -) available for marine calcification yet is simultaneously lowering the seawater pH and carbonate ion concentration ([CO3 2-]), and thus the saturation state of seawater with respect to aragonite (Ωar). We investigated the relative importance of [HCO3 -] versus [CO3 2-] for early calcification by new recruits (primary polyps settled from zooxanthellate larvae) of two tropical coral species, Favia fragum and Porites astreoides. The polyps were reared over a range of Ωar values, which were manipulated by both acid-addition at constant pCO2 (decreased total [HCO3 -] and [CO3 2-]) and by pCO2 elevation at constant alkalinity (increased [HCO3 -], decreased [CO3 2-]). Calcification after 2 weeks was quantified by weighing the complete skeleton (corallite) accreted by each polyp over the course of the experiment. Both species exhibited the same negative response to decreasing [CO3 2-] whether Ωar was lowered by acid-addition or by pCO2 elevation—calcification did not follow total DIC or [HCO3 -]. Nevertheless, the calcification response to decreasing [CO3 2-] was nonlinear. A statistically significant decrease in calcification was only detected between Ωar = <2.5 and Ωar = 1.1-1.5, where calcification of new recruits was reduced by 22-37% per 1.0 decrease in Ωar. Our results differ from many previous studies that report a linear coral calcification response to OA, and from those showing that calcification increases with increasing [HCO3 -]. Clearly, the coral calcification response to OA is variable and complex. A deeper understanding of the biomineralization mechanisms and environmental conditions underlying these variable responses is needed to support informed predictions about future OA impacts on corals and coral reefs.

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

αConotoxin ArIB[V11L,V16D] is a potent and selective antagonist at rat and human native α7 nicotinic acetylcholine receptors

PubMed Central

Innocent, Neal; Livingstone, Phil D.; Hone, Arik; Kimura, Atsuko; Young, Tracey; Whiteaker, Paul; McIntosh, J. Michael; Wonnacott, Susan

2008-01-01

A recently developed α-conotoxin, α-CtxArIB[V11L,V16D] is a potent and selective competitive antagonist at rat recombinant α7 nicotinic acetylcholine receptors (nAChRs), making it an attractive probe for this receptor subtype. α7 nAChRs are potential therapeutic targets that are widely expressed in both neuronal and non-neuronal tissues where they are implicated in a variety of functions. Here we evaluate this toxin at rat and human native nAChRs. Functional α7 nAChR responses were evoked by choline plus the allosteric potentiator PNU-120596 in rat PC12 cells and human SHSY5Y cells loaded with calcium indicators. α-CtxArIB[V11L,V16D] specifically inhibited α7 nAChR-mediated increases in Ca2+ in PC12 cells. Responses to other stimuli (5-iodo-A-85380, nicotine or KCl) that did not activate α7 nAChRs were unaffected. Human α7 nAChRs were also sensitive to α-CtxArIB[V11L,V16D]: ACh-evoked currents in X. laevis oocytes expressing human α7 nAChRs were inhibited by α-CtxArIB[V11L,V16D] (IC50 3.4 nM) in a slowly reversible manner, with full recovery taking 15 min. This is consistent with the timecourse of recovery from blockade of rat α7 nAChRs in PC12 cells. α-CtxArIB[V11L,V16D] inhibited human native α7 nAChRs in SHSY5Y cells, activated by either choline or AR-R17779 plus PNU-120596. Rat brain α7 nAChRs contribute to dopamine release from striatal minces: α-CtxArIB[V11L,V16D] (300 nM) selectively inhibited choline-evoked dopamine release without affecting responses evoked by nicotine that activates heteromeric nAChRs. This study establishes that α-CtxArIB[V11L,V16D] selectively inhibits human and rat native α7 nAChRs with comparable potency, making this a potentially useful antagonist for investigating α7 nAChR functions. PMID:18664588

Testosterone enables growth and hypertrophy in fusion impaired myoblasts that display myotube atrophy: deciphering the role of androgen and IGF-I receptors.

PubMed

Hughes, David C; Stewart, Claire E; Sculthorpe, Nicholas; Dugdale, Hannah F; Yousefian, Farzad; Lewis, Mark P; Sharples, Adam P

2016-06-01

We have previously highlighted the ability of testosterone (T) to improve differentiation and myotube hypertrophy in fusion impaired myoblasts that display reduced myotube hypertrophy via multiple population doublings (PD) versus their parental controls (CON); an observation which is abrogated via PI3K/Akt inhibition (Deane et al. 2013). However, whether the most predominant molecular mechanism responsible for T induced hypertrophy occurs directly via androgen receptor or indirectly via IGF-IR/PI3K/Akt pathway is currently debated. PD and CON C2C12 muscle cells were exposed to low serum conditions in the presence or absence of T (100 nM) ± inhibitors of AR (flutamide/F, 40 μm) and IGF-IR (picropodophyllin/PPP, 150 nM) for 72 h and 7 days (early/late muscle differentiation respectively). T increased AR and Akt abundance, myogenin gene expression, and myotube hypertrophy, but not ERK1/2 activity in both CON and PD cell types. Akt activity was not increased significantly in either cell type with T. Testosterone was also unable to promote early differentiation in the presence of IGF-IR inhibitor (PPP) yet still able to promote appropriate later increases in myotube hypertrophy and AR abundance despite IGF-IR inhibition. The addition of the AR inhibitor powerfully attenuated all T induced increases in differentiation and myotube hypertrophy with corresponding reductions in AR abundance, phosphorylated Akt, ERK1/2 and gene expression of IGF-IR, myoD and myogenin with increases in myostatin mRNA in both cell types. Interestingly, despite basally reduced differentiation and myotube hypertrophy, PD cells showed larger T induced increases in AR abundance vs. CON cells, a response abrogated in the presence of AR but not IGF-IR inhibitors. Furthermore, T induced increases in Akt abundance were sustained despite the presence of IGF-IR inhibition in PD cells only. Importantly, flutamide alone reduced IGF-IR mRNA in both cell types across time points, with an observed reduction in activity of ERK and Akt, suggesting that IGF-IR was transcriptionally regulated by AR. However, where testosterone increased AR protein content there was no increases observed in IGF-IR gene expression. This suggested that sufficient AR was important to enable normal IGF-IR expression and downstream signalling, yet elevated levels of AR due to testosterone had no further effect on IGF-IR mRNA, despite testosterone increasing Akt abundance in the presence of IGF-IR inhibitor. In conclusion, testosterones ability to improve differentiation and myotube hypertrophy occurred predominately via increases in AR and Akt abundance in both CON and PD cells, with fusion impaired cells (PD) showing an increased responsiveness to T induced AR levels. Finally, T induced increases in myotube hypertrophy (but not early differentiation) occurred independently of upstream IGF-IR input, however it was apparent  that normal AR function in basal conditions was required for adequate IGF-IR gene expression and downstream ERK/Akt activity.

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.

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.

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

COMT Val158Met and 5-HT1A-R -1019 C/G polymorphisms: effects on the negative symptom response to clozapine.

PubMed

Bosia, Marta; Lorenzi, Cristina; Pirovano, Adele; Guglielmino, Carmelo; Cocchi, Federica; Spangaro, Marco; Bramanti, Placido; Smeraldi, Enrico; Cavallaro, Roberto

2015-01-01

Clozapine is still considered the gold standard for treatment-resistant schizophrenia patients; however, up to 40% of patients do not respond adequately. Identifying potential predictors of clinical response to this last-line antipsychotic could represent an important goal for treatment. Among these, functional polymorphisms involved in dopamine system modulation, known to be disrupted in schizophrenia, may play a role. We examined the COMT Val158Met polymorphism, which plays a key role in dopamine regulation at the prefrontal level, and the 5-HT1A-R -1019 C/G polymorphism, a target of clozapine activity involved in the interaction between the serotonin and dopamine systems. 107 neuroleptic-refractory, biologically unrelated Italian patients (70 males and 37 females) with a DSM-IV diagnosis of schizophrenia who were being treated with clozapine were recruited. Psychopathology was assessed by the Positive and Negative Symptoms Scale (PANSS) at the beginning of treatment, and at weeks 8 and 12. Genomic DNA was extracted from venous blood samples. COMT rs4680 (Val158Met) and 5-HT1A-R rs6295 (-1019 C/G) polymorphisms were analyzed by PCR-based restriction fragment length and direct sequencing, respectively. We found a significant effect of COMT and 5-HT1A-R on the PANSS Negative Subscale variation, with greater improvement among COMT Val/Val and 5-HT1A-R G/G subjects. The findings support the hypothesis that COMT rs4680 and 5-HT1A-R rs6295 polymorphisms could influence the negative symptom response to clozapine, probably through modulation of the dopaminergic system.

Rapid auxin-induced nitric oxide accumulation and subsequent tyrosine nitration of proteins during adventitious root formation in sunflower hypocotyls

PubMed Central

Yadav, Sunita; David, Anisha; Baluška, František; Bhatla, Satish C.

2013-01-01

Using NO specific probe (MNIP-Cu), rapid nitric oxide (NO) accumulation as a response to auxin (IAA) treatment has been observed in the protoplasts from the hypocotyls of sunflower seedlings (Helianthus annuus L.). Incubation of protoplasts in presence of NPA (auxin efflux blocker) and PTIO (NO scavenger) leads to significant reduction in NO accumulation, indicating that NO signals represent an early signaling event during auxin-induced response. A surge in NO production has also been demonstrated in whole hypocotyl explants showing adventitious root (AR) development. Evidence of tyrosine nitration of cytosolic proteins as a consequence of NO accumulation has been provided by western blot analysis and immunolocalization in the sections of AR producing hypocotyl segments. Most abundant anti-nitrotyrosine labeling is evident in proteins ranging from 25–80 kDa. Tyrosine nitration of a particular protein (25 kDa) is completely absent in presence of NPA (which suppresses AR formation). Similar lack of tyrosine nitration of this protein is also evident in other conditions which do not allow AR differentiation. Immunofluorescent localization experiments have revealed that non-inductive treatments (such as PTIO) for AR develpoment from hypocotyl segments coincide with symplastic and apoplastic localization of tyrosine nitrated proteins in the xylem elements, in contrast with negligible (and mainly apoplastic) nitration of proteins in the interfascicular cells and phloem elements. Application of NPA does not affect tyrosine nitration of proteins even in the presence of an external source of NO (SNP). Tyrosine nitrated proteins are abundant around the nuclei in the actively dividing cells of the root primordium. Thus, NO-modulated rapid response to IAA treatment through differential distribution of tyrosine nitrated proteins is evident as an inherent aspect of the AR development. PMID:23299324

Metabotropic glutamate mGlu2 receptor is necessary for the pharmacological and behavioral effects induced by hallucinogenic 5-HT2A receptor agonists.

PubMed

Moreno, José L; Holloway, Terrell; Albizu, Laura; Sealfon, Stuart C; González-Maeso, Javier

2011-04-15

Hallucinogenic drugs, including mescaline, psilocybin and lysergic acid diethylamide (LSD), act at serotonin 5-HT2A receptors (5-HT2ARs). Metabotropic glutamate receptor 2/3 (mGluR2/3) ligands show efficacy in modulating the responses induced by activation of 5-HT2ARs. The formation of a 5-HT2AR-mGluR2 complex suggests a functional interaction that affects the hallucinogen-regulated cellular signaling pathways. Here, we tested the cellular and behavioral effects of hallucinogenic 5-HT2AR agonists in mGluR2 knockout (mGluR2-KO) mice. Mice were intraperitoneally injected with the hallucinogens DOI (2 mg/kg) and LSD (0.24 mg/kg), or vehicle. Head-twitch behavioral response, expression of c-fos, which is induced by all 5-HT2AR agonists, and expression of egr-2, which is hallucinogen-specific, were determined in wild type and mGluR2-KO mice. [(3)H]Ketanserin binding displacement curves by DOI were performed in mouse frontal cortex membrane preparations. Head twitch behavior was abolished in mGluR2-KO mice. The high-affinity binding site of DOI was undetected in mGluR2-KO mice. The hallucinogen DOI induced c-fos in both wild type and mGluR2-KO mice. However, the induction of egr-2 by DOI was eliminated in mGlu2-KO mice. These findings suggest that the 5-HT2AR-mGluR2 complex is necessary for the neuropsychological responses induced by hallucinogens. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Metabotropic glutamate mGlu2 receptor is necessary for the pharmacological and behavioral effects induced by hallucinogenic 5-HT2A receptor agonists

PubMed Central

Moreno, José L.; Holloway, Terrell; Albizu, Laura; Sealfon, Stuart C.; González-Maeso, Javier

2011-01-01

Hallucinogenic drugs, including mescaline, psilocybin and lysergic acid diethylamide (LSD), act at serotonin 5-HT2A receptors (5-HT2ARs). Metabotropic glutamate receptor 2/3 (mGluR2/3) ligands show efficacy in modulating the responses induced by activation of 5-HT2ARs. The formation of a 5-HT2AR-mGluR2 complex suggests a functional interaction that affects the hallucinogen-regulated cellular signaling pathways. Here, we tested the cellular and behavioral effects of hallucinogenic 5-HT2AR agonists in mGluR2 knockout (mGluR2-KO) mice. Mice were intraperitoneally injected with the hallucinogens DOI (2 mg/kg) and LSD (0.24 mg/kg), or vehicle. Head-twitch behavioral response, expression of c-fos, which is induced by all 5-HT2AR agonists, and expression of egr-2, which is hallucinogen-specific, were determined in wild type and mGluR2-KO mice. [3H]Ketanserin binding displacement curves by DOI were performed in mouse frontal cortex membrane preparations. Head twitch behavior was abolished in mGluR2-KO mice. The high-affinity binding site of DOI was undetected in mGluR2-KO mice. The hallucinogen DOI induced c-fos in both wild type and mGluR2-KO mice. However, the induction of egr-2 by DOI was eliminated in mGlu2-KO mice. These findings suggest that the 5-HT2AR-mGluR2 complex is necessary for the neuropsychological responses induced by hallucinogens. PMID:21276828

The Role of Secondary Frontal Waves in Causing Missed or False Alarm Flood Forecasts During Landfalling Atmospheric Rivers

NASA Astrophysics Data System (ADS)

Martin, A.; Ralph, F. M.; Lavers, D. A.; Kalansky, J.; Kawzenuk, B.

2015-12-01

The previous ten years has seen an explosion in research devoted to the Atmospheric River (AR) phenomena, features of the midlatitude circulation responsible for large horizontal water vapor transport. Upon landfall, ARs can be associated with 30-50% of annual precipitation in some regions, while also causing the largest flooding events in places such as coastal California. Little discussed is the role secondary frontal waves play in modulating precipitation during a landfalling AR. Secondary frontal waves develop along an existing cold front in response to baroclinic frontogenesis, often coinciding with a strong upper-tropospheric jet. If the secondary wave develops along a front associated with a landfalling AR, the resulting precipitation may be much greater or much less than originally forecasted - especially in regions where orographic uplift of horizontally transported water vapor is responsible for a large portion of precipitation. In this study, we present several cases of secondary frontal waves that have occurred in conjunction with a landfalling AR on the US West Coast. We put the impact of these cases in historical perspective using quantitative precipitation forecasts, satellite data, reanalyses, and estimates of damage related to flooding. We also discuss the dynamical mechanisms behind secondary frontal wave development and relate these mechanisms to the high spatiotemporal variability in precipitation observed during ARs with secondary frontal waves. Finally, we demonstrate that even at lead times less than 24 hours, current quantitative precipitation forecasting methods have difficulty accurately predicting the rainfall in the area near the secondary wave landfall, in some cases leading to missed or false alarm flood warnings, and suggest methods which may improve quantitative precipitation forecasts for this type of system in the future.

A Modified Compound From Paeoniflorin, CP-25, Suppressed Immune Responses and Synovium Inflammation in Collagen-Induced Arthritis Mice.

PubMed

Chen, Jingyu; Wang, Ying; Wu, Huaxun; Yan, Shangxue; Chang, Yan; Wei, Wei

2018-01-01

Paeoniflorin-6'- O -benzene sulfonate (CP-25) is a modified paeoniflorin, which is the main bioactive component of total glucosides of peony. This study evaluated the anti-inflammatory and immunoregulatory effects of CP-25 in mice with collagen-induced arthritis (CIA) and the potential mechanisms underlying these effects. After the onset of CIA, mice were given CP-25 (17.5, 35, or 70 mg/kg) or methotrexate (MTX, 2.0 mg/kg). The arthritis index, swollen joint count, and joint and spleen histopathology were evaluated. T and B cell subsets were assayed using flow cytometry, while the proliferation of these cells and fibroblast-like synoviocytes (FLSs) were evaluated using the Cell Counting Kit-8. β2-adrenoceptor (β2-AR) expression was assayed using flow cytometry, immunohistochemistry, and western blotting. FLS migration and invasion were assayed using Transwells. CP-25 (35 or 70 mg/kg) attenuated the arthritis index and swollen joint count, alleviated joint and spleen histopathology, suppressed excessive T cell activation, and attenuated humoral immunity in CIA mice. CP-25 increased β2-AR expression on T cells, B cells, dendritic cells, and the synovium in CIA mice. CP-25 up-regulated the β2-AR agonist response and attenuated FLS activation; these effects may reflect CP-25-mediated reduction of β2-AR desensitization due to down-regulation of membrane G protein-coupled receptor kinase 2 expression. These results suggest that CP-25 suppressed immune responses and synovium inflammation in mice with CIA, effects that were associated with reduced β2-AR desensitization and the promotion of β2-AR signaling.

Microphysiometric analysis of human α1a-adrenoceptor expressed in Chinese hamster ovary cells

PubMed Central

Taniguchi, Takanobu; Inagaki, Rika; Murata, Satoshi; Akiba, Isamu; Muramatsu, Ikunobu

1999-01-01

The human recombinant α1a-adrenoceptor (AR) has been stably expressed in Chinese hamster ovary cells. Four stable clones, aH4, aH5, aH6 and aH7, expressing 30, 370, 940 and 2900 fmol AR mg−1 protein, respectively, have been employed to characterize this AR subtype using radioligand binding and microphysiometry to measure extracellular acidification rates.Noradrenaline (NA) gave concentration-dependent responses in microphysiometry with increasing extracellular acidification rates. The potency of NA increased as the receptor density increased; pEC50 values of NA for the clones aH4, aH5, aH6 and aH7 were 6.9, 7.5, 7.8 and 8.1, respectively. This increase of potency according to receptor density indicates the presence of spare receptor for NA. Methoxamine, phenylephrine, oxymetazoline and clonidine also gave concentration-dependent responses with various intrinsic activities.Antagonists shifted concentration-response curves for NA rightward in a concentration-dependent manner. Schild analysis revealed that the affinity profile of this AR subtype to antagonists in the clone aH7 had a typical pattern for the α1a-AR; high affinity for prazosin and WB 4101, and low affinity for BMY7378 (pA2=9.5, 9.8 and 7.3, respectively). This profile is similar in the case of the clone aH4. These affinities were in good agreement with those obtained in binding experiments.These results have demonstrated that (1) classical receptor theory can be applied in microphysiometry, and (2) microphysiometry is a useful tool to investigate the pharmacological characterization of α1a-AR. PMID:10433504

Using an Audience Response System Smartphone App to Improve Resident Education in the Pediatric Intensive Care Unit.

PubMed

Chung, Hoyoung; Kallay, Tom; Anas, Nick; Bruno, Diana; Decamps, Jose; Evans, Darci; Vilasagar, Niveditha; Mink, Richard B

2018-01-01

In the Pediatric Intensive Care Unit (PICU), most teaching occurs during bedside rounds, but technology now provides new opportunities to enhance education. Specifically, smartphone apps allow rapid communication between instructor and student. We hypothesized that using an audience response system (ARS) app can identify resident knowledge gaps, guide teaching, and enhance education in the PICU. Third-year pediatric residents rotating through the PICU participated in ARS-based education or received traditional teaching. Before rounds, experimental subjects completed an ARS quiz using the Socrative app. Concomitantly, the fellow leading rounds predicted quiz performance. Then, discussion points based on the incorrect answers were used to guide instruction. Scores on the pre-rotation test were similar between groups. On the post-rotation examination, ARS participants did not increase their scores more than controls. The fellow's prediction of performance was poor. Residents felt that the method enhanced their education whereas fellows reported that it improved their teaching efficiency. Although there was no measurable increase in knowledge using the ARS app, it may still be a useful tool to rapidly assess learners and help instructors provide learner-centered education.

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

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

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

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

Targeting Androgen Receptor-Driven Resistance to CYP17A1 Inhibitors

DTIC Science & Technology

2016-11-01

unlimited The views, opinions and/or findings contained in this report are those of the author(s) and should not be construed as an official Department of...chemo- and radiotherapies that are efficacious against primary, androgen sensitive (AS)-CaP. CR-CaP progresses to metastatic disease in local lymph... AR ) protein, called AR -V, is directly responsible for malignancy of CR-CaP, and moreover, that ENZ or ABI treatment actually enhances production of AR

Disruption of the Interaction of the Androgen Receptor with Chromatin: A Novel Therapeutic Approach in Prostate Cancer

DTIC Science & Technology

2016-10-01

DISTRIBUTION STATEMENT: Approved for Public Release; Distribution Unlimited The views, opinions and/or findings contained in this report are those of...interface between AR -FOXA1 plays important roles in AR responsiveness and activity. We have designed, synthesized, and tested a panel of peptides...peptidomimetics to disrupt the interaction between AR and FOXA1. The effects of these candidate compounds have been tested in multiple assays and various

The A2b adenosine receptor antagonist PSB-603 promotes oxidative phosphorylation and ROS production in colorectal cancer cells via adenosine receptor-independent mechanism.

PubMed

Mølck, Christina; Ryall, James; Failla, Laura M; Coates, Janine L; Pascussi, Jean-Marc; Heath, Joan K; Stewart, Gregory; Hollande, Frédéric

2016-12-01

Adenosine is a multifaceted regulator of tumor progression. It modulates immune cell activity as well as acting directly on tumor cells. The A 2b adenosine receptor (A 2b -AR) is thought to be an important mediator of these effects. In this study we sought to analyze the contribution of the A 2b -AR to the behavior of colorectal cancer cells. The A 2b -AR antagonist PSB-603 changed cellular redox state without affecting cellular viability. Quantification of cellular bioenergetics demonstrated that PSB-603 increased basal oxygen consumption rates, indicative of enhanced mitochondrial oxidative phosphorylation. Unexpectedly, pharmacological and genetic approaches to antagonize AR-related signalling of PSB-603 did not abolish the response, suggesting that it was AR-independent. PSB-603 also induced acute increases in reactive oxygen species, and PSB-603 synergized with chemotherapy treatment to increase colorectal cancer cell death, consistent with the known link between cellular metabolism and chemotherapy response. PSB-603 alters cellular metabolism in colorectal cancer cells and increases their sensitivity to chemotherapy. Although requiring more mechanistic insight into its A 2b -AR-independent activity, our results show that PSB-603 may have clinical value as an anti-colorectal cancer therapeutic. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Adrenergic receptor-mediated modulation of striatal firing patterns.

PubMed

Ohta, Hiroyuki; Kohno, Yu; Arake, Masashi; Tamura, Risa; Yukawa, Suguru; Sato, Yoshiaki; Morimoto, Yuji; Nishida, Yasuhiro; Yawo, Hiromu

2016-11-01

Although noradrenaline and adrenaline are some of the most important neurotransmitters in the central nervous system, the effects of noradrenergic/adrenergic modulation on the striatum have not been determined. In order to explore the effects of adrenergic receptor (AR) agonists on the striatal firing patterns, we used optogenetic methods which can induce continuous firings. We employed transgenic rats expressing channelrhodopsin-2 (ChR2) in neurons. The medium spiny neuron showed a slow rising depolarization during the 1-s long optogenetic striatal photostimulation and a residual potential with 8.6-s half-life decay after the photostimulation. As a result of the residual potential, five repetitive 1-sec long photostimulations with 20-s onset intervals cumulatively increased the number of spikes. This 'firing increment', possibly relating to the timing control function of the striatum, was used to evaluate the AR modulation. The β-AR agonist isoproterenol decreased the firing increment between the 1st and 5th stimulation cycles, while the α 1 -AR agonist phenylephrine enhanced the firing increment. Isoproterenol and adrenaline increased the early phase (0-0.5s of the photostimulation) firing response. This adrenergic modulation was inhibited by the β-antagonist propranolol. Conversely, phenylephrine and noradrenaline reduced the early phase response. β-ARs and α 1 -ARs work in opposition controlling the striatal firing initiation and the firing increment. Copyright © 2016 Elsevier Ireland Ltd and Japan Neuroscience Society. All rights reserved.

MURC/Cavin-4 facilitates recruitment of ERK to caveolae and concentric cardiac hypertrophy induced by α1-adrenergic receptors

PubMed Central

Ogata, Takehiro; Naito, Daisuke; Nakanishi, Naohiko; Hayashi, Yukiko K.; Taniguchi, Takuya; Miyagawa, Kotaro; Hamaoka, Tetsuro; Maruyama, Naoki; Matoba, Satoaki; Ikeda, Koji; Yamada, Hiroyuki; Oh, Hidemasa; Ueyama, Tomomi

2014-01-01

The actions of catecholamines on adrenergic receptors (ARs) induce sympathetic responses, and sustained activation of the sympathetic nervous system results in disrupted circulatory homeostasis. In cardiomyocytes, α1-ARs localize to flask-shaped membrane microdomains known as “caveolae.” Caveolae require both caveolin and cavin proteins for their biogenesis and function. However, the functional roles and molecular interactions of caveolar components in cardiomyocytes are poorly understood. Here, we showed that muscle-restricted coiled-coil protein (MURC)/Cavin-4 regulated α1-AR–induced cardiomyocyte hypertrophy through enhancement of ERK1/2 activation in caveolae. MURC/Cavin-4 was expressed in the caveolae and T tubules of cardiomyocytes. MURC/Cavin-4 overexpression distended the caveolae, whereas MURC/Cavin-4 was not essential for their formation. MURC/Cavin-4 deficiency attenuated cardiac hypertrophy induced by α1-AR stimulation in the presence of caveolae. Interestingly, MURC/Cavin-4 bound to α1A- and α1B-ARs as well as ERK1/2 in caveolae, and spatiotemporally modulated MEK/ERK signaling in response to α1-AR stimulation. Thus, MURC/Cavin-4 facilitates ERK1/2 recruitment to caveolae and efficient α1-AR signaling mediated by caveolae in cardiomyocytes, which provides a unique insight into the molecular mechanisms underlying caveola-mediated signaling in cardiac hypertrophy. PMID:24567387

Hormonal Responses to Active and Passive Recovery After Load Carriage.

PubMed

Taipale, Ritva S; Heinaru, Siiri; Nindl, Bradley C; Vaara, Jani P; Santtila, Matti; Häkkinen, Keijo; Kyröläinen, Heikki

2015-11-01

Military operations often induce fatigue resulting from load carriage. Recovery promotes military readiness. This study investigated the acute effects of AR vs. PR after load carriage on maximal isometric leg extension force (MVC) and serum hormonal concentrations. Male reservists (27 ± 3 years, 180 ± 7 cm, 74 ± 11 kg, V[Combining Dot Above]O2max 64 ± 9 ml·kg⁻¹·min⁻¹) completed PR (n = 8) or AR (n = 8) after 50 minutes of loaded (16 kg) uphill (gradient 4.0%) treadmill marching at individual anaerobic threshold. No differences were observed between groups in relative changes in MVC during the marching loading, after AR or PR or the next morning. Significant differences in relative responses to AR and PR postmarching loading were observed in serum testosterone (T), cortisol, and sex-hormone binding globulin immediately post AR and PR; however the next morning, all serum hormone concentrations had returned to normal. This study did not reveal any significant differences between the effects of AR and PR after an hour-long marching protocol at approximately anaerobic threshold on MVC or serum hormones the morning after the experimental marching protocol. Thus, based on the variable measured in this study, marching performed by physically fit army reservists at an intensity at or below anaerobic threshold may not necessitate specialized recovery protocols.

New generation HMA mix designs : accelerated pavement testing of a type C mix with the ALF machine.

DOT National Transportation Integrated Search

2012-09-01

Recent changes to the Texas hot-mix asphalt (HMA) mix-design procedures, such as the adaption of the higher-stiffer performance-grade asphalt-binder grades and the Hamburg test, have ensured that the mixes that are routinely used on Texas highways ar...

Integrating Augmented Reality Technology to Enhance Children's Learning in Marine Education

ERIC Educational Resources Information Center

Lu, Su-Ju; Liu, Ying-Chieh

2015-01-01

Marine education comprises rich and multifaceted issues. Raising general awareness of marine environments and issues demands the development of new learning materials. This study adapts concepts from digital game-based learning to design an innovative marine learning program integrating augmented reality (AR) technology for lower grade primary…

Developing Mobile Support System for Augmented Reality in Clinical Constraint Teaching.

PubMed

Weng, Wei Kai; Hsu, Han Jen

2018-01-01

It's always been a big topic how to improve the efficiency of education. Reply teaching and image teaching had always performed better than text book. Furthermore, adapting AR technology will be a great add-on to reinforce it. That's the main purpose of this project.

Cross-talk from β-Adrenergic Receptors Modulates α2A-Adrenergic Receptor Endocytosis in Sympathetic Neurons via Protein Kinase A and Spinophilin*

PubMed Central

Cottingham, Christopher; Lu, Roujian; Jiao, Kai; Wang, Qin

2013-01-01

Inter-regulation of adrenergic receptors (ARs) via cross-talk is a long appreciated but mechanistically unclear physiological phenomenon. Evidence from the AR literature and our own extensive studies on regulation of α2AARs by the scaffolding protein spinophilin have illuminated a potential novel mechanism for cross-talk from β to α2ARs. In the present study, we have characterized a mode of endogenous AR cross-talk in native adrenergic neurons whereby canonical βAR-mediated signaling modulates spinophilin-regulated α2AAR endocytosis through PKA. Our findings demonstrate that co-activation of β and α2AARs, either by application of endogenous agonist or by simultaneous stimulation with distinct selective agonists, results in acceleration of endogenous α2AAR endocytosis in native neurons. We show that receptor-independent PKA activation by forskolin is sufficient to accelerate α2AAR endocytosis and that α2AAR stimulation alone drives accelerated endocytosis in spinophilin-null neurons. Endocytic response acceleration by β/α2AAR co-activation is blocked by PKA inhibition and lost in spinophilin-null neurons, consistent with our previous finding that spinophilin is a substrate for phosphorylation by PKA that disrupts its interaction with α2AARs. Importantly, we show that α2AR agonist-mediated α2AAR/spinophilin interaction is blocked by βAR co-activation in a PKA-dependent fashion. We therefore propose a novel mechanism for cross-talk from β to α2ARs, whereby canonical βAR-mediated signaling coupled to PKA activation results in phosphorylation of spinophilin, disrupting its interaction with α2AARs and accelerating α2AAR endocytic responses. This mechanism of cross-talk has significant implications for endogenous adrenergic physiology and for therapeutic targeting of β and α2AARs. PMID:23965992

An outbreak of Ebola in Uganda.

PubMed

Okware, S I; Omaswa, F G; Zaramba, S; Opio, A; Lutwama, J J; Kamugisha, J; Rwaguma, E B; Kagwa, P; Lamunu, M

2002-12-01

An outbreak of Ebola disease was reported from Gulu district, Uganda, on 8 October 2000. The outbreak was characterized by fever and haemorrhagic manifestations, and affected health workers and the general population of Rwot-Obillo, a village 14 km north of Gulu town. Later, the outbreak spread to other parts of the country including Mbarara and Masindi districts. Response measures included surveillance, community mobilization, case and logistics management. Three coordination committees were formed: National Task Force (NTF), a District Task Force (DTF) and an Interministerial Task Force (IMTF). The NTF and DTF were responsible for coordination and follow-up of implementation of activities at the national and district levels, respectively, while the IMTF provided political direction and handled sensitive issues related to stigma, trade, tourism and international relations. The international response was coordinated by the World Health Organization (WHO) under the umbrella organization of the Global Outbreak and Alert Response Network. A WHO/CDC case definition for Ebola was adapted and used to capture four categories of cases, namely, the 'alert', 'suspected', 'probable' and 'confirmed cases'. Guidelines for identification and management of cases were developed and disseminated to all persons responsible for surveillance, case management, contact tracing and Information Education Communication (IEC). For the duration of the epidemic that lasted up to 16 January 2001, a total of 425 cases with 224 deaths were reported countrywide. The case fatality rate was 53%. The attack rate (AR) was highest in women. The average AR for Gulu district was 12.6 cases/10 000 inhabitants when the contacts of all cases were considered and was 4.5 cases/10 000 if limited only to contacts of laboratory confirmed cases. The secondary AR was 2.5% when nearly 5000 contacts were followed up for 21 days. Uganda was finally declared Ebola free on 27 February 2001, 42 days after the last case was reported. The Government's role in coordination of both local and international support was vital. The NTF and the corresponding district committees harmonized implementation of a mutually agreed programme. Community mobilization using community-based resource persons and political organs, such as Members of Parliament was effective in getting information to the public. This was critical in controlling the epidemic. Past experience in epidemic management has shown that in the absence of regular provision of information to the public, there are bound to be deleterious rumours. Consequently rumour was managed by frank and open discussion of the epidemic, providing daily updates, fact sheets and press releases. Information was regularly disseminated to communities through mass media and press conferences. Thus all levels of the community spontaneously demonstrated solidarity and response to public health interventions. Even in areas of relative insecurity, rebel abductions diminished considerably.

Ocular vestibular evoked myogenic potential elicited from binaural air-conducted stimulations: clinical feasibility in patients with peripheral vestibular dysfunction.

PubMed

Iwasaki, Shinichi; Egami, Naoya; Inoue, Aki; Kinoshita, Makoto; Fujimoto, Chisato; Murofushi, Toshihisa; Yamasoba, Tatsuya

2013-07-01

Ocular vestibular evoked myogenic potentials (oVEMPs) to binaural air-conducted stimulation (ACS) may provide a convenient way of assessing the crossed vestibulo-ocular reflex in patients with vestibular dysfunction as well as in healthy subjects. To investigate the clinical feasibility of using oVEMPs in response to binaural ACS to assess normal subjects and patients with vestibular dysfunction. The study investigated 24 normal subjects (14 men and 10 women, aged from 23 to 60 years) and 14 patients with unilateral peripheral vestibular dysfunction. Each subject underwent oVEMP testing in response to monaural ACS and binaural ACS (500 Hz tone burst, 135 dBSPL). In normal subjects, bilateral oVEMPs were elicited in 75% of subjects in response to monaural ACS and in 91% in response to binaural ACS. Asymmetry ratios (ARs) of the responses to binaural ACS were significantly smaller than those of the responses to monaural ACS (p < 0.01). In patients with unilateral vestibular dysfunction, there were no significant differences in the amplitude, latency, or AR of the responses between monaural and binaural ACS. Approximately 30% of patients showed reduced ARs to binaural ACS relative to monaural ACS, primarily due to contamination by uncrossed responses elicited in healthy ears.

Nutrient and fiber utilization responses of supplemental xylanase in broiler chickens fed wheat based diets are independent of the adaptation period to test diets.

PubMed

Kiarie, E; Walsh, M C; Romero, L F; Arent, S; Ravindran, V

2017-09-01

The effects of adaptation (AD) to xylanase-supplemented diets on nutrient and fiber utilization in 21-d-old broilers were investigated. Six treatments, arranged in two levels of AD (starting at d 0 or d 14 of age) and three levels of xylanase (0 or 2,500 or 5,000 xylanase units/kg feed) were used. All diets had 500 phytase U/kg and 0.3% TiO2 as indigestible marker. A total of 384 d old male broiler (Ross 308) chicks were divided into two groups. The first group was assigned on weight basis to 24 cages (8 chicks per cage) and randomly allocated to the diets from d 0. Birds in the second group were reared on a commercial starter diet in the same room for 13 d. On d 14, the birds were individually weighed, assigned on weight basis to 24 cages (8 chicks per cage), and randomly allocated to the diets. Birds had free access to experimental diets and water. Excreta samples were collected from d 18 to 21. On d 21, all birds were euthanized to access ileal digesta. There was no interaction (P > 0.05) between AD and xylanase on the apparent ileal digestibility (AID) and apparent retention (AR) of components. The main effect of AD was such that the birds exposed to diets for 7 d (d 14 to 21) had higher (P < 0.01) AID of energy than those exposed for 21 d (d 0 to 21). In contrast, birds exposed to diets for 21 d had higher (P < 0.05) AMEn and AR of neutral detergent fiber. Xylanase improvements (P < 0.01) in the AID of energy and AMEn were dose dependent and coincided with linear improvements (P < 0.05) in the AID of nitrogen, fat, and starch. In conclusion, xylanase improvements on retention of fiber and nutrients were independent of AD (7 or 21 d) suggesting that the xylanase effects are not transitional. Greater retention of fiber with longer AD is suggestive of possible microbial adaptation. © 2017 Poultry Science Association Inc.

Cross-cultural adaptation and psychometric properties of an Arabic language version of the Brief Illness Perception Questionnaire in Lebanon.

PubMed

Saarti, Stéphanie; Jabbour, Hicham; El Osta, Nada; Hajj, Aline; Khabbaz, Lydia Rabbaa

2016-01-01

Patients' positive illness perceptions (IPs) significantly contribute to treatment success. The Brief Illness Perception Questionnaire (Brief IPQ) is widely used in various diseases for assessing IPs. It was developed in English-speaking countries and studies on it in Arab countries are scarce. This observational cross-sectional study aimed to cross-culturally adapt the Brief IPQ English version into a modern Arabic language version and determine its psychometric properties in a sample of Lebanese cardiac disease patients. This study was approved by the Institutional Review Board of Saint Joseph University of Beirut, Lebanon. A convenience sample of 30 patients with cardiac disease were recruited during routine visits to cardiologists' offices in Beirut, Lebanon. Inclusion criteria were at least one cardiac disease for at least 6 months with no acute episode or exacerbation of the disease during the 6 preceding months, age ≥ 18 years, and the ability to read and comprehend Arabic. The pre-final version of the Brief IPQ Arabic version was tested for face and content validity. The meaning, comprehensibility, and acceptability were studied by individual interviews. For discriminant validity and internal consistency of the Brief IPQ Arabic version (Brief IPQ-Ar), 100 patients were recruited in a similar manner using the same inclusion criteria. To assess reproducibility, 30 patients, selected randomly from the 100 patients, filled the questionnaire a second time, 3-4 weeks after its first administration and under the same conditions. Psychometric properties of the Brief IPQ-Ar among Lebanese patients suffering from cardiac diseases. Semantic equivalence between the Brief IPQ-Ar questions and patients' descriptions was 100%. Cronbach's alpha was 0.717, which shows good internal consistency. Reproducibility was satisfactory (ICC values>0.776). Moreover, the Brief IPQ-Ar discriminated participants according to the type of cardiac disease and treatment-related characteristics. We confirm that the Brief IPQ-Ar is appropriate for exploring IPs in cardiac disease patients whose first language is Arabic. Further research should be conducted to test this Arabic version in other types of diseases.

Cross-cultural adaptation and psychometric properties of an Arabic language version of the Brief Illness Perception Questionnaire in Lebanon

PubMed Central

Saarti, Stéphanie; Jabbour, Hicham; El Osta, Nada; Hajj, Aline; Khabbaz, Lydia Rabbaa

2016-01-01

Background Patients’ positive illness perceptions (IPs) significantly contribute to treatment success. The Brief Illness Perception Questionnaire (Brief IPQ) is widely used in various diseases for assessing IPs. It was developed in English-speaking countries and studies on it in Arab countries are scarce. Objectives, Setting and design This observational cross-sectional study aimed to cross-culturally adapt the Brief IPQ English version into a modern Arabic language version and determine its psychometric properties in a sample of Lebanese cardiac disease patients. This study was approved by the Institutional Review Board of Saint Joseph University of Beirut, Lebanon. Participants A convenience sample of 30 patients with cardiac disease were recruited during routine visits to cardiologists’ offices in Beirut, Lebanon. Inclusion criteria were at least one cardiac disease for at least 6 months with no acute episode or exacerbation of the disease during the 6 preceding months, age≥18 years, and the ability to read and comprehend Arabic. The pre-final version of the Brief IPQ Arabic version was tested for face and content validity. The meaning, comprehensibility, and acceptability were studied by individual interviews. For discriminant validity and internal consistency of the Brief IPQ Arabic version (Brief IPQ-Ar), 100 patients were recruited in a similar manner using the same inclusion criteria. To assess reproducibility, 30 patients, selected randomly from the 100 patients, filled the questionnaire a second time, 3–4 weeks after its first administration and under the same conditions. Main outcome measures Psychometric properties of the Brief IPQ-Ar among Lebanese patients suffering from cardiac diseases. Results Semantic equivalence between the Brief IPQ-Ar questions and patients’ descriptions was 100%. Cronbach's alpha was 0.717, which shows good internal consistency. Reproducibility was satisfactory (ICC values>0.776). Moreover, the Brief IPQ-Ar discriminated participants according to the type of cardiac disease and treatment-related characteristics. Conclusions We confirm that the Brief IPQ-Ar is appropriate for exploring IPs in cardiac disease patients whose first language is Arabic. Further research should be conducted to test this Arabic version in other types of diseases. PMID:27282197

Cross-cultural adaptation and psychometric properties of an Arabic language version of the Brief Illness Perception Questionnaire in Lebanon.

PubMed

Saarti, Stéphanie; Jabbour, Hicham; Osta, Nada El; Hajj, Aline; Khabbaz, Lydia Rabbaa

2016-01-01

Background Patients' positive illness perceptions (IPs) significantly contribute to treatment success. The Brief Illness Perception Questionnaire (Brief IPQ) is widely used in various diseases for assessing IPs. It was developed in English-speaking countries and studies on it in Arab countries are scarce. Objectives, Setting and design This observational cross-sectional study aimed to cross-culturally adapt the Brief IPQ English version into a modern Arabic language version and determine its psychometric properties in a sample of Lebanese cardiac disease patients. This study was approved by the Institutional Review Board of Saint Joseph University of Beirut, Lebanon. Participants A convenience sample of 30 patients with cardiac disease were recruited during routine visits to cardiologists' offices in Beirut, Lebanon. Inclusion criteria were at least one cardiac disease for at least 6 months with no acute episode or exacerbation of the disease during the 6 preceding months, age≥18 years, and the ability to read and comprehend Arabic. The pre-final version of the Brief IPQ Arabic version was tested for face and content validity. The meaning, comprehensibility, and acceptability were studied by individual interviews. For discriminant validity and internal consistency of the Brief IPQ Arabic version (Brief IPQ-Ar), 100 patients were recruited in a similar manner using the same inclusion criteria. To assess reproducibility, 30 patients, selected randomly from the 100 patients, filled the questionnaire a second time, 3-4 weeks after its first administration and under the same conditions. Main outcome measures Psychometric properties of the Brief IPQ-Ar among Lebanese patients suffering from cardiac diseases. Results Semantic equivalence between the Brief IPQ-Ar questions and patients' descriptions was 100%. Cronbach's alpha was 0.717, which shows good internal consistency. Reproducibility was satisfactory (ICC values>0.776). Moreover, the Brief IPQ-Ar discriminated participants according to the type of cardiac disease and treatment-related characteristics. Conclusions We confirm that the Brief IPQ-Ar is appropriate for exploring IPs in cardiac disease patients whose first language is Arabic. Further research should be conducted to test this Arabic version in other types of diseases.

Comprehensive transcriptome analysis unravels the existence of crucial genes regulating primary metabolism during adventitious root formation in Petunia hybrida.

PubMed

Ahkami, Amirhossein; Scholz, Uwe; Steuernagel, Burkhard; Strickert, Marc; Haensch, Klaus-Thomas; Druege, Uwe; Reinhardt, Didier; Nouri, Eva; von Wirén, Nicolaus; Franken, Philipp; Hajirezaei, Mohammad-Reza

2014-01-01

To identify specific genes determining the initiation and formation of adventitious roots (AR), a microarray-based transcriptome analysis in the stem base of the cuttings of Petunia hybrida (line W115) was conducted. A microarray carrying 24,816 unique, non-redundant annotated sequences was hybridized to probes derived from different stages of AR formation. After exclusion of wound-responsive and root-regulated genes, 1,354 of them were identified which were significantly and specifically induced during various phases of AR formation. Based on a recent physiological model distinguishing three metabolic phases in AR formation, the present paper focuses on the response of genes related to particular metabolic pathways. Key genes involved in primary carbohydrate metabolism such as those mediating apoplastic sucrose unloading were induced at the early sink establishment phase of AR formation. Transcriptome changes also pointed to a possible role of trehalose metabolism and SnRK1 (sucrose non-fermenting 1- related protein kinase) in sugar sensing during this early step of AR formation. Symplastic sucrose unloading and nucleotide biosynthesis were the major processes induced during the later recovery and maintenance phases. Moreover, transcripts involved in peroxisomal beta-oxidation were up-regulated during different phases of AR formation. In addition to metabolic pathways, the analysis revealed the activation of cell division at the two later phases and in particular the induction of G1-specific genes in the maintenance phase. Furthermore, results point towards a specific demand for certain mineral nutrients starting in the recovery phase.

Comprehensive Transcriptome Analysis Unravels the Existence of Crucial Genes Regulating Primary Metabolism during Adventitious Root Formation in Petunia hybrida

PubMed Central

Ahkami, Amirhossein; Scholz, Uwe; Steuernagel, Burkhard; Strickert, Marc; Haensch, Klaus-Thomas; Druege, Uwe; Reinhardt, Didier; Nouri, Eva; von Wirén, Nicolaus; Franken, Philipp; Hajirezaei, Mohammad-Reza

2014-01-01

To identify specific genes determining the initiation and formation of adventitious roots (AR), a microarray-based transcriptome analysis in the stem base of the cuttings of Petunia hybrida (line W115) was conducted. A microarray carrying 24,816 unique, non-redundant annotated sequences was hybridized to probes derived from different stages of AR formation. After exclusion of wound-responsive and root-regulated genes, 1,354 of them were identified which were significantly and specifically induced during various phases of AR formation. Based on a recent physiological model distinguishing three metabolic phases in AR formation, the present paper focuses on the response of genes related to particular metabolic pathways. Key genes involved in primary carbohydrate metabolism such as those mediating apoplastic sucrose unloading were induced at the early sink establishment phase of AR formation. Transcriptome changes also pointed to a possible role of trehalose metabolism and SnRK1 (sucrose non-fermenting 1- related protein kinase) in sugar sensing during this early step of AR formation. Symplastic sucrose unloading and nucleotide biosynthesis were the major processes induced during the later recovery and maintenance phases. Moreover, transcripts involved in peroxisomal beta-oxidation were up-regulated during different phases of AR formation. In addition to metabolic pathways, the analysis revealed the activation of cell division at the two later phases and in particular the induction of G1-specific genes in the maintenance phase. Furthermore, results point towards a specific demand for certain mineral nutrients starting in the recovery phase. PMID:24978694

Correlation between local hemodynamics and lesion distribution in a novel aortic regurgitation murine model of atherosclerosis.

PubMed

Hoi, Yiemeng; Zhou, Yu-Qing; Zhang, Xiaoli; Henkelman, R Mark; Steinman, David A

2011-05-01

Following surgical induction of aortic valve regurgitation (AR), extensive atherosclerotic plaque development along the descending thoracic and abdominal aorta of Ldlr⁻/⁻ mice has been reported, with distinct spatial distributions suggestive of a strong local hemodynamic influence. The objective of this study was to test, using image-based computational fluid dynamics (CFD), whether this is indeed the case. The lumen geometry was reconstructed from micro-CT scanning of a control Ldlr⁻/⁻ mouse, and CFD simulations were carried out for both AR and control flow conditions derived from Doppler ultrasound measurements and literature data. Maps of time-averaged wall shear stress magnitude (TAWSS), oscillatory shear index (OSI) and relative residence time (RRT) were compared against the spatial distributions of plaque stained with oil red O, previously acquired in a group of AR and control mice. Maps of OSI and RRT were found to be consistent with plaque distributions in the AR mice and the absence of plaque in the control mice. TAWSS was uniformly lower under control vs. AR flow conditions, suggesting that levels (> 100 dyn/cm²) exceeded those required to alone induce a pro-atherogenic response. Simulations of a straightened CFD model confirmed the importance of anatomical curvature for explaining the spatial distribution of lesions in the AR mice. In summary, oscillatory and retrograde flow induced in the AR mice, without concomitant low shear, may exacerbate or accelerate lesion formation, but the distinct anatomical curvature of the mouse aorta is responsible for the spatial distribution of lesions.

Use of an audience response system during peer teaching among physical therapy students in human gross anatomy: perceptions of peer teachers and students.

PubMed

Wait, Kevin R; Cloud, Beth A; Forster, Lindsey A; Jones, Tiffany M; Nokleby, Jessica J; Wolfe, Cortney R; Youdas, James W

2009-01-01

An audience response system (ARS) has become popular among educators in medicine and the health professions because of the system's ability to engage listeners during a lecture presentation. No one has described the usefulness of ARS technology during planned nonlecture peer teaching sessions in gross anatomy instruction for health professionals. The unique feature of each peer teaching session was a nongraded 12-15 item ARS quiz assembled by six second-year doctor of physical therapy (DPT) students and purposely placed at the beginning of the review session for those first-year DPT students in attendance. This study used a ten-item questionnaire and a five-point Likert scale in addition to three open ended questions to survey perceptions of both first-year and second-year DPT students about the usefulness of ARS technology implemented during weekly interactive peer teaching sessions during a semester course in Anatomy for Physical Therapists. First-year students overwhelmingly acknowledged the ARS system permitted each student to self-assess his/her preparedness for a quiz or examination and compare his/her performance with that of classmates. Peer teachers recognized an ARS quiz provided them an opportunity to: (1) estimate first-year students' level of understanding of anatomical concepts; and (2) effectively prepare first-year students for their weekly quizzes and future examinations. On the basis of the mutual benefits derived by both students/tutees and teachers/tutors, physical therapist educators may wish to consider using ARS technology to enhance teaching methods for a class in gross human anatomy.

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 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.

Evaluating citrus germplasm for huanglongbing (HLB) resistance: USDA-ARS Inoculation Program

USDA-ARS?s Scientific Manuscript database

The Asian citrus psyllid (ACP), Diaphorina citri, is an important pest because it vectors bacteria responsible for a serious disease of citrus known as huanglongbing (citrus greening disease). USDA-ARS researchers recently established a program for screening citrus germplasm for resistance to the di...

Developing a low cortisol responsive line of channel catfish, Ictalurus punctatus

USDA-ARS?s Scientific Manuscript database

Nagaraj G. Chatakondi and Brian C. Peterson USDA ARS Warmwater Aquaculture Research Unit, 141 Experiment Station Road, Stoneville, MS 38776. nagaraj.chatakondi@ars.usda.gov Channel catfish, Ictalurus punctatus is the most important farm-raised aquacultured species in the USA. Stressors in aquacultu...

Effects of antibiotic resistance (AR) and microbiota shifts on Campylobacter jejuni-mediated diseases.

PubMed

Brooks, Phillip T; Mansfield, Linda S

2017-12-01

Campylobacter jejuni is an important zoonotic pathogen recently designated a serious antimicrobial resistant (AR) threat. While most patients with C. jejuni experience hemorrhagic colitis, serious autoimmune conditions can follow including inflammatory bowel disease (IBD) and the acute neuropathy Guillain Barré Syndrome (GBS). This review examines inter-relationships among factors mediating C. jejuni diarrheal versus autoimmune disease especially AR C. jejuni and microbiome shifts. Because both susceptible and AR C. jejuni are acquired from animals or their products, we consider their role in harboring strains. Inter-relationships among factors mediating C. jejuni colonization, diarrheal and autoimmune disease include C. jejuni virulence factors and AR, the enteric microbiome, and host responses. Because AR C. jejuni have been suggested to affect the severity of disease, length of infections and propensity to develop GBS, it is important to understand how these interactions occur when strains are under selection by antimicrobials. More work is needed to elucidate host-pathogen interactions of AR C. jejuni compared with susceptible strains and how AR C. jejuni are maintained and evolve in animal reservoirs and the extent of transmission to humans. These knowledge gaps impair the development of effective strategies to prevent the emergence of AR C. jejuni in reservoir species and human populations.

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

Transcriptional up-regulation of the human androgen receptor by androgen in bone cells.

PubMed

Wiren, K M; Zhang, X; Chang, C; Keenan, E; Orwoll, E S

1997-06-01

Androgen regulation of androgen receptor (AR) expression has been observed in a variety of tissues, generally as inhibition, and is thought to attenuate cellular responses to androgen. AR is expressed in osteoblasts, the bone-forming cell, suggesting direct actions of androgens on bone. Here we characterized the effect of androgen exposure on AR gene expression in human osteoblastic SaOS-2 and U-2 OS cells. Treatment of osteoblastic cells with the nonaromatizable androgen 5alpha-dihydrotestosterone increased AR steady state messenger RNA levels in a time- and dose-dependent fashion. Reporter assays with 2.3 kilobases of the proximal 5'-flanking region of the human AR promoter linked to the chloramphenicol acetyltransferase gene in transfected cultures showed that up-regulation of AR promoter activity by androgen was time and dose dependent. Treatment with other steroid hormones, including progesterone, 17beta-estradiol, and dexamethasone, was without effect. The antiandrogen hydroxyflutamide completely antagonized androgen up-regulation. Thus, in contrast to many other androgen target tissues, androgen exposure increases steady state AR messenger RNA levels in osteoblasts. This regulation occurs at least partially at the level of transcription, is mediated by the 5'-promoter region of the AR gene, and is dependent on functional AR. These results suggest that physiological concentrations of androgens have significant effects on AR expression in skeletal tissue.

Sustained βAR Stimulation Mediates Cardiac Insulin Resistance in a PKA-Dependent Manner

PubMed Central

Denkaew, Tananat; Phosri, Sarawuth; Pinthong, Darawan; Parichatikanond, Warisara; Shimauchi, Tsukasa; Nishida, Motohiro

2016-01-01

Insulin resistance is a condition in which cells are defective in response to the actions of insulin in tissue glucose uptake. Overstimulation of β-adrenergic receptors (βARs) leads to the development of heart failure and is associated with the pathogenesis of insulin resistance in the heart. However, the mechanisms by which sustained βAR stimulation affects insulin resistance in the heart are incompletely understood. In this study, we demonstrate that sustained βAR stimulation resulted in the inhibition of insulin-induced glucose uptake, and a reduction of insulin induced glucose transporter (GLUT)4 expression that were mediated by the β2AR subtype in cardiomyocytes and heart tissue. Overstimulation of β2AR inhibited the insulin-induced translocation of GLUT4 to the plasma membrane of cardiomyocytes. Additionally, βAR mediated cardiac insulin resistance by reducing glucose uptake and GLUT4 expression via the cAMP-dependent and protein kinase A-dependent pathways. Treatment with β-blockers, including propranolol and metoprolol antagonized isoproterenol-mediated insulin resistance in the heart. The data in this present study confirm a critical role for protein kinase A in βAR-mediated insulin resistance. PMID:26652903

Aurora Kinase A Promotes AR Degradation via the E3 Ligase CHIP.

PubMed

Sarkar, Sukumar; Brautigan, David L; Larner, James M

2017-08-01

Reducing the levels of the androgen receptor (AR) is one of the most viable approaches to combat castration-resistant prostate cancer. Previously, we observed that proteasomal-dependent degradation of AR in response to 2-methoxyestradiol (2-ME) depends primarily on the E3 ligase C-terminus of HSP70-interacting protein (STUB1/CHIP). Here, 2-ME stimulation activates CHIP by phosphorylation via Aurora kinase A (AURKA). Aurora A kinase inhibitors and RNAi knockdown of Aurora A transcript selectively blocked CHIP phosphorylation and AR degradation. Aurora A kinase is activated by 2-ME in the S-phase as well as during mitosis, and phosphorylates CHIP at S273. Prostate cancer cells expressing an S273A mutant of CHIP have attenuated AR degradation upon 2-ME treatment compared with cells expressing wild-type CHIP, supporting the idea that CHIP phosphorylation by Aurora A activates its E3 ligase activity for the AR. These results reveal a novel 2-ME→Aurora A→CHIP→AR pathway that promotes AR degradation via the proteasome that may offer novel therapeutic opportunities for prostate cancer. Mol Cancer Res; 15(8); 1063-72. ©2017 AACR . ©2017 American Association for Cancer Research.

MicroRNAs Are Mediators of Androgen Action in Prostate and Muscle

PubMed Central

Narayanan, Ramesh; Jiang, Jinmai; Gusev, Yuriy; Jones, Amanda; Kearbey, Jeffrey D.; Miller, Duane D.; Schmittgen, Thomas D.; Dalton, James T.

2010-01-01

Androgen receptor (AR) function is critical for the development of male reproductive organs, muscle, bone and other tissues. Functionally impaired AR results in androgen insensitivity syndrome (AIS). The interaction between AR and microRNA (miR) signaling pathways was examined to understand the role of miRs in AR function. Reduction of androgen levels in Sprague-Dawley rats by castration inhibited the expression of a large set of miRs in prostate and muscle, which was reversed by treatment of castrated rats with 3 mg/day dihydrotestosterone (DHT) or selective androgen receptor modulators. Knockout of the miR processing enzyme, DICER, in LNCaP prostate cancer cells or tissue specifically in mice inhibited AR function leading to AIS. Since the only function of miRs is to bind to 3′ UTR and inhibit translation of target genes, androgens might induce miRs to inhibit repressors of AR function. In concordance, knock-down of DICER in LNCaP cells and in tissues in mice induced the expression of corepressors, NCoR and SMRT. These studies demonstrate a feedback loop between miRs, corepressors and AR and the imperative role of miRs in AR function in non-cancerous androgen-responsive tissues. PMID:21048966

Divergent agonist selectivity in activating β1- and β2-adrenoceptors for G-protein and arrestin coupling.

PubMed

Casella, Ida; Ambrosio, Caterina; Grò, Maria Cristina; Molinari, Paola; Costa, Tommaso

2011-08-15

The functional selectivity of adrenergic ligands for activation of β1- and β2-AR (adrenoceptor) subtypes has been extensively studied in cAMP signalling. Much less is known about ligand selectivity for arrestin-mediated signalling pathways. In the present study we used resonance energy transfer methods to compare the ability of β1- and β2-ARs to form a complex with the G-protein β-subunit or β-arrestin-2 in response to a variety of agonists with various degrees of efficacy. The profiles of β1-/β2-AR selectivity of the ligands for the two receptor-transducer interactions were sharply different. For G-protein coupling, the majority of ligands were more effective in activating the β2-AR, whereas for arrestin coupling the relationship was reversed. These data indicate that the β1-AR interacts more efficiently than β2-AR with arrestin, but less efficiently than β2-AR with G-protein. A group of ligands exhibited β1-AR-selective efficacy in driving the coupling to arrestin. Dobutamine, a member of this group, had 70% of the adrenaline (epinephrine) effect on arrestin via β1-AR, but acted as a competitive antagonist of adrenaline via β2-AR. Thus the structure of such ligands appears to induce an arrestin-interacting form of the receptor only when bound to the β1-AR subtype. © The Authors Journal compilation © 2011 Biochemical Society

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.

Molecular and genetic ecotoxicologic approaches to aquatic environmental bioreporting.

PubMed Central

Beaty, B J; Black, W C; Carlson, J O; Clements, W H; DuTeau, N; Harrahy, E; Nuckols, J; Kenneth, E; Olson, K E; Rayms-Keller, A

1998-01-01

Molecular and population genetic ecotoxicologic approaches are being developed for the utilization of arthropods as bioreporters of heavy metal mixtures in the environment. The explosion of knowledge in molecular biology, molecular genetics, and biotechnology provides an unparalleled opportunity to use arthropods as bioreporter organisms. Interspecific differences in aquatic arthropod populations have been previously demonstrated in response to heavy metal insult in the Arkansas River (AR) California Gulch Superfund site (CGSS). Population genetic analyses were conducted on the mayfly Baetis tricaudatus. Genetic polymorphisms were detected in polymerase chain reaction amplified 16S mitochondrial rDNA (a selectively neutral gene) of B tricaudatus using single-strand conformation polymorphism analysis. Genetic differences may have resulted from impediments to gene flow in the population caused by mortality arising from exposure to heavy metal mixture pollution. In laboratory studies a candidate metal-responsive mucinlike gene, which is metal and dose specific, has been identified in Chironomus tentans and other potential AR-CGSS bioreporter species. Population genetic analyses using the mucinlike gene may provide insight into the role of this selectable gene in determining the breeding structure of B. tricaudatus in the AR-CGSS and may provide mechanistic insight into determinants of aquatic arthropod response to heavy metal insult. Metal-responsive (MR) genes and regulatory sequences are being isolated, characterized, and assayed for differential gene expression in response to heavy metal mixture pollution in the AR-CGSS. Identified promoter sequences can then be engineered into previously developed MR constructs to provide sensitive in vitro assays for environmental bioreporting of heavy metal mixtures. The results of the population genetic studies are being entered into an AR geographic information system that contains substantial biological, chemical, and geophysical information. Integrated spatial, structural, and temporal analyses of these parameters will provide invaluable information concerning environmental determinants that restrict or promote gene flow in bioreporter populations. Images Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 PMID:9860898

Raf kinase inhibitor protein: lessons of a better way for β‐adrenergic receptor activation in the heart

PubMed Central

Rosner, Marsha Rich; Brand, Theresa; Schmitt, Joachim P

2017-01-01

Abstract Stimulation of β‐adrenergic receptors (βARs) provides the most efficient physiological mechanism to enhance contraction and relaxation of the heart. Activation of βARs allows rapid enhancement of myocardial function in order to fuel the muscles for running and fighting in a fight‐or‐flight response. Likewise, βARs become activated during cardiovascular disease in an attempt to counteract the restrictions of cardiac output. However, long‐term stimulation of βARs increases the likelihood of cardiac arrhythmias, adverse ventricular remodelling, decline of cardiac performance and premature death, thereby limiting the use of βAR agonists in the treatment of heart failure. Recently the endogenous Raf kinase inhibitor protein (RKIP) was found to activate βAR signalling of the heart without adverse effects. This review will summarize the current knowledge on RKIP‐driven compared to receptor‐mediated signalling in cardiomyocytes. Emphasis is given to the differential effects of RKIP on β1‐ and β2‐ARs and their downstream targets, the regulation of myocyte calcium cycling and myofilament activity. PMID:28444807

K-Ar constraints on fluid-rock interaction and dissolution-precipitation events within the actively creeping shear zones from SAFOD cores

NASA Astrophysics Data System (ADS)

Ali, S.; Hemming, S. R.; Torgersen, T.; Fleisher, M. Q.; Cox, S. E.; Stute, M.

2009-12-01

The San Andreas Fault Observatory at Depth (SAFOD) was drilled to study the physical and chemical processes responsible for faulting and earthquake generation along an active, plate-bounding fault at depth. SAFOD drill cores show multiple zones of alteration and deformation due to fluid-rock interaction in the fault rocks(Schleicher et al. 2008). In context of fluid studies in the SAFZ, noble gas and potassium measurements were performed on solid samples of sedimentary rocks obtained from drill cores across the fault (3050-4000m-MD). We used a combination of 40Ar/39Ar and K-Ar methods on crushed samples of mudrock with variable amounts of visible slickensides to constrain the degree of resetting of the K-Ar system across the San Andreas Fault zone. 40Ar/39Ar was analyzed from small fragments (sand sized grains) while K-Ar was measured in crushed bulk rock samples (100-250 mg for Ar, and 5-10 mg for K analyses). The apparent 40Ar/39Ar ages based on single step laser fusion of small fragments corresponding to the detrital component in the coarse fraction, show varying ages ranging from the provenance age to <13Ma. Although more data are needed to make detailed comparisons, the apparent K-Ar ages of bulk samples in the fault zone are biased toward authigenic materials contained in the fine fraction, similar to the 40Ar/39Ar ages reported for mineralogical separates from very fine size fractions of samples obtained from 3065.98m-MD and 3294.89m-MD (Schleicher et al., submitted to Geology). The small samples measured for 40Ar/39Ar show scatter in the apparent ages, generally bracketing the bulk ages. However they are picked from sieved portions of the samples, and it is likely that there may be a loss of the younger (finer) material. Detrital provenance ages appear to be 50-60Ma in the Pacific Plate, and 100Ma in the North American Plate. 40Ar/39Ar ages within the SAFZ, as defined by geophysical logs (3200-3400m MD), are dominated by apparent detrital ages of ˜100Ma. More work is needed to test whether this is a real provenance age, or if there could be some systematic process that could lead to age bias towards older values. We observe nearly complete resetting of K-Ar ages, indicating that the K content is dominated by newly formed authigenic minerals as a result of fluid rock interaction in the SAFZ. Because the authigenic minerals are subject to successive dissolution-precipitation events over a range of time (3 to 0 Ma) and because the detrital component may not be fully reset, the K-Ar apparent ages (<300,000 years) in the SAFZ provide a maximum age on the resetting event. Similar trends of relatively young ages across the SAFZ compared to the surrounding country rock in the Pacific and North American Plates are also observed in the apparent fluid ‘ages’, corresponding to the fluid event responsible for the fluid-rock interaction in the fault (Ali et al. this session).

Musa spp. germplasm management: microsatellite fingerprinting of USDA-ARS National Plant Germplasm System (NPGS) collection

USDA-ARS?s Scientific Manuscript database

The USDA-ARS Tropical Agriculture Research Station (TARS) is responsible for conserving germplasm of a number of important agricultural crop species. A banana (Musa spp.) collection has been established at TARS that is comprised of diploid, triploid and tetraploid accessions of cultivated, ornament...

THE TROPICAL AND SUBTROPICAL GERMPLASM COLLECTIONS AT THE NATIONAL GERMPLASM REPOSITORY IN MIAMI, FL

USDA-ARS?s Scientific Manuscript database

The Subtropical and Tropical USDA, ARS, National Germplasm Repositories (NGR) in Miami, FL; Mayaguez, PR; and Hilo, HI are responsible for the collections of subtropical and tropical fruits, nuts, grasses, and ornamentals for the USDA, ARS, National Plant Germplasm System (NPGS). The NPGS is respons...

Clickers in the Classroom

ERIC Educational Resources Information Center

Kenwright, Kathy

2009-01-01

The Clinical Laboratory Science (CLS) department at the University of Tennessee Health Science Center is investigating the use of audience response systems (ARS) in its lecture style classes. ARS, or clickers, as they are more commonly called, are wireless hand held devices about the size of a small calculator. Students may use clickers in class…

Soil health, crop productivity, microbial transport, and mine spoil response to biochars

USDA-ARS?s Scientific Manuscript database

Biochar is being evaluated by scientists from the United States Department of Agriculture (USDA) Agricultural Research Service (ARS) for its potential to sequester soil C, to improve soil health, and to increase crop yields. ARS scientists from multiple locations such as Florence, SC, Kimberly, ID,...

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.

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 ).

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.

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

Registration of ‘Ok101’ Wheat

USDA-ARS?s Scientific Manuscript database

‘Ok101’ (Reg. no. CV-932, PI 631493) is a hard red winter wheat (Triticum aestivum L.) developed cooperatively by the Oklahoma Agricultural Experiment Station and the USDA-ARS, and released in March 2001. Ok101 was released for its high tolerance to acidic soil, broad adaptation to both dual-purpose...

National Site for the Regional IPM Centers

Science.gov Websites

Agriculture USDA Soybean Rust Web Site Latest News - Southern Plant Diagnostic Network Soybean Rust Pest Alert , contact: Kent Smith, (202) 720-3186, ksmith@ars.usda.gov United States Department of Agriculture - National Institute of Food and Agriculture Website managed by the Southern IPM Center. Design adapted from

Influences of Regional Climate Change on Air Quality across the Continental U.S. Projected from Downscaling IPCC ARS Simulations

EPA Science Inventory

Projecting climate change scenarios to local scales is important for understanding, mitigating, and adapting to the effects of climate change on society and the environment. Many of the global climate models (GCMs) that are participating in the Intergovernmental Panel on Climate ...

Specific adaptation and genetic progress for grain yield in Great Plains hard winter wheats, 1987-2010

USDA-ARS?s Scientific Manuscript database

Meeting the food demands of a growing world population will become increasingly difficult should the rate of genetic improvement in grain yield of wheat (Triticum aestivum L.) and other grain crops decelerate. Data from USDA-ARS coordinated long-term regional performance nurseries was used to exami...

Role of genetic polymorphisms in NFKB-mediated inflammatory pathways in response to primary chemoradiation therapy for rectal cancer.

PubMed

Dzhugashvili, Maia; Luengo-Gil, Ginés; García, Teresa; González-Conejero, Rocío; Conesa-Zamora, Pablo; Escolar, Pedro Pablo; Calvo, Felipe; Vicente, Vicente; Ayala de la Peña, Francisco

2014-11-01

To investigate whether polymorphisms of genes related to inflammation are associated with pathologic response (primary endpoint) in patients with rectal cancer treated with primary chemoradiation therapy (PCRT). Genomic DNA of 159 patients with locally advanced rectal cancer treated with PCRT was genotyped for polymorphisms rs28362491 (NFKB1), rs1213266/rs5789 (PTGS1), rs5275 (PTGS2), and rs16944/rs1143627 (IL1B) using TaqMan single nucleotide polymorphism genotyping assays. The association between each genotype and pathologic response (poor response vs complete or partial response) was analyzed using logistic regression models. The NFKB1 DEL/DEL genotype was associated with pathologic response (odds ratio [OR], 6.39; 95% confidence interval [CI], 0.78-52.65; P=.03) after PCRT. No statistically significant associations between other polymorphisms and response to PCRT were observed. Patients with the NFKB1 DEL/DEL genotype showed a trend for longer disease-free survival (log-rank test, P=.096) and overall survival (P=.049), which was not significant in a multivariate analysis that included pathologic response. Analysis for 6 polymorphisms showed that patients carrying the haplotype rs28362491-DEL/rs1143627-A/rs1213266-G/rs5789-C/rs5275-A/rs16944-G (13.7% of cases) had a higher response rate to PCRT (OR, 8.86; 95% CI, 1.21-64.98; P=.034) than the reference group (rs28362491-INS/rs1143627-A/rs1213266-G/rs5789-C/rs5275-A/rs16944-G). Clinically significant (grade ≥2) acute organ toxicity was also more frequent in patients with that same haplotype (OR, 4.12; 95% CI, 1.11-15.36; P=.037). Our results suggest that genetic variation in NFKB-related inflammatory pathways might influence sensitivity to primary chemoradiation for rectal cancer. If confirmed, an inflammation-related radiogenetic profile might be used to select patients with rectal cancer for preoperative combined-modality treatment. Copyright © 2014 Elsevier Inc. All rights reserved.

Arabic cross cultural adaptation and validation of the National Institutes of Health Stroke Scale.

PubMed

Hussein, Haitham M; Abdel Moneim, Amr; Emara, Tamer; Abd-Elhamid, Yousry A; Salem, Haitham H; Abd-Allah, Foad; Farrag, Mohammad A; Tork, M Amir; Shalash, Ali S; Ezz El Dein, Khaled H; Osman, Gamaleldin; Georgy, Shady S; Ghali, Peter G; Lyden, Patrick D; Moustafa, Ramez R

2015-10-15

The National Institutes of Health Stroke Scale (NIHSS), the most commonly used tool to quantify neurological deficit in acute stroke, was initially developed in English. We present our experience in developing and validating an Arabic version of the NIHSS (arNIHSS). In 6months, 137 patients were recruited (mean age±standard deviation 62±12years; 48 women). For interrater agreement, weighted kappa value ranged from 0.36 to 0.66 and intraclass correlation coefficient (ICC) for the whole scale was excellent at 0.95 (95% confidence interval [CI] 0.94-0.97). For intrarater agreement, weighted kappa ranged from 0.52 to 1.0 and the ICC was 0.94 (95% CI 0.87-0.98). The construct validity of the arNIHSS is demonstrated by its correlation with the DWI-ASPECT and the 3months mRS score (Spearman correlation -0.46 and 0.58 respectively; P<0.001 for both). We developed and validated a culturally adapted Arabic version of the NIHSS. Further validation in other Arab countries is recommended. Copyright © 2015 Elsevier B.V. All rights reserved.

Adaptive Management Using Remote Sensing and Ecosystem Modeling in Response to Climate Variability and Invasive Aquatic Plants for the California Sacramento-San Joaquin Delta Water Resource

NASA Technical Reports Server (NTRS)

Bubenheim, David; Potter, Christopher; Zhang, Minghua; Madsen, John

2017-01-01

The California Sacramento-San Joaquin River Delta is the hub for California's water supply and supports important ecosystem services, agriculture, and communities in Northern to Southern California. Expansion of invasive aquatic plants in the Delta coupled with impacts of changing climate and long-term drought is detrimental to the San Francisco Bay/California Delta complex. NASA Ames Research Center and the USDA-ARS partnered with the State of California to develop science-based, adaptive-management strategies for invasive aquatic plant in the Sacramento-San Joaquin Delta. Specific mapping tools developed utilizing satellite and airborne platforms provide regular assessments of population dynamics on a landscape scale and support both strategic planning and operational decision making for resource managers. San Joaquin and Sacramento River watersheds water quality input to the Delta is modeled using the Soil-Water Assessment Tool (SWAT) and a modified SWAT tool has been customized to account for unique landscape and management of agricultural water supply and drainage within the Delta. Environmental response models for growth of invasive aquatic weeds are being parameterized and coupled with spatial distribution/biomass density mapping and water quality to study ecosystem response to climate and aquatic plant management practices. On the water validation and operational utilization of these tools by management agencies and how they are improving decision making, management effectiveness and efficiency will be discussed. The project combines science, operations, and economics related to integrated management scenarios for aquatic weeds to help land and water resource managers make science-informed decisions regarding management and outcomes.

Authorship in IPCC AR5 and its implications for content: climate change and Indigenous populations in WGII.

PubMed

Ford, James D; Vanderbilt, Will; Berrang-Ford, Lea

This essay examines the extent to which we can expect Indigenous Knowledge, understanding, and voices on climate change ('Indigenous content') to be captured in WGII of the IPCC Fifth Assessment Report (AR5), based on an analysis of chapter authorship. Reviewing the publishing history of 309 chapter authors (CAs) to WGII, we document 9 (2.9%) to have published on climate change and Indigenous populations and involved as authors in 6/30 chapters. Drawing upon recent scholarship highlighting how authorship affect structure and content of assessment reports, we argue that, unaddressed, this will affect the extent to which Indigenous content is examined and assessed. While it is too late to alter the structure of AR5, there are opportunities to prioritize the recruitment of contributing authors and reviewers with expertise on Indigenous issues, raise awareness among CAs on the characteristics of impacts, adaptation, and vulnerability faced by Indigenous peoples, and highlight how Indigenous perspectives can help broaden our understanding of climate change and policy interventions.

Dendritic cells tolerized with adenosine A2AR agonist attenuate acute kidney injury

PubMed Central

Li, Li; Huang, Liping; Ye, Hong; Song, Steven P.; Bajwa, Amandeep; Lee, Sang Ju; Moser, Emily K.; Jaworska, Katarzyna; Kinsey, Gilbert R.; Day, Yuan J.; Linden, Joel; Lobo, Peter I.; Rosin, Diane L.; Okusa, Mark D.

2012-01-01

DC-mediated NKT cell activation is critical in initiating the immune response following kidney ischemia/reperfusion injury (IRI), which mimics human acute kidney injury (AKI). Adenosine is an important antiinflammatory molecule in tissue inflammation, and adenosine 2A receptor (A2AR) agonists protect kidneys from IRI through their actions on leukocytes. In this study, we showed that mice with A2AR-deficient DCs are more susceptible to kidney IRI and are not protected from injury by A2AR agonists. In addition, administration of DCs treated ex vivo with an A2AR agonist protected the kidneys of WT mice from IRI by suppressing NKT production of IFN-γ and by regulating DC costimulatory molecules that are important for NKT cell activation. A2AR agonists had no effect on DC antigen presentation or on Tregs. We conclude that ex vivo A2AR–induced tolerized DCs suppress NKT cell activation in vivo and provide a unique and potent cell-based strategy to attenuate organ IRI. PMID:23093781

Differential regulation of the androgen receptor by protein phosphatase regulatory subunits

PubMed Central

Grey, James; Jones, Dominic; Wilson, Laura; Nakjang, Sirintra; Clayton, Jake; Temperley, Richard; Clark, Emma; Gaughan, Luke; Robson, Craig

2018-01-01

The Androgen Receptor (AR) is a key molecule in the development, maintenance and progression of prostate cancer (PC). However, the relationship between the AR and co-regulatory proteins that facilitate AR activity in castrate resistant settings remain understudied. Here we show that protein phosphatase 1 regulatory subunits, identified from a phosphatase RNAi screen, direct PP1 catalytic subunits to a varied yet significant response in AR function. As such, we have characterised the PP1β holoenzyme, myosin phosphatase (MLCP), as a novel ligand independent regulator of the AR. Sustained MLCP activity through down-regulation of the MLCP inhibitory subunit, PPP1R14C, results in impaired AR nuclear translocation, protein stability and transcriptional activity in distinct models of PC progression, culminating in restoration of a non-malignant prostate genotype. Phenotypically, a marked reduction in cell proliferation and migration, characterised by G1 cell cycle arrest is observed, confirming PP1 holoenzyme disruption as a novel treatment approach in PC. PMID:29423094

Cotargeting HSP90 and Its Client Proteins for Treatment of Prostate Cancer.

PubMed

Chen, Long; Li, Jie; Farah, Elia; Sarkar, Sukumar; Ahmad, Nihal; Gupta, Sanjay; Larner, James; Liu, Xiaoqi

2016-09-01

Castration-resistant prostate cancer (CRPC) is the later stage of prostate cancer when the disease has stopped responding to androgen deprivation therapy (ADT). It has been established that androgen receptor (AR) reactivation is responsible for the recurrence of prostate cancer after ADT. Thus, targeting different pathways that regulate AR stability and activity should be a promising strategy for treatment of CRPC. Heat shock proteins (HSP) are chaperones that modify stability and activity of their client proteins. HSP90, a major player in the HSP family, regulates stability of many proteins, including AR and Polo-like kinase 1 (Plk1), a critical regulator of many cell-cycle events. Further, HSP90 is overexpressed in different cancers, including prostate cancer. Herein, we show that cotreatment of prostate cancer with AR antagonist enzalutamide and HSP90 inhibitor leads to more severe cell death due to a synergistic reduction of AR protein. Interestingly, we show that overexpression of Plk1 rescued the synergistic effect and that cotargeting HSP90 and Plk1 also leads to more severe cell death. Mechanistically, we show that E3 ligase CHIP, in addition to targeting AR, is responsible for the degradation of Plk1 as well. These findings suggest that cotargeting HSP90 and some of its client proteins may be a useful strategy in treatment of CRPC. Mol Cancer Ther; 15(9); 2107-18. ©2016 AACR. ©2016 American Association for Cancer Research.

Chronic cannabis promotes pro-hallucinogenic signaling of 5-HT2A receptors through Akt/mTOR pathway.

PubMed

Ibarra-Lecue, Inés; Mollinedo-Gajate, Irene; Meana, J Javier; Callado, Luis F; Diez-Alarcia, Rebeca; Urigüen, Leyre

2018-04-27

Long-term use of potent cannabis during adolescence increases the risk of developing schizophrenia later in life, but to date, the mechanisms involved remain unknown. Several findings suggest that the functional selectivity of serotonin 2A receptor (5-HT2AR) through inhibitory G-proteins is involved in the molecular mechanisms responsible for psychotic symptoms. Moreover, this receptor is dysregulated in the frontal cortex of schizophrenia patients. In this context, studies involving cannabis exposure and 5-HT2AR are scarce. Here, we tested in mice the effect of an early chronic Δ 9 -tetrahydrocannabinol (THC) exposure on cortical 5-HT2AR expression, as well as on its in vivo and in vitro functionality. Long-term exposure to THC induced a pro-hallucinogenic molecular conformation of the 5-HT2AR and exacerbated schizophrenia-like responses, such as prepulse inhibition disruption. Supersensitive coupling of 5-HT2AR toward inhibitory Gαi1-, Gαi3-, Gαo-, and Gαz-proteins after chronic THC exposure was observed, without changes in the canonical Gαq/11-protein pathway. In addition, we found that inhibition of Akt/mTOR pathway by rapamycin blocks the changes in 5-HT2AR signaling pattern and the supersensitivity to schizophrenia-like effects induced by chronic THC. The present study provides the first evidence of a mechanistic explanation for the relationship between chronic cannabis exposure in early life and increased risk of developing psychosis-like behaviors in adulthood.

Phytase supplementation in diets rich in fiber from rapeseed enhances phosphorus and calcium digestibility but not retention in broiler chickens

PubMed Central

Lessire, M; Klein, S; Même, N; Peyronnet, C; Quinsac, A; Duclos, M J; Narcy, A

2018-01-01

Abstract Two experiments were conducted on broilers to assess the effect of dietary fiber from 00-rapeseed meal (RSM) on phosphorus (P) and calcium (Ca) apparent ileal digestibility (AID) and retention (AR) during the growing (Exp1: 10 to 21 d) or finishing period (Exp2: 21 to 31 d) in diets supplemented or not with microbial phytase. Each experiment involved 144 male Cobb 500 fed one of 8 diets. Fiber content was modulated by incorporating whole RSM, RSM from dehulled rapeseeds, either raw or supplemented with 2 levels of defatted rapeseed hulls. Diets were supplemented or not with 750 phytase units of microbial phytase per kg. Excreta were collected from d 14 to d 17 (Exp1) and from d 27 to d 30 (Exp2) to measure AR. At the end of experiments, digestive tracts were sampled and weighed. The distal ileum and tibias were collected to measure AID and bone mineralization, respectively. Age did not significantly alter the response of birds to the addition of dietary fiber. Inclusion of hulls decreased growth performance (P < 0.05). The weight of the proventriculus-gizzard (PG) increased with the dietary fiber content in Exp1: The decreased weight observed using dehulled RSM was reversed following the inclusion of hulls. In both trials, while the presence of phytase increased the AID of P (P < 0.001) but not Ca, the inclusion of hulls with phytase improved the AID of P and Ca [linear (Lin), P < 0.05]. This effect could depend on the effect of fiber on PG development and physiology. Hulls decreased the moisture content of excreta (P < 0.01), suggesting higher water retention or lower water consumption with fiber. The AR of P was lower than AID of P with hulls, contrary to Ca, suggesting a metabolic imbalance. The decrease of AR together with the decrease of bone characteristics indicates a lack of Ca in diets with hulls and suggests that P and Ca provision should be adapted to the level and the origin of fiber inclusion. PMID:29506047

Phytase supplementation in diets rich in fiber from rapeseed enhances phosphorus and calcium digestibility but not retention in broiler chickens.

PubMed

Bournazel, M; Lessire, M; Klein, S; Même, N; Peyronnet, C; Quinsac, A; Duclos, M J; Narcy, A

2018-05-01

Two experiments were conducted on broilers to assess the effect of dietary fiber from 00-rapeseed meal (RSM) on phosphorus (P) and calcium (Ca) apparent ileal digestibility (AID) and retention (AR) during the growing (Exp1: 10 to 21 d) or finishing period (Exp2: 21 to 31 d) in diets supplemented or not with microbial phytase. Each experiment involved 144 male Cobb 500 fed one of 8 diets. Fiber content was modulated by incorporating whole RSM, RSM from dehulled rapeseeds, either raw or supplemented with 2 levels of defatted rapeseed hulls. Diets were supplemented or not with 750 phytase units of microbial phytase per kg. Excreta were collected from d 14 to d 17 (Exp1) and from d 27 to d 30 (Exp2) to measure AR. At the end of experiments, digestive tracts were sampled and weighed. The distal ileum and tibias were collected to measure AID and bone mineralization, respectively. Age did not significantly alter the response of birds to the addition of dietary fiber. Inclusion of hulls decreased growth performance (P < 0.05). The weight of the proventriculus-gizzard (PG) increased with the dietary fiber content in Exp1: The decreased weight observed using dehulled RSM was reversed following the inclusion of hulls. In both trials, while the presence of phytase increased the AID of P (P < 0.001) but not Ca, the inclusion of hulls with phytase improved the AID of P and Ca [linear (Lin), P < 0.05]. This effect could depend on the effect of fiber on PG development and physiology. Hulls decreased the moisture content of excreta (P < 0.01), suggesting higher water retention or lower water consumption with fiber. The AR of P was lower than AID of P with hulls, contrary to Ca, suggesting a metabolic imbalance. The decrease of AR together with the decrease of bone characteristics indicates a lack of Ca in diets with hulls and suggests that P and Ca provision should be adapted to the level and the origin of fiber inclusion.

Effect of audience response system technology on learning outcomes in health students and professionals: an updated systematic review.

PubMed

Atlantis, Evan; Cheema, Birinder S

2015-03-01

: Audience response system (ARS) technology is a recent innovation that is increasingly being used by health educators to improve learning outcomes. Equivocal results from previous systematic review research provide weak support for the use of ARS for improving learning outcomes at both short and long terms. This review sought to update and critically review the body of controlled experimental evidence on the use of ARS technology on learning outcomes in health students and professionals. This review searched using all identified keywords both electronic databases (CINAHL, Embase, ERIC, Medline, Science Direct, Scopus, and Web of Science) and reference lists of retrieved articles to find relevant published studies for review, from 2010 to April 2014. A descriptive synthesis of important study characteristics and effect estimates for learning outcomes was done. Three controlled trials in 321 participants from the United States were included for review. ARS knowledge retention scores were lower than the control group in one study, higher than control group provided that immediate feedback was given about each question in one study, and equivalent between intervention and control groups in another study. There is an absence of good quality evidence on effectiveness of ARS technologies for improving learning outcomes in health students and professionals.

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.

Functional desensitization to isoproterenol without reducing cAMP production in canine failing cardiocytes.

PubMed

Laurent, C E; Cardinal, R; Rousseau, G; Vermeulen, M; Bouchard, C; Wilkinson, M; Armour, J A; Bouvier, M

2001-02-01

To corroborate alterations in the functional responses to beta-adrenergic receptor (beta-AR) stimulation with changes in beta-AR signaling in failing cardiomyocytes, contractile and L-type Ca(2+) current responses to isoproterenol along with stimulated cAMP generation were compared among cardiomyocytes isolated from canines with tachycardia-induced heart failure or healthy hearts. The magnitude of shortening of failing cardiomyocytes was significantly depressed (by 22 +/- 4.4%) under basal conditions, and the maximal response to isoproterenol was significantly reduced (by 45 +/- 18%). Similar results were obtained when the responses in the rate of contraction and rate of relaxation to isoproterenol were considered. The L-type Ca(2+) current amplitude measured in failing cardiomyocytes under basal conditions was unchanged, but the responses to isoproterenol were significantly reduced compared with healthy cells. Isoproterenol-stimulated cAMP generation was similar in sarcolemmal membranes derived from the homogenates of failing (45 +/- 6.8) and healthy cardiomyocytes (52 +/- 8.5 pmol cAMP. mg protein(-1). min(-1)). However, stimulated cAMP generation was found to be significantly reduced when the membranes were derived from the homogenates of whole tissue (failing: 67 +/- 8.1 vs. healthy: 140 +/- 27.8 pmol cAMP. mg protein(-1). min(-1)). Total beta-AR density was not reduced in membranes derived from either whole tissue or isolated cardiomyocyte homogenates, but the beta(1)/beta(2) ratio was significantly reduced in the former (failing: 45/55 vs. healthy: 72/28) without being altered in the latter (failing: 72/28, healthy: 77/23). We thus conclude that, in tachycardia-induced heart failure, reduction in the functional responses of isolated cardiomyocytes to beta-AR stimulation may be attributed to alterations in the excitation-contraction machinery rather than to limitation of cAMP generation.

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.

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.

Crosstalk Between Adrenergic and Toll-Like Receptors in Human Mesenchymal Stem Cells and Keratinocytes: A Recipe for Impaired Wound Healing

PubMed Central

Ramirez, Sandra R.; La, Thi Dinh; Gorouhi, Farzam; Nguyen, Chuong; Lin, Benjamin R.; Mashburn, Chelcy; Stewart, Heather; Peavy, Thomas R.; Nolta, Jan A.

2014-01-01

Previous studies demonstrate that skin wounds generate epinephrine (EPI) that can activate local adrenergic receptors (ARs), impairing healing. Bacterially derived activators of Toll-like receptors (TLRs) within the wound initiate inflammatory responses and can also impair healing. In this study, we examined the hypothesis that these two pathways crosstalk to one another, using EPI and macrophage-activating lipopeptide-2 (MALP2) to activate ARs and TLR2, respectively, in human bone marrow-derived mesenchymal stem cells (BM-MSCs) and neonatal keratinocytes (NHKs). BM-MSCs exposed to EPI significantly (p < .05) increased TLR2 message (sevenfold BM-MSCs), TLR2 protein (twofold), and myeloid differentiation factor 88 (MyD88) (fourfold). Conversely, activation of TLR2 by MALP2 in these cells increased β2-AR message (twofold in BM-MSCs, 2.7-fold in NHKs), β2-AR protein (2.5-fold), phosphorylation of β-AR-activated kinase (p-BARK, twofold), and induced release of EPI from both cell types (twofold). Treating cells with EPI and MALP2 together, as would be encountered in a wound, increased β2-AR and p-BARK protein expression (sixfold), impaired cell migration (BM-MSCs- 21%↓ and NHKs- 60%↓, p < .002), and resulted in a 10-fold (BM-MSCs) and 51-fold (NHKs) increase in release of IL-6 (p < .001) responses that were remarkably reduced by pretreatment with β2-AR antagonists. In vivo, EPI-stressed animals exhibited impaired healing, with elevated levels of TLR2, MyD88, and IL-6 in the wounds (p < .05) relative to nonstressed controls. Thus, our data describe a recipe for decreasing cell migration and exacerbating inflammation via novel crosstalk between the adrenergic and Toll-like receptor pathways in BM-MSCs and NHKs. PMID:24760207

A novel approach for needs assessment to build global orthopedic surgical capacity in a low-income country.

PubMed

Bhashyam, Abhiram R; Fils, Jacky; Lowell, Jim; Meara, John G; Dyer, George S M

2015-01-01

Visiting surgical teams are a vital aspect of capacity-building continuing medical education (CME) in low-income countries like Haiti. Imperfect understanding of the genuine needs of local surgeons limit CME initiatives. Previous paper-based needs assessment efforts have been unsuccessful because of low response rates. We explored using an electronic audience response system (ARS) during a Haitian CME conference to improve the response rates and better assess needs. Data were prospectively collected using an ARS from 78 conference participants (57 Haitian and 21 foreign) about current and desired knowledge of 7 topic and 8 skill areas using a 5-point Likert scale presented in English and in French. The response rates using ARS vs a similar paper survey were compared using a 2-sample test of proportions. The current and desired knowledge levels were compared using paired t tests. Analysis of variance and post hoc unpaired t tests were used to compare between demographic groups. The response rates were significantly greater for ARS vs a paper survey (87.7 vs 63.2%, p = 0.002). The 4 areas of least self-confidence for Haitians were pelvic and articular injury, joint dislocation, and osteomyelitis. The 4 skills of least self-confidence for Haitians were arthroscopy, open reduction and internal fixation-plate, external fixation, and fasciotomy. Haitians desired improvements in knowledge and management of articular, diaphyseal, and pelvic injury, joint dislocation, and osteomyelitis to a greater extent than foreigners (p < 0.05). Participants who previously attended the conference on open fractures felt more knowledgeable about open fractures as a topic (p < 0.05), but not in its management. We are the first to show that an ARS improves response rates to allow for better characterization of surgeon needs in the developing world. We also demonstrate the importance of skill building paired with topic area teaching. Lastly, we show how a CME conference is an effective tool to build surgical capacity and increase confidence level. Copyright © 2015 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.

Expectations for the methodology and translation of animal research: a survey of the general public, medical students and animal researchers in North America.

PubMed

Joffe, Ari R; Bara, Meredith; Anton, Natalie; Nobis, Nathan

2016-09-01

To determine what are considered acceptable standards for animal research (AR) methodology and translation rate to humans, a validated survey was sent to: a) a sample of the general public, via Sampling Survey International (SSI; Canada), Amazon Mechanical Turk (AMT; USA), a Canadian city festival (CF) and a Canadian children's hospital (CH); b) a sample of medical students (two first-year classes); and c) a sample of scientists (corresponding authors and academic paediatricians). There were 1379 responses from the general public sample (SSI, n = 557; AMT, n = 590; CF, n = 195; CH, n = 102), 205/330 (62%) medical student responses, and 23/323 (7%, too few to report) scientist responses. Asked about methodological quality, most of the general public and medical student respondents expect that: AR is of high quality (e.g. anaesthesia and analgesia are monitored, even overnight, and 'humane' euthanasia, optimal statistical design, comprehensive literature review, randomisation and blinding, are performed), and costs and difficulty are not acceptable justifications for lower quality (e.g. costs of expert consultation, or more laboratory staff). Asked about their expectations of translation to humans (of toxicity, carcinogenicity, teratogenicity and treatment findings), most expect translation more than 60% of the time. If translation occurred less than 20% of the time, a minority disagreed that this would "significantly reduce your support for AR". Medical students were more supportive of AR, even if translation occurred less than 20% of the time. Expectations for AR are much higher than empirical data show to have been achieved. 2016 FRAME.

Functional integration of skeletal traits: an intraskeletal assessment of bone size, mineralization, and volume covariance.

PubMed

Schlecht, Stephen H; Jepsen, Karl J

2013-09-01

Understanding the functional integration of skeletal traits and how they naturally vary within and across populations will benefit assessments of functional adaptation directed towards interpreting bone stiffness in contemporary and past humans. Moreover, investigating how these traits intraskeletally vary will guide us closer towards predicting fragility from a single skeletal site. Using an osteological collection of 115 young adult male and female African-Americans, we assessed the functional relationship between bone robustness (i.e. total area/length), cortical tissue mineral density (Ct.TMD), and cortical area (Ct.Ar) for the upper and lower limbs. All long bones demonstrated significant trait covariance (p < 0.005) independent of body size, with slender bones having 25-50% less Ct.Ar and 5-8% higher Ct.TMD compared to robust bones. Robustness statistically explained 10.2-28% of Ct.TMD and 26.6-64.6% of Ct.Ar within male and female skeletal elements. This covariance is systemic throughout the skeleton, with either the slender or robust phenotype consistently represented within all long bones for each individual. These findings suggest that each person attains a unique trait set by adulthood that is both predictable by robustness and partially independent of environmental influences. The variation in these functionally integrated traits allows for the maximization of tissue stiffness and minimization of mass so that regardless of which phenotype is present, a given bone is reasonably stiff and strong, and sufficiently adapted to perform routine, habitual loading activities. Covariation intrinsic to functional adaptation suggests that whole bone stiffness depends upon particular sets of traits acquired during growth, presumably through differing levels of cellular activity, resulting in differing tissue morphology and composition. The outcomes of this intraskeletal examination of robustness and its correlates may have significant value in our progression towards improved clinical assessments of bone strength and fragility. Copyright © 2013 Elsevier Inc. All rights reserved.

Enhanced Striatal β1-Adrenergic Receptor Expression Following Hormone Loss in Adulthood Is Programmed by Both Early Sexual Differentiation and Puberty: A Study of Humans and Rats

PubMed Central

Perry, Adam N.; Westenbroek, Christel; Hedges, Valerie L.; Becker, Jill B.; Mermelstein, Paul G.

2013-01-01

After reproductive senescence or gonadectomy, changes occur in neural gene expression, ultimately altering brain function. The endocrine mechanisms underlying these changes in gene expression beyond immediate hormone loss are poorly understood. To investigate this, we measured changes in gene expression the dorsal striatum, where 17β-estradiol modulates catecholamine signaling. In human caudate, quantitative PCR determined a significant elevation in β1-adrenergic receptor (β1AR) expression in menopausal females when compared with similarly aged males. No differences were detected in β2-adrenergic and D1- and D2-dopamine receptor expression. Consistent with humans, adult ovariectomized female rats exhibited a similar increase in β1AR expression when compared with gonadectomized males. No sex difference in β1AR expression was detected between intact adults, prepubertal juveniles, or adults gonadectomized before puberty, indicating the necessity of pubertal development and adult ovariectomy. Additionally, increased β1AR expression in adult ovariectomized females was not observed if animals were masculinized/defeminized with testosterone injections as neonates. To generate a model system for assessing functional impact, increased β1AR expression was induced in female-derived cultured striatal neurons via exposure to and then removal of hormone-containing serum. Increased β1AR action on cAMP formation, cAMP response element-binding protein phosphorylation and gene expression was observed. This up-regulation of β1AR action was eliminated with 17β-estradiol addition to the media, directly implicating this hormone as a regulator of β1AR expression. Beyond having implications for the known sex differences in striatal function and pathologies, these data collectively demonstrate that critical periods early in life and at puberty program adult gene responsiveness to hormone loss after gonadectomy and potentially reproductive senescence. PMID:23533220

Audience-response systems for evaluation of pediatric lectures – comparison with a classic end-of-term online-based evaluation

PubMed Central

Bode, Sebastian Felix Nepomuk; Straub, Christine; Giesler, Marianne; Biller, Silke; Forster, Johannes; Krüger, Marcus

2015-01-01

Aim: Course evaluations are often conducted and analyzed well after the course has taken place. By using a digital audience response system (ARS), it is possible to collect, view and discuss feedback during or directly following a course or lecture session. This paper analyzes a student evaluation of a lecture course with ARS to determine if significant differences exist between the results of the ARS lecture evaluation and those of the online evaluation at the end of the semester. In terms of the overall evaluation, consideration is given to the level of students’ prior knowledge, the presentation of the lecture material by the lecturers and the relevance of the lecture topic for students. Method: During the 2011-12 winter semester, the lecture on Pediatrics at the Freiburg Center for Pediatric and Adolescent Medicine (Zentrum für Kinder- und Jugendmedizin (ZKJ) Freiburg) was evaluated using ARS. Thirty-four lectures were evaluated by an average of 22 (range 8-44) students, who responded to four questions each time an evaluation took place. Results: On a 6-point Likert scale (1=very good to 6=deficient), the students rated their level of preparedness with a mean of 3.18, the presentation of the lecture with 2.44, and the relevance of the lecture topic with 2.19. The overall evaluation of the lecture course by means of ARS resulted in 2.31. The online evaluation conducted at the end of the semester yielded a score of 2.45. Highly significant correlations were seen between the results of the ARS for the overall evaluation, assessment of prior knowledge, lecture presentation, and the estimated relevance of the lecture topic. Conclusion: The use of ARS is suitable for immediate evaluation of lectures, in particular regarding timely feedback for the individual lecturerlecturers. In comparison with an end-of-term evaluation, ARS yielded a better assessment. PMID:26038683

Agonist-dependent phosphorylation of N-formylpeptide and activation peptide from the fifth component of C (C5a) chemoattractant receptors in differentiated HL60 cells.

PubMed

Tardif, M; Mery, L; Brouchon, L; Boulay, F

1993-04-15

Attenuation of signaling is a key step in controlling the cytotoxic potential of leukocyte responses to chemotactic factors. Antipeptide antibodies, directed against the N-formyl chemotactic peptide receptor (FPR) and the activation peptide from the fifth component of C (C5a) anaphylatoxin receptor (C5aR) of human neutrophils, were used to analyze the ability of these receptors to be phosphorylated. Our data show that, in granulocyte-like differentiated HL-60 cells, both FPR and C5aR undergo an agonist dose-dependent phosphorylation that reaches completion in less than 2 to 3 min, consistent with the rate and the dose-dependent attenuation of signaling in phagocytes. Therefore, phosphorylation might be one of the possible mechanisms involved in the desensitization process of FPR and C5aR. Addition of either C5a or the protein kinase C activator (PMA) did not appear to induce the phosphorylation of FPR in the absence of FMLP or to modulate the phosphorylation of the latter at low concentrations of agonist. In contrast, although FMLP at a saturating concentration barely stimulated the phosphorylation of unoccupied C5aR, it markedly potentiated C5aR phosphorylation in cells exposed to low concentrations of C5a. Moreover, PMA was able to induce C5aR phosphorylation in the absence of agonist, indicating that protein kinase C or protein kinase C-activated kinase(s) could be involved in the phosphorylation of C5aR. Pretreatment of cells with staurosporine, a potent but nonspecific inhibitor of protein kinase C, resulted in the partial inhibition of both FPR and C5aR phosphorylation induced by saturating concentrations of agonist, suggesting that a kinase different from protein kinase C might be mainly responsible for the phosphorylation of these chemotactic receptors.

How Stress and Anxiety Can Alter Immediate and Late Phase Skin Test Responses in Allergic Rhinitis

PubMed Central

Kiecolt-Glaser, Janice K.; Heffner, Kathi L.; Glaser, Ronald; Malarkey, William B.; Porter, Kyle; Atkinson, Cathie; Laskowski, Bryon; Lemeshow, Stanley; Marshall, Gailen D.

2010-01-01

Summary Allergic rhinitis (AR) is the fifth most common chronic disease, and the association between allergic disorders and anxiety is well-documented. To investigate how anxiety and stressors modulate skin prick test (SPT) responses and associated inflammatory responses, 28 men and women with AR were selected by clinical history and skin test responses. The participants were admitted twice to a hospital research unit for 4 hours in a crossover trial. Changes in SPT wheals were assessed before and after a standardized laboratory speech stressor, as well as again the following morning; skin responses assessed twice during a lab session without a stressor and again the following morning served as the contrast condition. Anxiety heightened the magnitude of allergen-induced wheals following the stressor. As anxiety increased, SPT wheal diameters increased after the stressor, compared to a slight decrease following the control task. Anxiety also substantially enhanced the effects of stress on late phase responses: even skin tests performed the day after the stressor reflected the continuing impact of the speech stressor among the more anxious participants. Greater anxiety was associated with more IL-6 production by Con A-stimulated leukocytes following the stressor compared to the control visit. The data suggest that stress and anxiety can enhance and prolong AR symptoms. PMID:19150180

Characteristics of Atmospheric River Families in California's Russian River Basin

NASA Astrophysics Data System (ADS)

Fish, M. A.; Wilson, A. M.; Ralph, F. M.

2017-12-01

Previous studies have shown the importance of antecedent conditions and storm duration on atmospheric river (AR) impacts in California's Russian River basin. This study concludes that successive ARs, or families of ARs, produce an enhanced streamflow response compared to individual storms. This amplifies the impacts of these storms, which contribute to 50% of the annual precipitation in the Russian River basin. Using the Modern Era Retrospective - analysis for Research and Applications 2 dataset and 228 AR events from November 2004 - April 2017 affecting Bodega Bay, CA (BBY), this study identified favorable characteristics for families vs single ARs and their associated impacts. It was found that 111 AR events ( 50%) occurred within 5 days of one another with 44 events ( 40%) occurring within 24 hours. Using the winter of 2017, which had a multitude of successive ARs in Northern California, this study evaluates the applicability of family composites using case study comparisons. The results of this study show large divergences of family composites from the overall AR pattern, depending on the time interval between events. A composite of all AR events show Bodega Bay generally south of the jet exit region, SW-NE tilt of 500mb heights and a more northerly subtropical high. ARs occurring on the same day have faster southerly winds, a weaker low off the coast and a southerly moisture plume extending along the CA coast. Comparatively ARs that occur the following day, feature a more zonal pattern with faster winds north of BBY, a deeper low off the coast and a moisture plume southwest of the Russian River watershed.

Zipper-interacting protein kinase is involved in regulation of ubiquitination of the androgen receptor, thereby contributing to dynamic transcription complex assembly.

PubMed

Felten, A; Brinckmann, D; Landsberg, G; Scheidtmann, K H

2013-10-10

We have recently identified apoptosis-antagonizing transcription factor (AATF), tumor-susceptibility gene 101 (TSG101) and zipper-interacting protein kinase (ZIPK) as novel coactivators of the androgen receptor (AR). The mechanisms of coactivation remained obscure, however. Here we investigated the interplay and interdependence between these coactivators and the AR using the endogenous prostate specific antigen (PSA) gene as model for AR-target genes. Chromatin immunoprecipitation in combination with siRNA-mediated knockdown revealed that recruitment of AATF and ZIPK to the PSA enhancer was dependent on AR, whereas recruitment of TSG101 was dependent on AATF. Association of AR and its coactivators with the PSA enhancer or promoter occurred in cycles. Dissociation of AR-transcription complexes was due to degradation because inhibition of the proteasome system by MG132 caused accumulation of AR at enhancer/promoter elements. Moreover, inhibition of degradation strongly reduced transcription, indicating that continued and efficient transcription is based on initiation, degradation and reinitiation cycles. Interestingly, knockdown of ZIPK by siRNA had a similar effect as MG132, leading to reduced transcription but enhanced accumulation of AR at androgen-response elements. In addition, knockdown of ZIPK, as well as overexpression of a dominant-negative ZIPK mutant, diminished polyubiquitination of AR. Furthermore, ZIPK cooperated with the E3 ligase Mdm2 in AR-dependent transactivation, assembled into a single complex on chromatin and phosphorylated Mdm2 in vitro. These results suggest that ZIPK has a crucial role in regulation of ubiquitination and degradation of the AR, and hence promoter clearance and efficient transcription.

High throughput microscopy identifies bisphenol AP, a bisphenol A analog, as a novel AR down-regulator.

PubMed

Stossi, Fabio; Dandekar, Radhika D; Bolt, Michael J; Newberg, Justin Y; Mancini, Maureen G; Kaushik, Akash K; Putluri, Vasanta; Sreekumar, Arun; Mancini, Michael A

2016-03-29

Prostate cancer remains a deadly disease especially when patients become resistant to drugs that target the Androgen Receptor (AR) ligand binding domain. At this stage, patients develop recurring castrate-resistant prostate cancers (CRPCs). Interestingly, CRPC tumors maintain dependency on AR for growth; moreover, in CRPCs, constitutively active AR splice variants (e.g., AR-V7) begin to be expressed at higher levels. These splice variants lack the ligand binding domain and are rendered insensitive to current endocrine therapies. Thus, it is of paramount importance to understand what regulates the expression of AR and its splice variants to identify new therapeutic strategies in CRPCs. Here, we used high throughput microscopy and quantitative image analysis to evaluate effects of selected endocrine disruptors on AR levels in multiple breast and prostate cancer cell lines. Bisphenol AP (BPAP), which is used in chemical and medical industries, was identified as a down-regulator of both full length AR and the AR-V7 splice variant. We validated its activity by performing time-course, dose-response, Western blot and qPCR analyses. BPAP also reduced the percent of cells in S phase, which was accompanied by a ~60% loss in cell numbers and colony formation in anchorage-independent growth assays. Moreover, it affected mitochondria size and cell metabolism. In conclusion, our high content analysis-based screening platform was used to classify the effect of compounds on endogenous ARs, and identified BPAP as being capable of causing AR (both full-length and variants) down-regulation, cell cycle arrest and metabolic alterations in CRPC cell lines.

Downregulation of aldose reductase is responsible for developmental abnormalities of the silkworm purple quail-like mutant (q-lp).

PubMed

Wang, Pingyang; Bi, Simin; Wei, Weiyang; Qiu, Zhiyong; Xia, Dingguo; Shen, Xingjia; Zhao, Qiaoling

2018-05-03

Aldose reductase (AR) is a rate-limiting enzyme in the polyol pathway and is also the key enzyme involved in diabetic complications. The silkworm purple quail-like mutant (q-l p ) exhibits pigmented dots on its epidermis. The q-l p mutant also shows developmental abnormalities and decreased vitality. In this study, fat bodies from the q-l p mutant and the wildtype 932VR strain were subjected to two-dimensional gel electrophoresis (2-DE) analysis, and the Bombyx mori AR (BmAR) protein was found to be significantly downregulated in the q-l p mutant. The expression of BmAR at the mRNA level was also significantly downregulated, as verified through quantitative reverse transcription PCR (qRT-PCR). Knockdown of the expression of BmAR via RNAi resulted in a reduction of silkworm weight. The sorbitol level in q-l p was significantly lower than in the wildtype. These results suggested that the BmAR gene is closely related to the development of the q-l p mutant. Investigation of the cause of BmAR downregulation in the q-l p mutant could contribute to revealing the function of AR in insects and offers a new method of identifying AR inhibitors for the treatment of diabetic complications. Copyright © 2017. Published by Elsevier B.V.

Atmospheric River Importance to Extratropical Climate and Hydrology

NASA Astrophysics Data System (ADS)

Nash, D.; Waliser, D. E.; Guan, B.; Ye, H.; Ralph, F. M.

2017-12-01

Atmospheric Rivers (ARs) are narrow, long, water vapor rich corridors of the atmosphere that are responsible for over 90% of the poleward moisture transport across mid-latitudes and into high latitudes. This suggests a crucial role for ARs in helping establish the extra-tropical atmospheric water budget and hydroclimate variability. However, the contribution of ARs to the extra-tropical atmospheric water budget has yet to be quantified, including impacts on water vapor transport and storage, and precipitation. This study characterizes the roles of AR related atmospheric transport on combined and individual atmospheric water budget variables over extratropical regions of both hemispheres based on MERRA2 reanalysis products during 1997-2014. Results show that poleward water vapor transport related to ARs is strongly related to changes in water vapor storage and especially precipitation in higher latitudes in both hemispheres, with the relationship dependent on averaging period. For example, for the annual cycle climatology, both AR transport and local evaporation support the variation in precipitation. However, on monthly time scales, the water budget at higher latitudes tends to be dominated by the balance between AR transport and precipitation. On pentad and daily time scales, AR transport is related to both precipitation and water vapor storage changes. These results indicate the important role of the episodic, extreme moisture transports associated with ARs in helping establish the high latitude water and energy cycles, and associated hydroclimate.

Recent progress in the development of protein-protein interaction inhibitors targeting androgen receptor-coactivator binding in prostate cancer.

PubMed

Biron, Eric; Bédard, François

2016-07-01

The androgen receptor (AR) is a key regulator for the growth, differentiation and survival of prostate cancer cells. Identified as a primary target for the treatment of prostate cancer, many therapeutic strategies have been developed to attenuate AR signaling in prostate cancer cells. While frontline androgen-deprivation therapies targeting either the production or action of androgens usually yield favorable responses in prostate cancer patients, a significant number acquire treatment resistance. Known as the castration-resistant prostate cancer (CRPC), the treatment options are limited for this advanced stage. It has been shown that AR signaling is restored in CRPC due to many aberrant mechanisms such as AR mutations, amplification or expression of constitutively active splice-variants. Coregulator recruitment is a crucial regulatory step in AR signaling and the direct blockade of coactivator binding to AR offers the opportunity to develop therapeutic agents that would remain effective in prostate cancer cells resistant to conventional endocrine therapies. Structural analyses of the AR have identified key surfaces involved in protein-protein interaction with coregulators that have been recently used to design and develop promising AR-coactivator binding inhibitors. In this review we will discuss the design and development of small-molecule inhibitors targeting the AR-coactivator interactions for the treatment of prostate cancer. Copyright © 2015 Elsevier Ltd. All rights reserved.

CIP2A is a candidate therapeutic target in clinically challenging prostate cancer cell populations.

PubMed

Khanna, Anchit; Rane, Jayant K; Kivinummi, Kati K; Urbanucci, Alfonso; Helenius, Merja A; Tolonen, Teemu T; Saramäki, Outi R; Latonen, Leena; Manni, Visa; Pimanda, John E; Maitland, Norman J; Westermarck, Jukka; Visakorpi, Tapio

2015-08-14

Residual androgen receptor (AR)-signaling and presence of cancer stem-like cells (SCs) are the two emerging paradigms for clinically challenging castration-resistant prostate cancer (CRPC). Therefore, identification of AR-target proteins that are also overexpressed in the cancer SC population would be an attractive therapeutic approach.Our analysis of over three hundred clinical samples and patient-derived prostate epithelial cultures (PPECs), revealed Cancerous inhibitor of protein phosphatase 2A (CIP2A) as one such target. CIP2A is significantly overexpressed in both hormone-naïve prostate cancer (HN-PC) and CRPC patients . CIP2A is also overexpressed, by 3- and 30-fold, in HN-PC and CRPC SCs respectively. In vivo binding of the AR to the intronic region of CIP2A and its functionality in the AR-moderate and AR-high expressing LNCaP cell-model systems is also demonstrated. Further, we show that AR positively regulates CIP2A expression, both at the mRNA and protein level. Finally, CIP2A depletion reduced cell viability and colony forming efficiency of AR-independent PPECs as well as AR-responsive LNCaP cells, in which anchorage-independent growth is also impaired.These findings identify CIP2A as a common denominator for AR-signaling and cancer SC functionality, highlighting its potential therapeutic significance in the most clinically challenging prostate pathology: castration-resistant prostate cancer.

β2-adrenoceptor signaling reduction in dendritic cells is involved in the inflammatory response in adjuvant-induced arthritic rats

PubMed Central

Wu, Huaxun; Chen, Jingyu; Song, Shasha; Yuan, Pingfan; Liu, Lihua; Zhang, Yunfang; Zhou, Aiwu; Chang, Yan; Zhang, Lingling; Wei, Wei

2016-01-01

Rheumatoid arthritis (RA) is characterized by inflammation of the synovium, which leads to the progressive destruction of cartilage and bone. Adrenoreceptor (AR) signaling may play an important role in modulating dendritic cell (DC), which may be involved in the pathogenesis of RA. We examined the effect of the β-AR agonist isoprenaline (ISO) on DC function, the impact of the β2-AR agonist salbutamol on adjuvant-induced arthritic (AA) rats, and changes in β2-AR signaling in DCs during the course of AA. ISO inhibited the expression of the surface molecules CD86 and MHC-II, inhibited the stimulation of T lymphocyte proliferation by DC and TNF-α secretion, and promoted DC antigen uptake and IL-10 secretion. The effects of ISO on MHC-II expression, DC stimulation of T lymphocyte proliferation, and DC antigen uptake were mediated by β2-AR. Treatment with salbutamol ameliorated the severity of AA and histopathology of the joints and inhibited proliferation of thymus lymphocytes and FLS in vivo. β2-AR signaling was weaker in AA rats compared to the control. Elevated GRK2 and decreased β2-AR expression in DC cytomembranes were observed in AA and may have decreased the anti-inflammatory effect of β2-AR signaling. Decreased β2-AR signaling may be relevant to the exacerbation of arthritis inflammation. PMID:27079168

Evolution of Metal(Loid) Binding Sites in Transcriptional Regulators

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

Ordonez, E.; Thiyagarajan, S.; Cook, J.D.

2009-05-22

Expression of the genes for resistance to heavy metals and metalloids is transcriptionally regulated by the toxic ions themselves. Members of the ArsR/SmtB family of small metalloregulatory proteins respond to transition metals, heavy metals, and metalloids, including As(III), Sb(III), Cd(II), Pb(II), Zn(II), Co(II), and Ni(II). These homodimeric repressors bind to DNA in the absence of inducing metal(loid) ion and dissociate from the DNA when inducer is bound. The regulatory sites are often three- or four-coordinate metal binding sites composed of cysteine thiolates. Surprisingly, in two different As(III)-responsive regulators, the metalloid binding sites were in different locations in the repressor, andmore » the Cd(II) binding sites were in two different locations in two Cd(II)-responsive regulators. We hypothesize that ArsR/SmtB repressors have a common backbone structure, that of a winged helix DNA-binding protein, but have considerable plasticity in the location of inducer binding sites. Here we show that an As(III)-responsive member of the family, CgArsR1 from Corynebacterium glutamicum, binds As(III) to a cysteine triad composed of Cys{sup 15}, Cys{sup 16}, and Cys{sup 55}. This binding site is clearly unrelated to the binding sites of other characterized ArsR/SmtB family members. This is consistent with our hypothesis that metal(loid) binding sites in DNA binding proteins evolve convergently in response to persistent environmental pressures.« less

75 FR 11936 - Unit Structures LLC, Magnolia, AR; Notice of Termination of Investigation

Federal Register 2010, 2011, 2012, 2013, 2014

2010-03-12

... DEPARTMENT OF LABOR Employment and Training Administration [TA-W-70,367] Unit Structures LLC, Magnolia, AR; Notice of Termination of Investigation Pursuant to Section 223 of the Trade Act of 1974, as... Arkansas Rapid Response Coordinator on behalf of workers of Unit Structures LLC, Magnolia, Arkansas. The...

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.

Inhibition of beta-adrenergic receptor trafficking in adult cardiocytes by MAP4 decoration of microtubules.

PubMed

Cheng, Guangmao; Qiao, Fei; Gallien, Thomas N; Kuppuswamy, Dhandapani; Cooper, George

2005-03-01

Decreased beta-adrenergic receptor (beta-AR) number occurs both in animal models of cardiac hypertrophy and failure and in patients. beta-AR recycling is an important mechanism for the beta-AR resensitization that maintains a normal complement of cell surface beta-ARs. We have shown that 1) in severe pressure overload cardiac hypertrophy, there is extensive microtubule-associated protein 4 (MAP4) decoration of a dense microtubule network; and 2) MAP4 microtubule decoration inhibits muscarinic acetylcholine receptor recycling in neuroblastoma cells. We asked here whether MAP4 microtubule decoration inhibits beta-AR recycling in adult cardiocytes. [(3)H]CGP-12177 was used as a beta-AR ligand, and feline cardiocytes were isolated and infected with adenovirus containing MAP4 (AdMAP4) or beta-galactosidase (Adbeta-gal) cDNA. MAP4 decorated the microtubules extensively only in AdMAP4 cardiocytes. beta-AR agonist exposure reduced cell surface beta-AR number comparably in AdMAP4 and Adbeta-gal cardiocytes; however, after agonist withdrawal, the cell surface beta-AR number recovered to 78.4 +/- 2.9% of the pretreatment value in Adbeta-gal cardiocytes but only to 56.8 +/- 1.4% in AdMAP4 cardiocytes (P < 0.01). This result was confirmed in cardiocytes isolated from transgenic mice having cardiac-restricted MAP4 overexpression. In functional terms of cAMP generation, beta-AR agonist responsiveness of AdMAP4 cells was 47% less than that of Adbeta-gal cells. We conclude that MAP4 microtubule decoration interferes with beta-AR recycling and that this may be one mechanism for beta-AR downregulation in heart failure.

Influence of atmospheric rivers on vegetation productivity and fire patterns in the southwestern U.S.

USGS Publications Warehouse

Albano, Christine M.; Dettinger, Michael; Soulard, Christopher E.

2017-01-01

In the southwestern U.S., the meteorological phenomenon known as atmospheric rivers (ARs) has gained increasing attention due to its strong connections to floods, snowpacks, and water supplies in the West Coast states. Relatively less is known about the ecological implications of ARs, particularly in the interior Southwest, where AR storms are less common. To address this gap, we compared a chronology of AR landfalls on the west coast between 1989 and 2011 and between 25°N and 42.5°N to annual metrics of the normalized difference vegetation index (NDVI; an indicator of vegetation productivity) and daily resolution precipitation data to assess influences of AR-fed winter precipitation on vegetation productivity across the southwestern U.S. We mapped correlations between winter AR precipitation during landfalling ARs and (1) annual maximum NDVI and (2) area burned by large wildfires summarized by ecoregion during the same year as the landfalls and during the following year. Interannual variations of AR precipitation strongly influenced both NDVI and area burned by wildfire in some dryland ecoregions. The influence of ARs on dryland vegetation varied significantly depending on the latitude of landfall, with those ARs making landfall below 35°N latitude more strongly influencing these systems, and with effects observed as far as 1300 km from the landfall location. As climatologists' understanding of the synoptic patterns associated with the occurrence of ARs continues to evolve, an increased understanding of how AR landfalls, in aggregate, influence vegetation productivity and associated wildfire activity in dryland ecosystems may provide opportunities to better predict ecological responses to climate and climate change.

Down, But Not Out: Partial Elimination of Androgen Receptors in the Male Mouse Brain Does Not Affect Androgenic Regulation of Anxiety or HPA Activity.

PubMed

Chen, Chieh V; Brummet, Jennifer L; Jordan, Cynthia L; Breedlove, S Marc

2016-02-01

We previously found that androgen receptor (AR) activity mediates two effects of T in adult male mice: reduction of anxiety-like behaviors and dampening of the hypothalamic-pituitary-adrenal response to stress. To determine whether brain ARs mediate these effects, we used the Cre/loxP technology seeking to disable AR throughout the central nervous system (CNS). Female mice carrying the floxed AR allele (ARlox) were crossed with males carrying cre recombinase transgene controlled by the nestin promoter (NesCre), producing cre in developing neurons and glia. Among male offspring, four genotypes resulted: males carrying ARlox and NesCre (NesARko), and three control groups (wild types, NesCre, and ARlox). Reporter mice indicated ubiquitous Cre expression throughout the CNS. Nevertheless, AR immunocytochemistry in NesARko mice revealed efficient knockout (KO) of AR in some brain regions (hippocampus and medial prefrontal cortex [mPFC]), but not others. Substantial AR protein was seen in the amygdala and hypothalamus among other regions, whereas negligible AR remained in others like the bed nucleus of the stria terminalis and dorsal periaqueductal gray. This selective KO allowed for testing the role of AR in hippocampus and mPFC. Males were castrated and implanted with T at postnatal day 60 before testing on postnatal day 90-100. In contrast with males with global KO of AR, T still modulated anxiety-related behavior and hypothalamic-pituitary-adrenal activity in NesARko males. These results leave open the possibility that AR acting in the CNS mediates these effects of T, but demonstrate that AR is not required in the hippocampus or mPFC for T's anxiolytic effects.

Down, But Not Out: Partial Elimination of Androgen Receptors in the Male Mouse Brain Does Not Affect Androgenic Regulation of Anxiety or HPA Activity

PubMed Central

Brummet, Jennifer L.; Jordan, Cynthia L.; Breedlove, S. Marc

2016-01-01

We previously found that androgen receptor (AR) activity mediates two effects of T in adult male mice: reduction of anxiety-like behaviors and dampening of the hypothalamic-pituitary-adrenal response to stress. To determine whether brain ARs mediate these effects, we used the Cre/loxP technology seeking to disable AR throughout the central nervous system (CNS). Female mice carrying the floxed AR allele (ARlox) were crossed with males carrying cre recombinase transgene controlled by the nestin promoter (NesCre), producing cre in developing neurons and glia. Among male offspring, four genotypes resulted: males carrying ARlox and NesCre (NesARko), and three control groups (wild types, NesCre, and ARlox). Reporter mice indicated ubiquitous Cre expression throughout the CNS. Nevertheless, AR immunocytochemistry in NesARko mice revealed efficient knockout (KO) of AR in some brain regions (hippocampus and medial prefrontal cortex [mPFC]), but not others. Substantial AR protein was seen in the amygdala and hypothalamus among other regions, whereas negligible AR remained in others like the bed nucleus of the stria terminalis and dorsal periaqueductal gray. This selective KO allowed for testing the role of AR in hippocampus and mPFC. Males were castrated and implanted with T at postnatal day 60 before testing on postnatal day 90–100. In contrast with males with global KO of AR, T still modulated anxiety-related behavior and hypothalamic-pituitary-adrenal activity in NesARko males. These results leave open the possibility that AR acting in the CNS mediates these effects of T, but demonstrate that AR is not required in the hippocampus or mPFC for T's anxiolytic effects. PMID:26562258

Influence of atmospheric rivers on vegetation productivity and fire patterns in the southwestern U.S.

NASA Astrophysics Data System (ADS)

Albano, Christine M.; Dettinger, Michael D.; Soulard, Christopher E.

2017-02-01

In the southwestern U.S., the meteorological phenomenon known as atmospheric rivers (ARs) has gained increasing attention due to its strong connections to floods, snowpacks, and water supplies in the West Coast states. Relatively less is known about the ecological implications of ARs, particularly in the interior Southwest, where AR storms are less common. To address this gap, we compared a chronology of AR landfalls on the west coast between 1989 and 2011 and between 25°N and 42.5°N to annual metrics of the normalized difference vegetation index (NDVI; an indicator of vegetation productivity) and daily resolution precipitation data to assess influences of AR-fed winter precipitation on vegetation productivity across the southwestern U.S. We mapped correlations between winter AR precipitation during landfalling ARs and (1) annual maximum NDVI and (2) area burned by large wildfires summarized by ecoregion during the same year as the landfalls and during the following year. Interannual variations of AR precipitation strongly influenced both NDVI and area burned by wildfire in some dryland ecoregions. The influence of ARs on dryland vegetation varied significantly depending on the latitude of landfall, with those ARs making landfall below 35°N latitude more strongly influencing these systems, and with effects observed as far as 1300 km from the landfall location. As climatologists' understanding of the synoptic patterns associated with the occurrence of ARs continues to evolve, an increased understanding of how AR landfalls, in aggregate, influence vegetation productivity and associated wildfire activity in dryland ecosystems may provide opportunities to better predict ecological responses to climate and climate change.

Interaction of the androgen receptor, ETV1 and PTEN pathways in mouse prostate varies with pathological stage and predicts cancer progression

PubMed Central

Higgins, Jake; Brogley, Michele; Palanisamy, Nallasivam; Mehra, Rohit; Ittmann, Michael M.; Li, Jun Z.; Tomlins, Scott A.; Robins, Diane M.

2015-01-01

To examine the impact of common somatic mutations in prostate cancer (PCa) on androgen receptor (AR) signaling, mouse models were designed to perturb sequentially the AR, ETV1 and PTEN pathways. Mice with "humanized" AR (hAR) alleles that modified AR transcriptional strength by varying polyglutamine tract (Q-tract) length were crossed with mice expressing a prostate-specific, AR-responsive ETV1 transgene (ETV1Tg). While hAR allele did not grossly affect ETV1-induced neoplasia, ETV1 strongly antagonized global AR regulation and repressed critical androgen-induced differentiation and tumor suppressor genes, such as Nkx3-1 and Hoxb13. When Pten was varied to determine its impact on disease progression, mice lacking one Pten allele (Pten+/−) developed more frequent prostatic intraepithelial neoplasia (PIN). Yet only those with the ETV1 transgene progressed to invasive adenocarcinoma. Furthermore, progression was more frequent with the short Q-tract (stronger) AR, suggesting that the AR, ETV1 and PTEN pathways cooperate in aggressive disease. On the Pten+/− background, ETV1 had markedly less effect on AR target genes. However, a strong inflammatory gene expression signature, notably upregulation of Cxcl16, was induced by ETV1. Comparison of mouse and human patient data stratified by presence of ETS fusion genes highlighted additional factors, some not previously associated with prostate cancer but for which targeted therapies are in development for other diseases. In sum, concerted use of these mouse models illuminates the complex interplay of AR, ETV1 and PTEN pathways in pre-cancerous neoplasia and early tumorigenesis, disease stages difficult to analyze in man. PMID:25631336

Gain in Transcriptional Activity by Primate-specific Coevolution of Melanoma Antigen-A11 and Its Interaction Site in Androgen Receptor*

PubMed Central

Liu, Qiang; Su, Shifeng; Blackwelder, Amanda J.; Minges, John T.; Wilson, Elizabeth M.

2011-01-01

Male sex development and growth occur in response to high affinity androgen binding to the androgen receptor (AR). In contrast to complete amino acid sequence conservation in the AR DNA and ligand binding domains among mammals, a primate-specific difference in the AR NH2-terminal region that regulates the NH2- and carboxyl-terminal (N/C) interaction enables direct binding to melanoma antigen-A11 (MAGE-11), an AR coregulator that is also primate-specific. Human, mouse, and rat AR share the same NH2-terminal 23FQNLF27 sequence that mediates the androgen-dependent N/C interaction. However, the mouse and rat AR FXXLF motif is flanked by Ala33 that evolved to Val33 in primates. Human AR Val33 was required to interact directly with MAGE-11 and for the inhibitory effect of the AR N/C interaction on activation function 2 that was relieved by MAGE-11. The functional importance of MAGE-11 was indicated by decreased human AR regulation of an androgen-dependent endogenous gene using lentivirus short hairpin RNAs and by the greater transcriptional strength of human compared with mouse AR. MAGE-11 increased progesterone and glucocorticoid receptor activity independently of binding an FXXLF motif by interacting with p300 and p160 coactivators. We conclude that the coevolution of the AR NH2-terminal sequence and MAGE-11 expression among primates provides increased regulatory control over activation domain dominance. Primate-specific expression of MAGE-11 results in greater steroid receptor transcriptional activity through direct interactions with the human AR FXXLF motif region and indirectly through steroid receptor-associated p300 and p160 coactivators. PMID:21730049

Androgen receptor expression in the human vagina under different physiological and treatment conditions.

PubMed

Baldassarre, M; Perrone, A M; Giannone, F A; Armillotta, F; Battaglia, C; Costantino, A; Venturoli, S; Meriggiola, M C

2013-01-01

Recent data report an important role of testosterone (T) in modulating female sexual responses, but little is known about the expression and distribution of androgen receptor (AR) in the human vagina. Therefore, the aims of our study were to evaluate the expression of AR in the human vagina in premenopausal (PrM) and menopausal (M) women and in T-treated women. Vaginal biopsies were obtained from PrM and postmenopausal women and from women with gender identity disorder (female to male (FtM)) receiving exogenous T. AR gene and protein expression levels in vaginal tissues were determined by real-time PCR and western blot analysis, respectively, whereas the localization of AR in vaginal mucosa and stroma was performed by immunohistochemistry. ARs were detected by immunostaining both in the mucosa and stroma. In vaginal mucosa, AR density score decreases with age but does not change with T administration. In stromal tissue, AR density score does not change with age but significantly increases with T administration (P<0.01). AR protein expression was significantly increased in FtM subjects (P<0.001). The expression of AR messenger RNA (mRNA) evaluated by Real-time PCR showed a significantly higher mRNA expression in FtM versus M patients (P<0.01) and in PrM versus M subjects (P<0.05). In conclusion, we found AR protein and mRNA expression both in the epithelium and stroma of the human vagina in all groups of women. A negative correlation exists between age and AR expression in the vaginal mucosa. T administration increases AR expression in both the mucosa and stroma.

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

Dzhugashvili, Maia; Department of Radiation Oncology, Madrid Oncology Institute; Luengo-Gil, Ginés

Purpose: To investigate whether polymorphisms of genes related to inflammation are associated with pathologic response (primary endpoint) in patients with rectal cancer treated with primary chemoradiation therapy (PCRT). Methods and Materials: Genomic DNA of 159 patients with locally advanced rectal cancer treated with PCRT was genotyped for polymorphisms rs28362491 (NFKB1), rs1213266/rs5789 (PTGS1), rs5275 (PTGS2), and rs16944/rs1143627 (IL1B) using TaqMan single nucleotide polymorphism genotyping assays. The association between each genotype and pathologic response (poor response vs complete or partial response) was analyzed using logistic regression models. Results: The NFKB1 DEL/DEL genotype was associated with pathologic response (odds ratio [OR], 6.39; 95%more » confidence interval [CI], 0.78-52.65; P=.03) after PCRT. No statistically significant associations between other polymorphisms and response to PCRT were observed. Patients with the NFKB1 DEL/DEL genotype showed a trend for longer disease-free survival (log-rank test, P=.096) and overall survival (P=.049), which was not significant in a multivariate analysis that included pathologic response. Analysis for 6 polymorphisms showed that patients carrying the haplotype rs28362491-DEL/rs1143627-A/rs1213266-G/rs5789-C/rs5275-A/rs16944-G (13.7% of cases) had a higher response rate to PCRT (OR, 8.86; 95% CI, 1.21-64.98; P=.034) than the reference group (rs28362491-INS/rs1143627-A/rs1213266-G/rs5789-C/rs5275-A/rs16944-G). Clinically significant (grade ≥2) acute organ toxicity was also more frequent in patients with that same haplotype (OR, 4.12; 95% CI, 1.11-15.36; P=.037). Conclusions: Our results suggest that genetic variation in NFKB-related inflammatory pathways might influence sensitivity to primary chemoradiation for rectal cancer. If confirmed, an inflammation-related radiogenetic profile might be used to select patients with rectal cancer for preoperative combined-modality treatment.« less

Front surface passivation of silicon solar cells with antireflection coating

NASA Technical Reports Server (NTRS)

Crotty, G.; Daud, T.; Kachare, R.

1987-01-01

It is demonstrated that the deposition and postdeposition sintering of an antireflection (AR) coating in hydrogen acts to passivate silicon solar cells. Cells with and without an SiO2 passivating layer, coated with a TiO(x)/Al2O3 AR coating, showed comparable enhancements in short-wavelength spectral response and in open-circuit voltage Voc after sintering at 400 C for 5 min in a hydrogen ambient. The improvement in Voc of cells without SiO2 is attributed to front-surface passivation by the AR coating during processing.

[The expression and significance of chemokines eotaxin and RANTES in the rat model of allergic rhinitis].

PubMed

Tian, Cuiling; Lei, Xiaoping; Shui, Minhong; Zhang, Yanhong; Jia, Qianwei; Tu, Jing; Lian, Gang; Tang, Siquan

2014-07-01

To explore the expression and significance of Eotaxin and RANTES in the rat model of allergic rhinitis (AR). 20 female SD rats in 6-7 weeks were randomly divided into control group and AR group (n = 10, respectively). AR rat model was made with ovalbumin stimulation. To detect pathological changes in mucosa and chemokine Eotaxin, RANTES in their nasal and lung tissues after execution. Compared with the control group, Lung EOS cell counted higher in AR group and the difference was significant (P < 0.01); the AR rats nasal mucosa and lung tissue of Eotaxin, RANTES expression was significantly increased (P < 0.01). There exist high expression of Eotaxin, RANTES, infiltration of eosinophils in nasal and lung tissue of model rats with allergic rhinitis, inferring that the upper and lower respiratory tract inflammatory response has obvious consistency.

Up-Regulation of Follistatin-Like 1 By the Androgen Receptor and Melanoma Antigen-A11 in Prostate Cancer.

PubMed

Su, Shifeng; Parris, Amanda B; Grossman, Gail; Mohler, James L; Wang, Zengjun; Wilson, Elizabeth M

2017-04-01

High affinity androgen binding to the androgen receptor (AR) activates genes required for male sex differentiation and promotes the development and progression of prostate cancer. Human AR transcriptional activity involves interactions with coregulatory proteins that include primate-specific melanoma antigen-A11 (MAGE-A11), a coactivator that increases AR transcriptional activity during prostate cancer progression to castration-resistant/recurrent prostate cancer (CRPC). Microarray analysis and quantitative RT-PCR were performed to identify androgen-regulated MAGE-A11-dependent genes in LAPC-4 prostate cancer cells after lentivirus shRNA knockdown of MAGE-A11. Chromatin immunoprecipitation was used to assess androgen-dependent AR recruitment, and immunocytochemistry to localize an androgen-dependent protein in prostate cancer cells and tissue and in the CWR22 human prostate cancer xenograft. Microarray analysis of androgen-treated LAPC-4 prostate cancer cells indicated follistatin-like 1 (FSTL1) is up-regulated by MAGE-A11. Androgen-dependent up-regulation of FSTL1 was inhibited in LAPC-4 cells by lentivirus shRNA knockdown of AR or MAGE-A11. Chromatin immunoprecipitation demonstrated AR recruitment to intron 10 of the FSTL1 gene that contains a classical consensus androgen response element. Increased levels of FSTL1 protein in LAPC-4 cells correlated with higher levels of MAGE-A11 relative to other prostate cancer cells. FSTL1 mRNA levels increased in CRPC and castration-recurrent CWR22 xenografts in association with predominantly nuclear FSTL1. Increased nuclear localization of FSTL1 in prostate cancer was suggested by predominantly cytoplasmic FSTL1 in benign prostate epithelial cells and predominantly nuclear FSTL1 in epithelial cells in CRPC tissue and the castration-recurrent CWR22 xenograft. AR expression studies showed nuclear colocalization of AR and endogenous FSTL1 in response to androgen. AR and MAGE-A11 cooperate in the up-regulation of FSTL1 to promote growth and progression of CRPC. Prostate 77:505-516, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

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.

Cell-Free Expression, Purification, and Characterization of the Functional β2-Adrenergic Receptor for Multianalyte Detection of β-Agonists.

PubMed

Wang, Jian; Liu, Yuan; Zhang, Junhua; Han, Zhengzheng; Wang, Wei; Liu, Yang; Wei, Dong; Huang, Wei

2017-11-01

Large-scale expression of β 2 -adrenergic receptor (β 2 -AR) in functional form is necessary for establishment of receptor assays for detecting illegally abused β-adrenergic agonists (β-agonists). Cell-based heterologous expression systems have manycritical difficulties in synthesizing this membrane protein, such as low protein yields and aberrant folding. To overcome these challenges, the main objective of the present work was to synthesize large amounts of functional β 2 -AR in a cell-free system based on Escherichia coli extracts. A codon-optimized porcine β 2 -AR gene (codon adaptation index: 0.96) suitable for high expression in E. coli was synthesized and transcribed to the cell-free system, which contributed to increase the expression up to 1.1 mg/ml. After purification using Ni-affinity chromatography, the bioactivity of the purified receptor was measured by novel enzyme-linked receptor assays. It was determined that the relative affinities of the purified β 2 -AR for β-agonists in descending order were as follows: clenbuterol > salbutamol > ractopamine. Moreover, their IC 50 values were 45.99, 60.38, and 78.02 µg/liter, respectively. Although activity of the cell-free system was slightly lower than activity of systems based on insect and mammalian cells, this system should allow production of β 2 -AR in bulk amounts sufficient for the development of multianalyte screening methods for detecting β-agonist residues.

Estimation of confidence limits for descriptive indexes derived from autoregressive analysis of time series: Methods and application to heart rate variability.

PubMed

Beda, Alessandro; Simpson, David M; Faes, Luca

2017-01-01

The growing interest in personalized medicine requires making inferences from descriptive indexes estimated from individual recordings of physiological signals, with statistical analyses focused on individual differences between/within subjects, rather than comparing supposedly homogeneous cohorts. To this end, methods to compute confidence limits of individual estimates of descriptive indexes are needed. This study introduces numerical methods to compute such confidence limits and perform statistical comparisons between indexes derived from autoregressive (AR) modeling of individual time series. Analytical approaches are generally not viable, because the indexes are usually nonlinear functions of the AR parameters. We exploit Monte Carlo (MC) and Bootstrap (BS) methods to reproduce the sampling distribution of the AR parameters and indexes computed from them. Here, these methods are implemented for spectral and information-theoretic indexes of heart-rate variability (HRV) estimated from AR models of heart-period time series. First, the MS and BC methods are tested in a wide range of synthetic HRV time series, showing good agreement with a gold-standard approach (i.e. multiple realizations of the "true" process driving the simulation). Then, real HRV time series measured from volunteers performing cognitive tasks are considered, documenting (i) the strong variability of confidence limits' width across recordings, (ii) the diversity of individual responses to the same task, and (iii) frequent disagreement between the cohort-average response and that of many individuals. We conclude that MC and BS methods are robust in estimating confidence limits of these AR-based indexes and thus recommended for short-term HRV analysis. Moreover, the strong inter-individual differences in the response to tasks shown by AR-based indexes evidence the need of individual-by-individual assessments of HRV features. Given their generality, MC and BS methods are promising for applications in biomedical signal processing and beyond, providing a powerful new tool for assessing the confidence limits of indexes estimated from individual recordings.

Estimation of confidence limits for descriptive indexes derived from autoregressive analysis of time series: Methods and application to heart rate variability

PubMed Central

2017-01-01

The growing interest in personalized medicine requires making inferences from descriptive indexes estimated from individual recordings of physiological signals, with statistical analyses focused on individual differences between/within subjects, rather than comparing supposedly homogeneous cohorts. To this end, methods to compute confidence limits of individual estimates of descriptive indexes are needed. This study introduces numerical methods to compute such confidence limits and perform statistical comparisons between indexes derived from autoregressive (AR) modeling of individual time series. Analytical approaches are generally not viable, because the indexes are usually nonlinear functions of the AR parameters. We exploit Monte Carlo (MC) and Bootstrap (BS) methods to reproduce the sampling distribution of the AR parameters and indexes computed from them. Here, these methods are implemented for spectral and information-theoretic indexes of heart-rate variability (HRV) estimated from AR models of heart-period time series. First, the MS and BC methods are tested in a wide range of synthetic HRV time series, showing good agreement with a gold-standard approach (i.e. multiple realizations of the "true" process driving the simulation). Then, real HRV time series measured from volunteers performing cognitive tasks are considered, documenting (i) the strong variability of confidence limits' width across recordings, (ii) the diversity of individual responses to the same task, and (iii) frequent disagreement between the cohort-average response and that of many individuals. We conclude that MC and BS methods are robust in estimating confidence limits of these AR-based indexes and thus recommended for short-term HRV analysis. Moreover, the strong inter-individual differences in the response to tasks shown by AR-based indexes evidence the need of individual-by-individual assessments of HRV features. Given their generality, MC and BS methods are promising for applications in biomedical signal processing and beyond, providing a powerful new tool for assessing the confidence limits of indexes estimated from individual recordings. PMID:28968394

Complement C3a binding to its receptor as a negative modulator of Th2 response in liver injury in trichloroethylene-sensitized mice.

PubMed

Wang, Feng; Zha, Wan-sheng; Zhang, Jia-xiang; Li, Shu-long; Wang, Hui; Ye, Liang-ping; Shen, Tong; Wu, Chang-hao; Zhu, Qi-xing

2014-08-17

Trichloroethylene (TCE) is a major occupational health hazard and causes occupational medicamentosa-like dermatitis (OMLDT) and liver damage. Recent evidence suggests immune response as a distinct mode of action for TCE-induced liver damage. This study aimed to explore the role of the key complement activation product C3a and its receptor C3aR in TCE-induced immune liver injury. A mouse model of skin sensitization was induced by TCE in the presence and absence of the C3aR antagonist SB 290157. Liver function was evaluated by alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in conjunction with histopathological characterizations. C3a and C3aR were detected by immunohistochemistry and C5b-9 was assessed by immunofluorescence. IFN-γ and IL4 expressions were determined by flow cytometry and ELISA. The total sensitization rate was 44.1%. TCE sensitization caused liver cell necrosis and inflammatory infiltration, elevated serum ALT and AST, expression of C3a and C3aR, and deposition of C5b-9 in the liver. IFN-γ and IL-4 expressions were up-regulated in spleen mononuclear cells and their serum levels were also increased. Pretreatment with SB 290157 resulted in more inflammatory infiltration in the liver, higher levels of AST, reduced C3aR expression on Kupffer cells, and decreased IL-4 levels while IFN-γ remained unchanged. These data demonstrate that blocking of C3a binding to C3aR reduces IL4, shifts IFN-γ and IL-4 balance, and aggravates TCE-sensitization induced liver damage. These findings reveal a novel mechanism whereby modulation of Th2 response by C3a binding to C3a receptor contributes to immune-mediated liver damage by TCE exposure. Copyright © 2014. Published by Elsevier Ireland Ltd.

Complement C5a Receptor 1 Exacerbates the Pathophysiology of N. meningitidis Sepsis and Is a Potential Target for Disease Treatment

PubMed Central

Herrmann, Johannes B.; Muenstermann, Marcel; Strobel, Lea; Schubert-Unkmeir, Alexandra; Woodruff, Trent M.; Klos, Andreas

2018-01-01

ABSTRACT Sepsis caused by Neisseria meningitidis (meningococcus) is a rapidly progressing, life-threatening disease. Because its initial symptoms are rather unspecific, medical attention is often sought too late, i.e., when the systemic inflammatory response is already unleashed. This in turn limits the success of antibiotic treatment. The complement system is generally accepted as the most important innate immune determinant against invasive meningococcal disease since it protects the host through the bactericidal membrane attack complex. However, complement activation concomitantly liberates the C5a peptide, and it remains unclear whether this potent anaphylatoxin contributes to protection and/or drives the rapidly progressing immunopathogenesis associated with meningococcal disease. Here, we dissected the specific contribution of C5a receptor 1 (C5aR1), the canonical receptor for C5a, using a mouse model of meningococcal sepsis. Mice lacking C3 or C5 displayed susceptibility that was enhanced by >1,000-fold or 100-fold, respectively, consistent with the contribution of these components to protection. In clear contrast, C5ar1−/− mice resisted invasive meningococcal infection and cleared N. meningitidis more rapidly than wild-type (WT) animals. This favorable outcome stemmed from an ameliorated inflammatory cytokine response to N. meningitidis in C5ar1−/− mice in both in vivo and ex vivo whole-blood infections. In addition, inhibition of C5aR1 signaling without interference with the complement bactericidal activity reduced the inflammatory response also in human whole blood. Enticingly, pharmacologic C5aR1 blockade enhanced mouse survival and lowered meningococcal burden even when the treatment was administered after sepsis induction. Together, our findings demonstrate that C5aR1 drives the pathophysiology associated with meningococcal sepsis and provides a promising target for adjunctive therapy. PMID:29362231

Audience Response System Facilitates Prediction of Scores on In-Training Examination.

PubMed

Shah, Kaushal H; Jordan, Jaime; Jahnes, Katherine; Lisbon, David P; Lutfy-Clayton, Lucienne; Wei, Grant; Winkel, Gary; Santen, Sally A

2017-04-01

Audience response systems (ARS) are increasingly popular; however, their contribution to education is not completely clear. Our study found that scores from review quizzes delivered by an ARS correlate with in-training exam (ITE) scores and are viewed positively by residents. This information may be useful in identifying poor performers early so that targeted educational interventions can be made. The objective was to determine if scores on review quizzes delivered by an ARS correlate with ITE scores and to obtain participant feedback on use of the ARS for ITE preparation. This was a prospective observational study of emergency medicine (EM) residents at six accredited EM residency programs. Subjects included residents who had taken previous ITEs. Subjects participated in bimonthly review sessions using an ARS. Twelve review quizzes were administered, each consisting of 10 multiple-choice questions. After the ITE, subjects completed an attitudinal survey consisting of six Likert-scale items and one "yes/no" item. We used a mixed linear model to analyze the data, accounting for prior 2012 ITE scores and nesting due to institution. Among 192 participants, 135 (70.3%) completed the ITE in both 2012 and 2013; we analyzed their data for the first objective. Results from the mixed linear model indicate that the total mean score on the review quizzes was a significant [t(127) = 6.68; p < 0.001] predictor of the 2013 ITE after controlling for the 2012 ITE score. One hundred forty-six (76.0%) participants completed the attitudinal survey; 96% of respondents stated that they would like ARS to be used more often in resident education. Respondents felt the sessions aided in learning (mean 7.7/10), assisted in preparation for the ITE (mean 6.7/10), and helped identify content areas of weakness (mean 7.6/10). Our results suggest that scores from review quizzes delivered by an audience response system correlate with in-training exam scores and is viewed positively by residents.

Effects of intra-session exercise sequence during water-based concurrent training.

PubMed

Pinto, S S; Cadore, E L; Alberton, C L; Zaffari, P; Bagatini, N C; Baroni, B M; Radaelli, R; Lanferdini, F J; Colado, J C; Pinto, R S; Vaz, M A; Bottaro, M; Kruel, L F M

2014-01-01

The aim was to investigate the effects of the intra-session exercise order during water-based concurrent training on the neuromuscular adaptations in young women. 26 women (25.1±2.9 years) were placed into 2 groups: resistance prior to (RA) or after (AR) aerobic training. Subjects performed resistance (sets at maximal effort) and aerobic training (exercises at heart rate corresponding to the second ventilatory threshold) twice a week over 12 weeks, performing both exercise types in the same training session. Upper (elbow flexion) and lower-body (knee extension) one-repetition maximum test (1RM) and peak torque (PT) were evaluated. The muscle thickness (MT) of upper (sum of MT of biceps brachii and brachialis) and lower-body (sum of MT of vastus lateralis, vastus medialis, vastus intermedius, and rectus femoris) was determined by ultrasonography. Moreover, the maximal electromyographic activity (EMG) of upper (biceps brachii) and lower-body (sum of EMG of vastus lateralis and rectus femoris) was measured. Both RA and AR groups increased the upper and lower-body 1RM and PT, while the lower-body 1RM increases observed in the RA was greater than AR (43.58±14.00 vs. 27.01±18.05%). RA and AR showed MT increases in all muscles evaluated, while the lower-body MT increases observed in the RA were also greater than AR (10.24±3.11 vs. 5.76±1.88%). There were increases in the maximal EMG of upper and lower-body in both RA and AR, with no differences between groups. Performing resistance prior to aerobic exercise during water-based concurrent training seems to optimize the lower-body strength and hypertrophy. © Georg Thieme Verlag KG Stuttgart · New York.

Improved mass resolution and mass accuracy in TOF-SIMS spectra and images using argon gas cluster ion beams.

PubMed

Shon, Hyun Kyong; Yoon, Sohee; Moon, Jeong Hee; Lee, Tae Geol

2016-06-09

The popularity of argon gas cluster ion beams (Ar-GCIB) as primary ion beams in time-of-flight secondary ion mass spectrometry (TOF-SIMS) has increased because the molecular ions of large organic- and biomolecules can be detected with less damage to the sample surfaces. However, Ar-GCIB is limited by poor mass resolution as well as poor mass accuracy. The inferior quality of the mass resolution in a TOF-SIMS spectrum obtained by using Ar-GCIB compared to the one obtained by a bismuth liquid metal cluster ion beam and others makes it difficult to identify unknown peaks because of the mass interference from the neighboring peaks. However, in this study, the authors demonstrate improved mass resolution in TOF-SIMS using Ar-GCIB through the delayed extraction of secondary ions, a method typically used in TOF mass spectrometry to increase mass resolution. As for poor mass accuracy, although mass calibration using internal peaks with low mass such as hydrogen and carbon is a common approach in TOF-SIMS, it is unsuited to the present study because of the disappearance of the low-mass peaks in the delayed extraction mode. To resolve this issue, external mass calibration, another regularly used method in TOF-MS, was adapted to enhance mass accuracy in the spectrum and image generated by TOF-SIMS using Ar-GCIB in the delayed extraction mode. By producing spectra analyses of a peptide mixture and bovine serum albumin protein digested with trypsin, along with image analyses of rat brain samples, the authors demonstrate for the first time the enhancement of mass resolution and mass accuracy for the purpose of analyzing large biomolecules in TOF-SIMS using Ar-GCIB through the use of delayed extraction and external mass calibration.

Control of Adventitious Root Architecture in Rice by Darkness, Light, and Gravity1[OPEN

PubMed Central

2018-01-01

Rice (Oryza sativa) is a semiaquatic plant that is well adapted to partial flooding. Rice stems develop adventitious root (AR) primordia at each node that slowly mature but emerge only when the plant gets flooded, leading to the formation of a whole new secondary root system upon flooding. AR growth is induced by ethylene that accumulates in submerged plant tissues due to its lowered diffusion rate in water. Here, we report that the architecture of the secondary root system in flooded rice plants is controlled not only by altered gas diffusion but also by gravity and light. While ethylene promotes the emergence and growth of ARs, gravity and light determine their gravitropic setpoint angle (i.e. the deviation of growth direction relative to vertical). ARs grow upward at about 120° in the dark and downward at 54° in the light. The upward growth direction is conserved in indica and japonica rice varieties, suggestive of a conserved trait in rice. Experiments with a klinostat and with inverted stem orientation revealed that gravity promotes upward growth by about 10°. Red, far-red, and blue light lead to negative phototropism in a dose-dependent manner, with blue light being most effective, indicating that phytochrome and blue light signaling control AR system architecture. The cpt1 (coleoptile phototropism1) mutant, which lacks one of the phototropin-interacting CPT proteins, shows reduced sensitivity to blue light. Hence, the gravitropic setpoint angle of rice ARs is controlled by genetic and environmental factors that likely balance the need for oxygen supply (upward growth) with avoidance of root desiccation (downward growth). PMID:29242375

Control of Adventitious Root Architecture in Rice by Darkness, Light, and Gravity.

PubMed

Lin, Chen; Sauter, Margret

2018-02-01

Rice ( Oryza sativa ) is a semiaquatic plant that is well adapted to partial flooding. Rice stems develop adventitious root (AR) primordia at each node that slowly mature but emerge only when the plant gets flooded, leading to the formation of a whole new secondary root system upon flooding. AR growth is induced by ethylene that accumulates in submerged plant tissues due to its lowered diffusion rate in water. Here, we report that the architecture of the secondary root system in flooded rice plants is controlled not only by altered gas diffusion but also by gravity and light. While ethylene promotes the emergence and growth of ARs, gravity and light determine their gravitropic setpoint angle (i.e. the deviation of growth direction relative to vertical). ARs grow upward at about 120° in the dark and downward at 54° in the light. The upward growth direction is conserved in indica and japonica rice varieties, suggestive of a conserved trait in rice. Experiments with a klinostat and with inverted stem orientation revealed that gravity promotes upward growth by about 10°. Red, far-red, and blue light lead to negative phototropism in a dose-dependent manner, with blue light being most effective, indicating that phytochrome and blue light signaling control AR system architecture. The cpt1 ( coleoptile phototropism1 ) mutant, which lacks one of the phototropin-interacting CPT proteins, shows reduced sensitivity to blue light. Hence, the gravitropic setpoint angle of rice ARs is controlled by genetic and environmental factors that likely balance the need for oxygen supply (upward growth) with avoidance of root desiccation (downward growth). © 2018 American Society of Plant Biologists. All Rights Reserved.

High repetition rate laser induced fluorescence applied to Surfatron Induced Plasmas

NASA Astrophysics Data System (ADS)

van der Mullen, J. J. A. M.; Palomares, J. M.; Carbone, E. A. D.; Graef, W.; Hübner, S.

2012-05-01

The reaction kinetics in the excitation space of Ar and the conversion space of Ar-molecule mixtures are explored using a combination of high rep-rate YAG-Dye laser systems with a well defined and easily controllable Surfatron Induced Plasma set-up. Applying the method of Saturation Time Resolved Laser Induced Fluorescence (SaTiRe-LIF), we could trace excitation and conversion channels and determine rates of electron and heavy particle excitation kinetics. The time resolved density disturbances observed in the Ar excitation space, which are initiated by the laser, reveal the excitation channels and corresponding rates; responses of the molecular radiation in Ar-molecule mixtures corresponds to the presence of conversion processes induced by heavy particle excitation kinetics.

Clinical practice guideline: Allergic rhinitis.

PubMed

Seidman, Michael D; Gurgel, Richard K; Lin, Sandra Y; Schwartz, Seth R; Baroody, Fuad M; Bonner, James R; Dawson, Douglas E; Dykewicz, Mark S; Hackell, Jesse M; Han, Joseph K; Ishman, Stacey L; Krouse, Helene J; Malekzadeh, Sonya; Mims, James Whit W; Omole, Folashade S; Reddy, William D; Wallace, Dana V; Walsh, Sandra A; Warren, Barbara E; Wilson, Meghan N; Nnacheta, Lorraine C

2015-02-01

Allergic rhinitis (AR) is one of the most common diseases affecting adults. It is the most common chronic disease in children in the United States today and the fifth most common chronic disease in the United States overall. AR is estimated to affect nearly 1 in every 6 Americans and generates $2 to $5 billion in direct health expenditures annually. It can impair quality of life and, through loss of work and school attendance, is responsible for as much as $2 to $4 billion in lost productivity annually. Not surprisingly, myriad diagnostic tests and treatments are used in managing this disorder, yet there is considerable variation in their use. This clinical practice guideline was undertaken to optimize the care of patients with AR by addressing quality improvement opportunities through an evaluation of the available evidence and an assessment of the harm-benefit balance of various diagnostic and management options. The primary purpose of this guideline is to address quality improvement opportunities for all clinicians, in any setting, who are likely to manage patients with AR as well as to optimize patient care, promote effective diagnosis and therapy, and reduce harmful or unnecessary variations in care. The guideline is intended to be applicable for both pediatric and adult patients with AR. Children under the age of 2 years were excluded from the clinical practice guideline because rhinitis in this population may be different than in older patients and is not informed by the same evidence base. The guideline is intended to focus on a limited number of quality improvement opportunities deemed most important by the working group and is not intended to be a comprehensive reference for diagnosing and managing AR. The recommendations outlined in the guideline are not intended to represent the standard of care for patient management, nor are the recommendations intended to limit treatment or care provided to individual patients. The development group made a strong recommendation that clinicians recommend intranasal steroids for patients with a clinical diagnosis of AR whose symptoms affect their quality of life. The development group also made a strong recommendation that clinicians recommend oral second-generation/less sedating antihistamines for patients with AR and primary complaints of sneezing and itching. The panel made the following recommendations: (1) Clinicians should make the clinical diagnosis of AR when patients present with a history and physical examination consistent with an allergic cause and 1 or more of the following symptoms: nasal congestion, runny nose, itchy nose, or sneezing. Findings of AR consistent with an allergic cause include, but are not limited to, clear rhinorrhea, nasal congestion, pale discoloration of the nasal mucosa, and red and watery eyes. (2) Clinicians should perform and interpret, or refer to a clinician who can perform and interpret, specific IgE (skin or blood) allergy testing for patients with a clinical diagnosis of AR who do not respond to empiric treatment, or when the diagnosis is uncertain, or when knowledge of the specific causative allergen is needed to target therapy. (3) Clinicians should assess patients with a clinical diagnosis of AR for, and document in the medical record, the presence of associated conditions such as asthma, atopic dermatitis, sleep-disordered breathing, conjunctivitis, rhinosinusitis, and otitis media. (4) Clinicians should offer, or refer to a clinician who can offer, immunotherapy (sublingual or subcutaneous) for patients with AR who have inadequate response to symptoms with pharmacologic therapy with or without environmental controls. The panel recommended against (1) clinicians routinely performing sinonasal imaging in patients presenting with symptoms consistent with a diagnosis of AR and (2) clinicians offering oral leukotriene receptor antagonists as primary therapy for patients with AR. The panel group made the following options: (1) Clinicians may advise avoidance of known allergens or may advise environmental controls (ie, removal of pets; the use of air filtration systems, bed covers, and acaricides [chemical agents formulated to kill dust mites]) in patients with AR who have identified allergens that correlate with clinical symptoms. (2) Clinicians may offer intranasal antihistamines for patients with seasonal, perennial, or episodic AR. (3) Clinicians may offer combination pharmacologic therapy in patients with AR who have inadequate response to pharmacologic monotherapy. (4) Clinicians may offer, or refer to a surgeon who can offer, inferior turbinate reduction in patients with AR with nasal airway obstruction and enlarged inferior turbinates who have failed medical management. (5) Clinicians may offer acupuncture, or refer to a clinician who can offer acupuncture, for patients with AR who are interested in nonpharmacologic therapy. The development group provided no recommendation regarding the use of herbal therapy for patients with AR. © American Academy of Otolaryngology—Head and Neck Surgery Foundation 2014.

[Treatment of chronic refractory idiopathic thrombocytopenia purpura. 10 years experience at the Salvador Zubiran National Institute of Nutrition].

PubMed

Pita-Ramírez, L; Hurtado-Monroy, R; Labardini-Méndez, J

1992-01-01

A total of 126 patients with chronic idiopathic thrombocytopenic purpura were diagnosed from January 1980 to January 1990 in our institute. In this group of patients, 21 were refractory to prednisone therapy, splenectomy or both, or had had a relapse after a good response with these treatments. They were given other therapies. There was enough information for evaluation in 16 of the 21 patients. The treatment responses were classified according to the post-therapy platelet counts: complete response (CR) = > 150 x 10(9)/L for more than three months; partial response (PR) = 50-150 x 10(9)/L for more than three months; any response (AR) = CR + PR; no response (NR) = < 50 x 10(9)/L. There were 15 women and one male. The median age was 41 years (range 11 to 65). 6-mercaptopurine was given in all patients with CR = 31.2%, PR = 18.8%, AR = 50% and NR = 50%. Seven patients received cyclophosphamide with CR = 28.6%, PR = 14.3%, AR = 42.9% and NR = 57%. Vincristine was given in four patients with only one PR. Interferon alpha 2B was given in four patients with two transitory PR. One patient received colchicine and vitamin C without response. It is concluded that 6-mercaptopurine and cyclophosphamide are useful drugs in refractory thrombocytopenic purpura.

Smoke and mirrors: Testing the scope of chimpanzees’ appearance-reality understanding

PubMed Central

Lurz, Robert; Russell, Jamie L.; Hopkins, William D.

2016-01-01

The ability to make appearance-reality (AR) discriminations is an important higher-order cognitive adaptation in humans but is still poorly understood in our closest primate relatives. Previous research showed that chimpanzees are capable of AR discrimination when choosing between food items that appear, due to the effects of distorting lenses, to be smaller or larger than they actually are (Krachun, Call & Tomasello, 2009). In the current study, we investigated the scope and flexibility of chimpanzees’ AR discrimination abilities by presenting them with a wider range of illusory stimuli. In addition to using lenses to change the apparent size of food items (Experiment 1), we used a mirror to change the apparent number of items (Experiment 2), and tinted filters to change their apparent color (Experiment 3). In all three experiments, some chimpanzees were able to maximize their food rewards by making a choice based on the real properties of the stimuli in contrast to their manifest apparent properties. These results replicate the earlier findings for size illusions and extend them to additional situations involving illusory number and color. Control tests, together with findings from previous studies, ruled out lower-level explanations for the chimpanzees’ performance. The findings thus support the hypothesis that chimpanzees are capable of making AR discriminations with a range of illusory stimuli. PMID:26848736

Radiolabeled 5-Iodo-3′-O-(17β-succinyl-5α-androstan-3-one)-2′-deoxyuridine and Its 5′-Monophosphate for Imaging and Therapy of Androgen Receptor-Positive Cancers: Synthesis and Biological Evaluation

PubMed Central

Kortylewicz, Zbigniew P.; Nearman, Jessica; Baranowska-Kortylewicz, Janina

2014-01-01

High levels of androgen receptor (AR) are often indicative of recurrent, advanced, or metastatic cancers. These conditions are also characterized by a high proliferative fraction. 5-Radioiodo-3′-O-(17β-succinyl-5α-androstan-3-one)-2′-deoxyuridine 8 and 5-radioiodo-3′-O-(17β-succinyl-5α-androstan-3-one)-2′-deoxyuridin-5′-yl monophosphate 13 target AR. They are also degraded intracellularly to 5-radioiodo-2′-deoxyuridine 1 and its monophosphate 20, respectively, which can participate in the DNA synthesis. Both drugs were prepared at the no-carrier-added level. Precursors and methods are readily adaptable to radiolabeling with various radiohalides suitable for SPECT and PET imaging, as well as endoradiotherapy. In vitro and in vivo studies confirm the AR-dependent interactions. Both drugs bind to sex hormone binding globulin. This binding significantly improves their stability in serum. Biodistribution and imaging studies show preferential uptake and retention of 8 and 13 in ip xenografts of human ovarian adenocarcinoma cells NIH:OVCAR-3, which overexpress AR. When these drugs are administered at therapeutic dose levels, a significant tumor growth arrest is observed. PMID:19653647

Employing Augmented-Reality-Embedded Instruction to Disperse the Imparities of Individual Differences in Earth Science Learning

NASA Astrophysics Data System (ADS)

Chen, Cheng-ping; Wang, Chang-Hwa

2015-12-01

Studies have proven that merging hands-on and online learning can result in an enhanced experience in learning science. In contrast to traditional online learning, multiple in-classroom activities may be involved in an augmented-reality (AR)-embedded e-learning process and thus could reduce the effects of individual differences. Using a three-stage AR-embedded instructional process, we conducted an experiment to investigate the influences of individual differences on learning earth science phenomena of "day, night, and seasons" for junior highs. The mixed-methods sequential explanatory design was employed. In the quantitative phase, factors of learning styles and ICT competences were examined alongside with the overall learning achievement. Independent t tests and ANCOVAs were employed to achieve inferential statistics. The results showed that overall learning achievement was significant for the AR-embedded instruction. Nevertheless, neither of the two learner factors exhibited significant effect on learning achievement. In the qualitative phase, we analyzed student interview records, and a wide variation on student's preferred instructional stages were revealed. These findings could provide an alternative rationale for developing ICT-supported instruction, as our three-stage AR-embedded comprehensive e-learning scheme could enhance instruction adaptiveness to disperse the imparities of individual differences between learners.

Analysis of Parametric Adaptive Signal Detection with Applications to Radars and Hyperspectral Imaging

DTIC Science & Technology

2010-02-01

98 8.4.5 Training Screening ............................. .................................................................99 8.5 Experimental...associated with the proposed parametric model. Several im- portant issues are discussed, including model order selection, training screening , and time...parameters associated with the NS-AR model. In addition, we develop model order selection, training screening , and time-series based whitening and